No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Modafinil effects on cognition and emotion in schizophrenia and its neurochemical modulation in the brain
... (S)-MK-26, synthetized following previously described protocols [41], has structural similarities to the very well-characterized nootropic modafinil [42], with the carboxamide replaced with thiazole (five-membered heterocycle attached through position 5) and with a chlorine atom added in the meta position on both phenyl rings, thus also being a close structural analogue of the previously described compounds (S,S)-CE-158 and (S)-CE-123 [39,[41][42][43] (Figure 1). transporter type-2 and was used in these studies because it induces depressive-like symptoms in humans [31]. ...
... (S)-MK-26, synthetized following previously described protocols [41], has structural similarities to the very well-characterized nootropic modafinil [42], with the carboxamide replaced with thiazole (five-membered heterocycle attached through position 5) and with a chlorine atom added in the meta position on both phenyl rings, thus also being a close structural analogue of the previously described compounds (S,S)-CE-158 and (S)-CE-123 [39,[41][42][43] (Figure 1). transporter type-2 and was used in these studies because it induces depressive-like symptoms in humans [31]. ...
... (S)-MK-26, synthetized following previously described protocols [41], has structural similarities to the very well-characterized nootropic modafinil [42], with the carboxamide replaced with thiazole (five-membered heterocycle attached through position 5) and with a chlorine atom added in the meta position on both phenyl rings, thus also being a close structural analogue of the previously described compounds (S,S)-CE-158 and (S)-CE-123 [39,[41][42][43] (Figure 1). molecule has only one chiral center (having thus only two optical enantiomeric, "R" and "S" stereoisomers). ...
Dopamine (DA), the most abundant human brain catecholaminergic neurotransmitter, modulates key behavioral and neurological processes in young and senescent brains, including motricity, sleep, attention, emotion, learning and memory, and social and reward-seeking behaviors. The DA transporter (DAT) regulates transsynaptic DA levels, influencing all these processes. Compounds targeting DAT (e.g., cocaine and amphetamines) were historically used to shape mood and cognition, but these substances typically lead to severe negative side effects (tolerance, abuse, addiction, and dependence). DA/DAT signaling dysfunctions are associated with neuropsychiatric and progressive brain disorders, including Parkinson’s and Alzheimer diseases, drug addiction and dementia, resulting in devastating personal and familial concerns and high socioeconomic costs worldwide. The development of low-side-effect, new/selective medicaments with reduced abuse-liability and which ameliorate DA/DAT-related dysfunctions is therefore crucial in the fields of medicine and healthcare. Using the rat as experimental animal model, the present work describes the synthesis and pharmacological profile of (S)-MK-26, a new modafinil analogue with markedly improved potency and selectivity for DAT over parent drug. Ex vivo electrophysiology revealed significantly augmented hippocampal long-term synaptic potentiation upon acute, intraperitoneally delivered (S)-MK-26 treatment, whereas in vivo experiments in the hole-board test showed only lesser effects on reference memory performance in aged rats. However, in effort-related FR5/chow and PROG/chow feeding choice experiments, (S)-MK-26 treatment reversed the depression-like behavior induced by the dopamine-depleting drug tetrabenazine (TBZ) and increased the selection of high-effort alternatives. Moreover, in in vivo microdialysis experiments, (S)-MK-26 significantly increased extracellular DA levels in the prefrontal cortex and in nucleus accumbens core and shell. These studies highlight (S)-MK-26 as a potent enhancer of transsynaptic DA and promoter of synaptic plasticity, with predominant beneficial effects on effort-related behaviors, thus proposing therapeutic potentials for (S)-MK-26 in the treatment of low-effort exertion and motivational dysfunctions characteristic of depression and aging-related disorders.
... For instance, methylphenidate (MPH) and dexamphetamine are the first-choice treatment for attention deficit hyperactivity disorder (ADHD), while MPH and modafinil are prescribed for narcolepsy. Modafinil is also being clinically tested in ADHD, depression, schizophrenia, and mood disorders [4][5][6][7][8][9]. Finally, modafinil is considered as a potential therapy against substance abuse disorders at different stages [2,10], in particular against psychostimulant abuse and withdrawal [11][12][13][14][15], as well as against alcohol dependence [16]. ...
... By contrast, R-modafinil at the same doses did not produce a significant effect on the neuron firing rate (example rate histogram in Figure 1A,B; one-way ANOVA for repeated measures F (6,24) = 0.231, p = 0.684). As expected, vehicle administration was also ineffective (example rate histogram in Figure 1A,B; one-way ANOVA for repeated measures, F (4,16) = 0.928, p = 0.414). ...
... Successful cognitive enhancement with a reduced risk potential for addiction should be then based on the selective modulation of the mesocortical dopamine pathway, such that cognition-enhancing doses of dopamine modulators preferentially elevate extracellular dopamine within the IL/PrL cortex [3,47]. Interestingly, the administration of modafinil in humans has been associated with increased prefrontal cortical activation [4]. Our experiments in the rat IL/PrL cortex showed that pyramidal neuron firing frequency was not affected by R-modafinil (cumulative 10 mg/kg i.v.) in anesthetized rats, while (S)-CE-123 produced a dose-dependent decrease. ...
Treatments for cognitive impairments associated with neuropsychiatric disorders, such as attention deficit hyperactivity disorder or narcolepsy, aim at modulating extracellular dopamine levels in the brain. CE-123 (5-((benzhydrylsulfinyl)methyl) thiazole) is a novel modafinil analog with improved specificity and efficacy for dopamine transporter inhibition that improves cognitive and motivational processes in experimental animals. We studied the neuropharmacological and behavioral effects of the S-enantiomer of CE-123 ((S)-CE-123) and R-modafinil in cognitive- and reward-related brain areas of adult male rats. In vivo single unit recordings in anesthetized animals showed that (S)-CE-123, but not R-modafinil, dose-dependently (1.25 to 10 mg/kg i.v.) reduced firing of pyramidal neurons in the infralimbic/prelimbic (IL/PrL) cortex. Neither compound the affected firing activity of ventral tegmental area dopamine cells. In freely moving animals, (S)-CE-123 (10 mg/kg i.p.) increased extracellular dopamine levels in the IL/PrL, with different patterns when compared to R-modafinil (10 mg/kg i.p.); in the nucleus accumbens shell, a low and transitory increase of dopamine was observed only after (S)-CE-123. Neither (S)-CE-123 nor R-modafinil initiated the emission of 50-kHz ultrasonic vocalizations, a behavioral marker of positive affect and drug-mediated reward. Our data support previous reports of the procognitive effects of (S)-CE-123, and show a minor impact on reward-related dopaminergic areas.
... Compared with typical amphetamine-type stimulants, the wakefulness-promoting agent modafinil (MOD), which has been approved for the treatment of narcolepsy, has a relatively low risk for abuse, cardiovascular [23,24] and anxiogenic side effects [25] and thus represents a particular promising candidate to enhance cognitive control. On the neurochemical level, MOD increases extracellular levels of dopamine [26], norepinephrine [27], glutamate [28] and serotonin [29], and attenuates GABAergic neurotransmission in the PFC [30], with effects on catecholaminergic neurotransmission being considered as primary mechanism for improving prefrontal cognitive functions [9,22]. ...
... Although the amygdala has been considered as emotional, specifically fear-specific region [66], accumulating evidence suggests a broader role of the amygdala in general arousal and salience signaling [67], attention orientation [68] and response monitoring [69]. Early animal models reported increased activation and serotonergic neurotransmission in the amygdala following MOD [30]. On the other hand, converging translational evidence suggests a stronger involvement of noradrenergic rather than serotonergic signaling in cognitive control [60]. ...
... Importantly, the effects were selectively observed in the cognitive but not emotional conflict domain and in the absence of impact on subjective performance perception and affective states. Initial studies have demonstrated cognitive enhancing effects of MOD in remitted depression [9], schizophrenia [30] and addiction [33]. These disorders are characterized by residual cognitive impairments even after affective recovery [73]. ...
Cognitive control regulates cognitive and emotional systems to facilitate goal-directed behavior in the context of task-irrelevant distractors. Cognitive control deficits contribute to residual functional impairments across psychiatric disorders and represent a promising novel treatment target. Translational evidence suggests that Modafinil may enhance performance in executive functions; however, differential effects on regulatory control in cognitive and emotional domains have not been examined. The present preregistered randomized-controlled pharmacological fMRI trial examined differential effects of modafinil (single-dose, 200 mg) on cognitive and emotional conflict processing. To further separate objective cognitive enhancing effects from subjective performance perception, metacognitive paradigm was employed. Results indicated that modafinil specifically enhanced cognitive conflict performance and concomitantly increased activation in the inferior frontal gyrus and its functional communication with the dorsomedial prefrontal cortex. Exploratory analysis further revealed modafinil-enhanced basolateral amygdala reactivity to cognitive conflict, with stronger reactivity being associated with higher cognitive conflict performance. Whereas modafinil enhanced cognitive performance in the metacognitive paradigm, confidence indices remained unaffected. Overall, the present results suggest that modafinil has the potential to enhance cognitive conflict processing while leaving emotional conflict processing unaffected. On the neural level modafinil enhanced the recruitment of a network engaged in general conflict and regulatory control processes, whereas effects on the amygdala may reflect improved arousal-mediated attention processes for conflicting information. The pattern of cognitive enhancing effects in the absence of effects on affective process suggests a promising potential to enhance cognitive control in clinical populations.
... Modafinil and amphetamine can improve cognitive functions in humans [66][67][68] and experimental animals 42,[69][70][71][72] . The drugs nevertheless have both common and distinct biochemical effects 68 . ...
... Modafinil and amphetamine can improve cognitive functions in humans [66][67][68] and experimental animals 42,[69][70][71][72] . The drugs nevertheless have both common and distinct biochemical effects 68 . The vigilance-promoting effects of amphetamine have been attributed primarily to increased dopamine/noradrenaline activity in prefrontal systems 33 , whereas modafinil has additional actions on serotonin, hypocretin/orexin, glutamate, histamine and acetylcholine functions 68 . ...
... The drugs nevertheless have both common and distinct biochemical effects 68 . The vigilance-promoting effects of amphetamine have been attributed primarily to increased dopamine/noradrenaline activity in prefrontal systems 33 , whereas modafinil has additional actions on serotonin, hypocretin/orexin, glutamate, histamine and acetylcholine functions 68 . Our data indicate that acute treatment with these drugs exerts modest but bidirectional effects on attentional performance in Df (h22q11)/+ mice. ...
The 22q11.2 deletion syndrome (22q11.2DS) confers high risk of neurodevelopmental disorders such as schizophrenia and attention-deficit hyperactivity disorder. These disorders are associated with attentional impairment, the remediation of which is important for successful therapeutic intervention. We assessed a 22q11.2DS mouse model (Df(h22q11)/+) on a touchscreen rodent continuous performance test (rCPT) of attention and executive function that is analogous to human CPT procedures. Relative to wild-type littermates, Df(h22q11)/+ male mice showed impaired attentional performance as shown by decreased correct response ratio (hit rate) and a reduced ability to discriminate target stimuli from non-target stimuli (discrimination sensitivity, or d’). The Df(h22q11)/+ model exhibited decreased prefrontal cortical-hippocampal oscillatory synchrony within multiple frequency ranges during quiet wakefulness, which may represent a biomarker of cognitive dysfunction. The stimulant amphetamine (0–1.0 mg/kg, i.p.) dose-dependently improved d’ in Df(h22q11)/+ mice whereas the highest dose of modafinil (40 mg/kg, i.p.) exacerbated their d’ impairment. This is the first report to directly implicate attentional impairment in a 22q11.2DS mouse model, mirroring a key endophenotype of the human disorder. The capacity of the rCPT to detect performance impairments in the 22q11.2DS mouse model, and improvement following psychostimulant-treatment, highlights the utility and translational potential of the Df(h22q11)/+ model and this automated behavioral procedure.
... A systematic review of the effects of modafinil on cognition and emotion in schizophrenia found that modafinil improves cognitive functions, with pro-mnemonic effects and problem-solving improvements, and enhances emotional processing [14]. Reviewing evidence reported subsequence to this review supports these findings [15]. ...
... Reviewing evidence reported subsequence to this review supports these findings [15]. Evidence reviews have concluded that improvement in cognitive functions induced by modafinil could have a beneficial effect on broader aspects of patients' lives, including functional outcomes, quality of life and wellbeing [14]. In studies which employed neuroimaging, modafinil produced an increased activation of the anterior cingulate cortex and dorsolateral prefrontal cortex [16] [17]. ...
... Research has shown that modafinil can enhance cognitive function in schizophrenia [14] [15] and has potential to enhance real life functioning [16] and reduce negative symptoms [17]. This potential requires further research. ...
... The high percentage of healthy individuals using stimulant drugs for cognitive enhancement suggests that most people are seeking for memory benefits [4]. Thus, outweighing that in some cases of short or long-term use may trigger or exacerbate mental illnesses such as anxiety, depression, psychosis and even addiction [5][6][7]. ...
... Also, it has been used 'off-label' as a cognitive enhancer in other neuropsychiatric conditions [18,19] as well as for the treatment of substance disorders [20]. The MOD mechanism of action is poorly understood and appears to involve multiple neurotransmitter systems resulting in a wide range of neurological effects [6,21]. Taken together, current evidence suggests that MOD can act as a weak dopamine transporter (DAT) inhibitor binding to the DAT, increasing extracellular DA levels in synapses [7,22,23]. ...
... Thus, we sought to investigate the impact of MOD treatment during adolescence on mechanisms involved in the seeking of AMPH. In fact, adolescence is a critical period of development during which not all brain areas are fully developed [42], and few studies investigated the influence of MOD exposure during this period on hippocampal changes [6]. The dopaminergic system can be considered a target for psychostimulant drugs such as MOD and AMPH. ...
Addiction is a serious health problem which leads to general social impairment. The period of adolescence plays a significant role in drug abuse liability. Psychostimulants, such as modafinil (MOD), are majorly used by teenagers seeking improvements in cognition, which contributes to its indiscriminate use. The present study aimed to investigate the influence of MOD (64 mg/kg by gavage, once a day) treatment during adolescence (PND 28-42) on amphetamine (AMPH, 4 mg/kg i.p.) conditioned place preference (CPP) in early adulthood (PND 60). Our findings showed that AMPH increased CPP for the drug and anxiety-like behaviours; on the other hand, AMPH decreased the number of crossings and recognition index. In addition, AMPH decreased catalase activity and increased reactive species, malondialdehyde and carbonyl protein levels in the hippocampus. AMPH also increased pro-BDNF, Trk-B, DAT, D1R and decreased BDNF and D2R immunoreactivity. Contrarily, animals pre-exposed to MOD showed reduced AMPH-CPP, no locomotor impairment, less anxiety-like behaviours and no memory deficits. In addition, MOD showed antioxidant activity by preventing AMPH-induced oxidative damage in the hippocampus. Moreover, molecular analysis showed that MOD was able to modulate the hippocampal dopaminergic system, thus preventing AMPH-induced impairments. Animals that received MOD during adolescence showed reduced AMPH-CPP in early adulthood. These unexpected behavioural effects of MOD on CPP could be due to its hippocampal dopaminergic system modulation, mainly by its action on D1R, which is closely linked to drug addiction. Nevertheless, further studies are necessary. This article is protected by copyright. All rights reserved.
... 6 Augmenting dopamine and serotonin transmission was shown to augment limbic and cortical activity. 7 In small trials, modafinil has been studied with the expectation of improving negative symptoms and cognitive deficits. 8 The biological rationale for using this class of drugs is that it increases the levels of several neurotransmitters (eg, dopamine, glutamate, serotonin) and reduces the levels of γ-aminobutyric acid, resulting in more neuronal activation. ...
... 8 The biological rationale for using this class of drugs is that it increases the levels of several neurotransmitters (eg, dopamine, glutamate, serotonin) and reduces the levels of γ-aminobutyric acid, resulting in more neuronal activation. 7 Our aim was to assess if modafinil as an add-on drug could reduce refractory negative symptoms. ...
... 21 Some trials showed no influence in cognition, but with improvement in social cognition -recognition of sad facial expressions. 7 But there are also negative results in some trials, showing no significant difference from placebo. 7 18 In neuroimaging studies, modafinil showed an increased activation of the anterior cingulate cortex and dorsolateral prefrontal cortex. ...
Schizophrenia is a severe mental disorder characterised by positive and negative symptoms. Negative symptoms are difficult to treat and there is no specific treatment. In small trials, modafinil has been studied in association with antipsychotic treatment. We present three cases of its use; two have developed positive symptoms and one developed renal impairment. Further studies are needed to assess its usefulness in schizophrenia and safety in this group of patients. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
... Over the past 2 decades, the cognition-enhancing potential of modafinil has been shown for various domains of cognitive performance in healthy volunteers (11)(12)(13). Modafinil also improved cognitive dysfunction in other psychiatric conditions, including attention-deficit/hyperactivity disorder (14) and schizophrenia (15). Procognitive effects of modafinil on working memory were associated with its effects on noradrenaline and dopamine in the prefrontal cortex. ...
... Procognitive effects of modafinil on working memory were associated with its effects on noradrenaline and dopamine in the prefrontal cortex. It was suggested that modafinil's action on glutamatergic pathways may be linked with positive effects on encoding (15). ...
... However, there were no effects on attention and planning. It has been reported that modafinil can improve forms of cognition in both healthy volunteers and people with cognitive impairment owing to psychiatric conditions (11)(12)(13)(14)(15). Findings from the current study indicate that modafinil can also improve domains of cognition in those with remitted depression. ...
\textbf{Background}$: Cognitive dysfunction is a core feature of depression and tends to persist even after mood symptoms recover, leading to detrimental effects on clinical and functional outcomes. However, most currently available treatments have not typically addressed cognition. Modafinil has been shown to have beneficial effects on cognitive function and therefore has the potential to improve cognition in depression. The objective of this double-blind, placebo-controlled study was to investigate the effects of modafinil on cognitive functions in patients with remitted depression. $\textbf{Methods}$: In total, 60 patients with remitted depression participated in the study. Cognitive functions were evaluated with tests of working memory, planning, attention, and episodic memory from the Cambridge Neuropsychological Test Automated Battery at the baseline session and after treatment. A double-blind, randomized, placebo-controlled, parallel groups design was used to assess the effects of single-dose (200 mg) modafinil ($\textit{n}$ = 30) or placebo ($\textit{n}$ = 30) on cognition and fatigue. The main outcome measures were neurocognitive test scores from the Cambridge Neuropsychological Test Automated Battery. Visual analogue scales for subjective feelings and fatigue were used as secondary measures. $\textbf{Results}$: The modafinil group had significantly better performance on tests of episodic memory ($\textit{p}$ = .01, η$_{p}$$^{2}$ = .10) and working memory ($\textit{p}$ = .04, η$_{p}$$^{2}$ = .06). Modafinil did not improve planning or sustained attention. $\textbf{Conclusions}$: This study suggested that modafinil (200 mg) could improve episodic memory and working memory performance in patients with remitted depression. Modafinil may have potential as a therapeutic agent to help remitted depressed patients with persistent cognitive difficulties.
... Over the past 2 decades, the cognition-enhancing potential of modafinil has been shown for various domains of cognitive performance in healthy volunteers (11)(12)(13). Modafinil also improved cognitive dysfunction in other psychiatric conditions, including attention-deficit/hyperactivity disorder (14) and schizophrenia (15). Procognitive effects of modafinil on working memory were associated with its effects on noradrenaline and dopamine in the prefrontal cortex. ...
... Procognitive effects of modafinil on working memory were associated with its effects on noradrenaline and dopamine in the prefrontal cortex. It was suggested that modafinil's action on glutamatergic pathways may be linked with positive effects on encoding (15). ...
... However, there were no effects on attention and planning. It has been reported that modafinil can improve forms of cognition in both healthy volunteers and people with cognitive impairment owing to psychiatric conditions (11)(12)(13)(14)(15). Findings from the current study indicate that modafinil can also improve domains of cognition in those with remitted depression. ...
Background
Cognitive dysfunction is a core feature of depression and tends to persist even after mood symptoms recover, leading to detrimental effects on clinical and functional outcomes. However, most currently available treatments have not typically addressed cognition. Modafinil has been shown to have beneficial effects on cognitive function and therefore has the potential to improve cognition in depression. The objective of this double-blind placebo-controlled study was to investigate the effects of modafinil on cognitive functions in patients with remitted depression.
Methods
Sixty participants with remitted depression participated in the study. Cognitive functions were evaluated with tests of working memory, planning, attention, and episodic memory from the CANTAB battery at the baseline session and after treatment. A double-blind, randomized, placebo-controlled, parallel groups design was used to assess the effects of single dose (200 mg) modafinil (n=30) or placebo (n=30) on cognition and fatigue. Main outcome measures were neurocognitive test scores from the CANTAB battery. Visual analogue scales for subjective feelings and fatigue were used as secondary measures.
Results
The modafinil group had significantly better performance on tests of episodic memory (p=0.01, partial eta squared=0.10) and working memory (p=0.04, partial eta squared=0.06). Modafinil did not improve planning or sustained attention.
Conclusions
This study suggested that modafinil (200 mg) could improve episodic memory and working memory performance in patients with remitted depression. Modafinil may have potential as a therapeutic agent to help remitted depressed patients with persistent cognitive difficulties
... However, the drug did not show notable benefits in planning or sustained attention. Moreover, based on a systematic review examining modafinil's use in schizophrenia and related disorders, the drug demonstrated promising benefits in addressing cognitive, emotional, functional, and motor dysfunctions (29). Specifically, modafinil was observed to enhance various cognitive aspects, including working memory, short-term and long-term memory, attention, cognitive flexibility, and inhibitory control in Reg. ...
... Frontiers in Psychiatry 08 frontiersin.org individuals diagnosed with schizophrenia (29). Research in patients with a first episode psychosis revealed that modafinil exhibits positive effects on verbal and spatial working memory, as well as improvements in impulsivity-related tasks (30). ...
Introduction
Despite advances in the treatment of bipolar disorder (BD), most patients do not achieve complete inter-episode recovery and functional disability is common. During periods of relative remission, many patients continue to experience neurocognitive dysfunction, reduced daytime activity levels, and sleep disturbances. This 8-week, randomized, placebo-controlled pilot study evaluated the feasibility, safety and preliminary efficacy of the wake-promoting drug, modafinil (Provigil®), on neurocognitive functioning, daytime sleepiness, and sleep quality in affectively-stable BD patients.
Methods
Twelve individuals with affectively-stable BD were recruited and randomized to a flexible dose of modafinil (100 to 200 mg/day) or placebo, adjunctive to a therapeutic dose of a mood stabilizer. Weekly in-person visits tracked sleep quality and daytime sleepiness as well as side effects and mood symptoms. Neurocognitive functioning was assessed at baseline, week 4, and week 8.
Results
No serious adverse events were reported. Newly emergent side effects in the modafinil group included heart palpitations, itching, fatigue, and decreased energy. Two patients discontinued modafinil owing to side effects and one of these patients withdrew from the study. One patient discontinued placebo and was withdrawn from the study. Preliminary evaluations of clinical efficacy showed a marginally significant interaction between treatment group and time in two cognitive domains (speed of processing and verbal learning), indicating greater improvement in the modafinil group versus placebo. Additionally, there was a marginally significant effect of treatment group on daytime sleepiness, suggesting lower daytime sleepiness in the modafinil group versus placebo. Counterintuitively, we found a significant treatment group by time interaction effect on sleep quality, suggesting greater improvement in sleep quality in the placebo group versus the modafinil group.
Discussion
Results suggest that modafinil is a relatively safe medication for affectively-stable BD patients when given with adjunctive mood stabilizers. Results are suggestive of cognitive benefit and improved daytime sleepiness, but worse sleep quality in those patients prescribed modafinil. A fully powered clinical trial is warranted with specific attention to the characteristics of patients who are most likely to benefit from treatment with modafinil and other methodological lessons learned from this pilot.
Clinical trial registration
ClinicalTrials.gov, identifier NCT01965925.
... Modafinil has also been shown to activate various brain regions and neurotransmitters, including glutamate, that have been implicated in the neurobiology of schizophrenia (Scoriels 2013). Indeed, modafinil has been shown to enhance cognition in cohorts of healthy individuals and those with neuropsychiatric conditions (Minzenberg 2008;Gileen 2014). ...
... Previous neuropsychological and clinical trials have tended to be small pilot studies that ran for short durations and yielded conflicting results (Turner 2004;Hunter 2006;Freudenreich 2009;Shafti 2016). A subset of studies found that modafinil can improve cognitive functioning in schizophrenia and lead to an improvement in sub-domains of clinical rating scales (Rosenthal 2004;Turner 2004;Scoriels 2013;Kredlow 2019). ...
Antipsychotics are the cornerstone of schizophrenia management but they are not adequate in treating the negative and cognitive symptoms of the illness. The Cochrane review discussed in this commentary examines the safety and effectiveness of the wakefulness-promoting agent, modafinil, as an adjunct to standard care in the mitigation of negative and cognitive symptoms of schizophrenia. Add-on modafinil, compared to add-on placebo and standard treatment, did not result in a clear benefit. Due to the heterogenous body of evidence, the quality of which ranged from very low to moderate, the review's conclusions are equivocal.
... Additionally, imaging studies in rats have shown increase glucose metabolism in hippocampus and thalamus (100 mg/kg) (Engber et al., 1998a(Engber et al., , 1998b and increases in cerebral blood volume in prefrontal and cingulate cortices, thalamus and amygdala (10 mg/kg) (Gozzi et al., 2012;Vodovar et al., 2018). Additionally, imaging studies in humans have shown that modafinil (100-200 mg) decreases activity in cortical hubs that are part of the default mode network (Minzenberg et al., , 2011, as well as a decrease in activity in amygdala and prefrontal cortex (Rasetti et al., 2010;Scoriels et al., 2013). ...
... Furthermore, modafinil increases extracellular glutamate levels in the thalamus, hypothalamus, hippocampus, and striatum (Ferraro et al., 1997(Ferraro et al., , 1998 consistent with our findings of a dosedependent increase in cFOS expression across the whole brain. Although there are multiple imaging studies in humans assessing the effects of modafinil, all of them have focused on changes in a few brain regions (Ellis et al., 1999;Minzenberg et al., , 2011Scoriels et al., 2013). In rats, modafinil causes increases in cerebral blood flow that correlate with increases in cFOS expression (Gozzi et al., 2012), highlighting the functional significance of our whole-brain cFOS quantification. ...
While neuropsychiatric drugs influence neural activity across multiple brain regions, the current understanding of their mechanism of action derives from studies that investigate an influence of a given drug onto a pre-selected and small number of brain regions. To understand how neuropsychiatric drugs affect coordinated activity across brain regions and to detect the brain regions most relevant to pharmacological action in an unbiased way, studies that assess brain-wide neuronal activity are paramount. Here, we used whole-brain immunostaining of the neuronal activity marker cFOS, and graph theory to generate brain-wide maps of neuronal activity upon pharmacological challenges. We generated brain-wide maps 2.5 h after treatment of the atypical dopamine transporter inhibitor modafinil (10, 30, and 100 mg/kg) or the vesicular monoamine transporter 2 inhibitor tetrabenazine (0.25, 0.5 and 1 mg/kg). Modafinil increased the number of cFOS positive neurons in a dose-dependent manner. Moreover, modafinil significantly reduced functional connectivity across the entire brain. Graph theory analysis revealed that modafinil decreased the node degree of cortical and subcortical regions at the three doses tested, followed by a reduction in global efficiency. Simultaneously, we identified highly interconnected hub regions that emerge exclusively upon modafinil treatment. These regions were the mediodorsal thalamus, periaqueductal gray, subiculum, and rhomboid nucleus. On the other hand, while tetrabenazine had mild effects on cFOS counts, it reduced functional connectivity across the entire brain, cortical node degree, and global efficiency. As hub regions, we identified the substantia innominata and ventral pallidum. Our results uncovered novel mechanisms of action at a brain-wide scale for modafinil and tetrabenazine. Our analytical approach offers a tool to characterize signatures of whole-brain functional connectivity for drug candidates and to identify potential undesired effects at a mesoscopic scale. Additionally, it offers a guide towards targeted experiments on newly identified hub regions.
... It is impaired in some neurological and the majority of psychiatric disorders (Millan et al., 2012), including schizophrenia (Barch and Smith, 2008). Pathologically occurring WM deficits are often pharmacoresistant; e.g., guanfacine was ineffective in patients with schizophrenia (Friedman et al., 2001) as well as in a delayed-matching-to-position (DMTP) paradigm in healthy humans (Jäkälä et al., 1999b), and modafinil was found effective in schizophrenia only in a subset of studies (Scoriels et al., 2013). Therefore, translational rodent assays, which can predict WM-enhancing effects in humans are sought-after (Barch et al., 2009). ...
... However, it should be noted that the WM-enhancing effects of these compounds in humans are disputed as well. Both drugs show limited efficacy in schizophrenia (Friedman et al., 2001;Millan et al., 2012;Scoriels et al., 2013). But also in healthy humans, a considerable number of studies have failed to see WM-improvement by modafinil in non-sleep-deprived subjects (Battleday and Brem, 2015) or by guanfacine in a DMTP WM paradigm (Jäkälä et al., 1999b). ...
Working memory (WM) is required to bridge the time between the moment of sensory perception and the usage of the acquired information for subsequent actions. Its frequent and pharmacoresistent impairment in mental health disorders urges the development of rodent paradigms through back-translation of human WM tests, ideally avoiding the confounds of alternation-based assays. Here we show, that mice can acquire a delayed-matching-to-position (DMTP) operant spatial WM (SWM) paradigm that is akin to the combined attention and memory (CAM) task previously developed for rats, and that relies on a 5-choice wall [5-CSWM, 5-choice based operant testing of SWM (5-CSWM)]. Requiring ca. 3 months of daily training with a non-illuminated operant box in the default state, mice could attain a performance level of ≥70% choice accuracy with short (2 s) delays in the DMTP 5-CSWM task. Performance decreased with extended delays, as expected for WM processes. Modafinil (15 and 30 mg/kg) and guanfacine (0.3 and 1 mg/kg) showed no consistent efficacy in enhancing task performance. We also found, that mice did not improve beyond chance level, when trained in the DNMTP-version of the 5-CSWM. Our results outline the methodical possibility and constraints of assessing spatial WM in mice with an operant paradigm that provides high control over potentially confounding variables, such as cue-directed attention, motivation or mediating strategies like body-positioning.
... The GABAergic system appears to be systematically down-regulated by modafinil (in the hippocampus, hypothalamus, thalamus, striatum, globus pallidus), whereas other neurotransmitters seem to be upregulated by the drug (Scoriels, Jones et al. 2012). After administration of modafinil, increases in glutamate are seen in the cortex, the hippocampus, the hypothalamus, the thalamus, substantia nigra, and LC, but not the striatum (Touret, Sallanon-Moulin et al. 1994;Ferraro, Antonelli et al. 1999;Xiao, Fu et al. 2004;Dawson, Thompson et al. 2012). ...
... Overall, the findings of this thesis converge with the current thinking that atomoxetine has relatively specific effects on the noradrenergic system (although some increase in DA is seen in the PFC after administration of the drug), whereas modafinil seems to modulate a number of neurotransmitter systems. It has recently been proposed that a parsimonious explanation for modafinil's action may be that it increases glutamatergic activation (Scoriels, Jones et al. 2012), so this may be an area for future research. The difference between the profiles of atomoxetine and modafinil suggests that they may have a distinct utility in clinical practice. ...
Cognitive impairments are a common feature of neurological and neuropsychiatric disorders, as well as of substance-abuse disorders. The impairments seen in these disorders can be caused by disruptions to common neural substrates, and therefore pharmacological agents can be repositioned from use in neuropsychiatric to neurological disorders, and vice versa. Together, these disorders have been estimated to comprise 13% of the global burden of disease. Indeed, an individual’s ability to successfully perform everyday activities can be limited by deficits in crucial cognitive functions such as attention, response inhibition, planning and working memory. Frontal-striatal networks in the brain have been shown to underlie these vital functions, which are modulated by neurotransmitters including acetylcholine, dopamine, and noradrenaline. Importantly, these functions are susceptible to pharmacological intervention with drugs such as physostigmine, modafinil, and atomoxetine.
In order to explore the nature of a variety of forms of cognitive impairment, which were diverse in severity from mild to more severe, studies were carried out on amateur boxers and sleep-deprived doctors, as well as on patients with subarachnoid haemorrhage (SAH) and on patients with Parkinson’s disease (PD). Quantification of cognitive impairment is the crucial first step in determining which neural networks are involved, and thus which pharmacological agents would be suitable candidates for treatment.
A longitudinal study was carried out using a comprehensive battery of well-validated cognitive tasks, in order to quantify the change in cognitive ability in healthy individuals who participated in amateur boxing. Subtle cognitive impairments, which were related to structural changes, were documented.
Using existing understanding of pharmacological agents, novel treatments for cognitive impairments were explored in relation to sleep-deprived doctors, as well as to PD and SAH patients. A novel treatment for specific cognitive problems in PD was investigated: atomoxetine, a noradrenaline reuptake inhibitor. A double-blind placebo-controlled study revealed that atomoxetine may be a candidate for treatment of response inhibition impairments seen in PD. This finding is important as noradrenergic treatments are not currently used in PD, despite degeneration in the locus coeruleus, the main cortical source of noradrenaline. Another novel treatment explored was modafinil, a drug that has also been shown to modulate the noradrenergic system, as well as the dopaminergic system. Modafinil is currently licensed for use in narcolepsy and shift work sleep disorder. It was found that modafinil remediates task set-switching impairments and reduces impulsivity in sleep-deprived doctors. Furthermore, it was shown that modafinil might be a potential treatment for cognitive impairments found in neurological patients with SAH. In contrast to this, physostigmine, a cholinesterase inhibitor, did not seem to alter the cognitive symptoms investigated.
To summarise, this thesis aims to quantify cognitive impairment in a range of groups, and to explore the potential use of existing pharmacological agents that could be repurposed to treat cognitive impairments in novel ways.
... lek może wpływać na przetwarzanie emocjonalne [28]. Pierwotne badania dotyczące poprawy klinicznej objawów negatywnych schizofrenii skupiały się na armodafinilu, izomerze modafinilu o dłuższym działaniu [29]. ...
Modafinil is used to treat narcolepsy with cataplexy and is also being extensively studied to find new therapeutic uses. In recent years, there have been reports suggesting the potential benefits of modafinil in the treatment of psychiatric illnesses such as depression and bipolar depression. In the case of depression, modafinil can be used as an adjuvant or as monotherapy in patients who do not respond sufficiently to antidepressants. Studies have shown that modafinil improves symptoms of depression, reduces fatigue and improves cognitive function. There are also reports of a beneficial effect of modafinil in the treatment of seasonal depression. For bipolar depression, modafinil can be used as an adjunct therapy during the depressive phase, particularly in patients experiencing slowness, lethargy and loss of pleasure. Studies suggest that modafinil may improve depressive symptoms without inducing manic episodes. There are also data indicating modafinil's potential efficacy in treating negative symptoms and improving cognitive function in patients with schizophrenia. In conclusion, modafinil appears to be a promising drug in aiding the treatment of various psychiatric illnesses.
... However, MOD is believed to additionally affect other neurotransmitter systems such as promoting glutamate, serotonin, histamine pathways (Minzenberg & Carter, 2008;Repantis et al., 2010). In general, MOD affects frontal lobe areas (Scoriels et al., 2013 for a review) and has been associated with improved attention, vigilance as well as memory and learning (Battleday & Brem, 2015;Linssen et al., 2014;Müller et al., 2013;Randall et al., 2005;Repantis et al., 2010). ...
Stimulants like methylphenidate, modafinil, and caffeine have repeatedly shown to enhance cognitive processes such as attention and memory. However, brain-functional mechanisms underlying such cognitive enhancing effects of stimulants are still poorly characterized. Here, we utilized behavioral and resting-state fMRI data from a double-blind randomized placebocontrolled study of methylphenidate, modafinil, and caffeine in 48 healthy male adults. The results show that performance in different memory tasks is enhanced, and functional connectivity (FC) specifically between the frontoparietal network (FPN) and default mode network (DMN) is modulated by the stimulants in comparison to placebo. Decreased negative connectivity between right prefrontal and medial parietal but also between medial temporal lobe and visual brain regions predicted stimulant-induced latent memory enhancement. We discuss dopamine's role in attention and memory as well as its ability to modulate FC between large-scale neural networks (e.g., FPN and DMN) as a potential cognitive enhancement mechanism.
... However, MOD is believed to additionally affect other neurotransmitter systems such as promoting glutamate, serotonin, histamine pathways (Minzenberg & Carter 2008;Repantis et al., 2010). In general, MOD affects frontal lobe areas (Scoriels et al., 2013 for a review) and has been associated with improved attention, vigilance as well as memory and learning (Linssen et al., 2014;Repantis, 2010;Battleday & Brem, 2015, Müller et al., 2013Randall et al., 2005). ...
Stimulants like methylphenidate, modafinil and caffeine have repeatedly shown to enhance cognitive processes such as attention and memory. However, brain-functional mechanisms underlying such cognitive enhancing effects of stimulants are still poorly characterized. Here, we utilized behavioral and resting-state fMRI data from a double-blind randomized placebo-controlled study of methylphenidate, modafinil and caffeine in 48 healthy male adults. The results show that performance in different memory tasks is enhanced, and functional connectivity (FC) specifically between the fronto-parietal (FPN) and default mode (DMN) network is modulated by the stimulants in comparison to placebo. Decreased negative connectivity between right prefrontal and medial parietal but also between medial temporal lobe and visual brain regions predicted stimulant-induced latent memory enhancement. We discuss dopamine’s role in attention and memory as well as its ability to modulate FC between large-scale neural networks (e.g. FPN and DMN) as a potential cognitive enhancement mechanism.
... However, MOD is believed to additionally affect other neurotransmitter systems such as promoting glutamate, serotonin, histamine pathways (Minzenberg & Carter 2008;Repantis et al., 2010). In general, MOD affects frontal lobe areas (Scoriels et al., 2013 for a review) and has been associated with improved attention, vigilance as well as memory and learning (Linssen et al., 2014;Repantis, 2010;Battleday & Brem, 2015, Müller et al., 2013Randall et al., 2005). ...
Stimulants like methylphenidate, modafinil and caffeine have repeatedly shown to enhance cognitive processes such as attention and memory. However, brain-functional mechanisms underlying such cognitive enhancing effects of stimulants are still poorly characterized. Here, we utilized behavioral and resting-state fMRI data from a double-blind randomized placebo-controlled study of methylphenidate, modafinil and caffeine in 48 healthy male adults. The results show that performance in different memory tasks is enhanced, and functional connectivity (FC) specifically between the fronto-parietal (FPN) and default mode (DMN) network is modulated by the stimulants in comparison to placebo. Decreased negative connectivity between right prefrontal and medial parietal but also between medial temporal lobe and visual brain regions predicted stimulant-induced latent memory enhancement. We discuss dopamine's role in attention and memory as well as its ability to modulate FC between large-scale neural networks (e.g. FPN and DMN) as a potential cognitive enhancement mechanism.
... On the other hand, modafinil knows to have more important effects on hypocretin/orexin, serotonin, glutamate, acetylcholine, and histamine functions, which shows how it affects brain activities, especially cognitively, depending on the various neurochemical activity of the brain. [120] In this test, drug discrimination is a striking element in the system because this gives us information that will enable us to relate to the reward system. On the other hand, a focused visual attention assessment was not performed in 22q11.2DS ...
Attention deficit and hyperactivity disorder (ADHD) is a neurodevelopmental and neuropsychiatric disorder that appears as a subset of attention deficit and different subspecies in which both occur together and is generally observed in childhood. Pharmacological agents such as atomoxetine and methylphenidate, which are widely used against the disease, appear with different and important side effects. Since the causes of the disease are not clearly understood, many studies are carried out on various animal models in order to both understand the etiology and develop new treatment models. In this review, a holistic approach to ADHD will be presented and advances in animal models, neuroimaging, neurodevelopmental, and neurochemical conditions will be presented using different perspectives. It is very important to understand how different animal models are effective in the development of pharmacological agents. In addition, comparing ADHD with different types of disease can detect similarities and further strengthen the etiological basis. Our major proposal is to draw attention to the further development of animal models related to the importance of the thalamus, which officially sees a filter of perception. Different animal models are needed to do all this because the disease is not fully modeled, except for the symptoms of ADHD. The current review will conclude that none of the currently discussed models meet all the necessary validation criteria, but that newly created genetic models, therapeutic strategies, and the disease mechanism may be radically important points.
... There is also an improvement in working memory with the cognitive-enhancing drug modafinil that is hypothesized to be mediated by a 1 -ARs since effects are blocked by prazosin (Duteil et al., 1990;Stone et al., 2002;Winder-Rhodes et al., 2010). Moda fi nil is a wake-promoting non-amphetamine neurochemical with complex properties that can directly stimulate cortical catecholamine levels and indirectly stimulate serotonin along with other neurotransmitters (Minzenberg and Carter, 2008;Chen et al., 2013;Scoriels et al., 2013). Together, these results suggest that a 1 -AR activation could be used to target enhancement of spatial working memory. ...
α1-adrenergic receptors are G-Protein Coupled Receptors that are involved in neurotransmission and regulate the sympathetic nervous system through binding and activating the neurotransmitter, norepinephrine, and the neurohormone, epinephrine. There are three α1-adrenergic receptor subtypes (α1A, α1B, α1D) that are known to play various roles in neurotransmission and cognition. They are related to two other adrenergic receptor families that also bind norepinephrine and epinephrine, the β- and α2-, each with three subtypes (β1, β2, β3, α2A, α2B, α2C). Previous studies assessing the roles of α1-adrenergic receptors in neurotransmission and cognition have been inconsistent. This was due to the use of poorly-selective ligands and many of these studies were published before the characterization of the cloned receptor subtypes and the subsequent development of animal models. With the availability of more-selective ligands and the development of animal models, a clearer picture of their role in cognition and neurotransmission can be assessed. In this review, we highlight the significant role that the α1-adrenergic receptor plays in regulating synaptic efficacy, both short and long-term synaptic plasticity, and its regulation of different types of memory. We will also present evidence that the α1-adrenergic receptors, and particularly the α1A-adrenergic receptor subtype, are a potentially good target to treat a wide variety of neurological conditions with diminished cognition.
... The results from this proof-of-concept study were promising, suggesting that the potential of modafinil should be investigated further. One of the proposed mechanisms for the pro-cognitive effect of modafinil is through augmenting glutamatergic transmission in the hippocampus (25). Modafinil has other beneficial effects on mood, fatigue, and motivation that may help patients with depression. ...
Cognitive dysfunction is an important yet overlooked aspect of depression. Cognitive problems in depression tend to be persistent and are associated with poorer psychosocial functioning. Most available treatments for depression do not specifically address cognition. A comprehensive approach is required to investigate the underlying mechanisms and examine the potential treatment options to match the unmet clinical need.
This paper is an updated version of "cognition as a. treatment target in depression" previously published in Psychological Medicine, 2017 Apr; 47(6):987-989
... In the present work, we did not divide our experimental group into subgroups based on measures of individual impulsivity but found consistent effects of modafinil in reducing gambling choices. The psychological substrates of these effects from the data to hand remain unknown but the most prominent and robust effect of modafinil seems to be on general arousal and attention, rather than any specific cognitive process, via cortical mechanisms (Scoriels et al. 2013;Smart et al. 2013). On that basis, it might be speculated that modafinil could impact on multiple facets of loss-chasing behaviour, including, as we demonstrate here, the control of impulses to gamble in the first place to the control of persistent gambling in the face of repeated losses. ...
RationaleProblematic patterns of gambling are characterised by loss of control and persistent gambling often to recover losses. However, little is known about the mechanisms that mediate initial choices to begin gambling and then continue to gamble in the face of losing outcomes.Objectives
These experiments first assessed gambling and loss-chasing performance under different win/lose probabilities in C57Bl/6 mice, and then investigated the effects of antagonism of 5-HT2CR with SB242084, 5-HT1AR agonism with 8-OH-DPAT and modafinil, a putative cognitive enhancer.ResultsAs seen in humans and other species, mice demonstrated the expected patterns of behaviour as the odds for winning were altered increasing gambling and loss-chasing when winning was more likely. SB242084 decreased the likelihood to initially gamble, but had no effects on subsequent gambling choices in the face of repeated losses. In contrast, 8-OH-DPAT had no effects on choosing to gamble in the first place, but once started 8-OH-DPAT increased gambling choices in a dose-sensitive manner. Modafinil effects were different to the serotonergic drugs in both decreasing the propensity to initiate gambling and chase losses.Conclusions
We present evidence for dissociable effects of systemic drug administration on different aspects of gambling behaviour. These data extend and reinforce the importance of serotonergic mechanisms in mediating discrete components of gambling behaviour. They further demonstrate the ability of modafinil to reduce gambling behaviour. Our work using a novel mouse paradigm may be of utility in modelling the complex psychological and neurobiological underpinnings of gambling problems, including the analysis of genetic and environmental factors.
... Its neurochemical action is complex; whilst it acts as a weak blocker of catecholamine transporters, it has several other actions that distinguish it from typical stimulant drugs, including possible indirect actions on glutamate and acetylcholine. 28,29 However, modafinil has not been licensed to date for ADHD medication and it is not thought be as clinically effective as the classical stimulants. 6 ...
Evidence for pharmacological remediation of cognitive deficits in three major psychiatric disorders-attention deficit- hyperactivity disorder (ADHD), schizophrenia, and depression-is reviewed. ADHD is effectively treated with the stimulant medications methylphenidate and d-amphetamine, as well as nonstimulants such as atomoxetine, implicating cognitive enhancing effects mediated by noradrenaline and dopamine. However, the precise mechanisms underlying these effects remains unclear. Cognitive deficits in schizophrenia are less effectively treated, but attempts via a variety of neurotransmitter strategies are surveyed. The possibility of treating cognitive deficits in depression via antidepressant medication (eg, selective serotonin reuptake inhibitors) and by adjunctive drug treatment has only recently received attention because of confounding, or possibly interactive, effects on mood. Prospects for future advances in this important area may need to take into account transdiagnostic perspectives on cognition (including neurodegenerative diseases) as well as improvements in neuropsychological, neurobiological, and clinical trial design approaches to cognitive enhancement.
.
... Modafinil's effects include wake-promotion and neuroprotection [65]. It has been approved for the treatment of narcolepsy and it has shown potential benefits in Attention Deficit Hyperactivity Disorder (ADHD) [66,67] and psychiatric diseases [68], such as depression [69] and schizophrenia [70]. Its exact mechanism of action is unknown [71] and to date no single receptor binding site has been isolated for the drug. ...
Disorders of the cerebellum may present with motor, cognitive, behavioral and affective symptoms. There is a growing interest in developing neuroanatomical models of symptoms generation that involve the cerebellum and the cerebello-cortical connections.
We describe an exciting first case report of successful use of Modafinil in an adult patient with post-operative posterior fossa syndrome. Following resection of a melanoma metastasis in the cerebellum the patient developed striking affective and behavioral symptoms in the form of withdrawn flat mood and disengagement. This neurobehavioral presentation severely impacted on his quality of life, independence, and ability to engage in the neuro-rehabilitative program. Pharmacological treatment with Modafinil ameliorated these emotional and behavioral aspects, and also fatigue. Treatment with Modafinil hence affected recovery and outcome for the patient.
To our knowledge, this is the first description of a successful pharmacological intervention in an adult with post-surgical posterior fossa syndrome and negative neurobehavioral presentation. Our findings illustrate the variability of the presentation of post-operative posterior fossa syndrome in adults, and the importance of delivering targeted treatment to maximize the benefits of neurorehabilitation.
The manuscript highlights the following points: 1. post-operative consequences currently under the wide umbrella of posterior fossa syndrome, can indeed manifest in adults; 2. a wide spectrum of neurobehavioral symptoms can occur, including a presentation with predominantly negative features; 3. the type of neurobehavioral presentation should guide the treatment choice with particular consideration of drugs that potentially modulate the cerebello-frontal connections; 4. Modafinil can be a candidate for effective treatment in presentations with predominantly negative behavioral symptoms.
... Efficacy of cognitive enhancers of the miscellaneous category No beneficial effects for the miscellaneous group or modafinil/ armodafinil subgroup were found. Recent reviews on modafinil and armodafinil 24 and modafinil alone 25 reported beneficial effects in single dose studies for some cognitive domains, in particular working memory. All, except one of the reviewed studies with longer treatment duration found no beneficial effects of modafinil/armodafinil on cognition. ...
Cognitive impairment is a core feature of schizophrenia, which is predictive for functional outcomes and is, therefore, a treatment target in itself. Yet, literature on efficacy of different pharmaco-therapeutic options is inconsistent. This quantitative review provides an overview of studies that investigated potential cognitive enhancers in schizophrenia. We included pharmacological agents, which target different neurotransmitter systems and evaluated their efficacy on overall cognitive functioning and seven separate cognitive domains. In total, 93 studies with 5630 patients were included. Cognitive enhancers, when combined across all different neurotransmitter systems, which act on a large number of different mechanisms, showed a significant (yet small) positive effect size of 0.10 (k = 51, p = 0.023; 95% CI = 0.01 to 0.18) on overall cognition. Cognitive enhancers were not superior to placebo for separate cognitive domains. When analyzing each neurotransmitter system separately, agents acting predominantly on the glutamatergic system showed a small significant effect on overall cognition (k = 29, Hedges’ g = 0.19, p = 0.01), as well as on working memory (k = 20, Hedges’ g = 0.13, p = 0.04). A sub-analysis of cholinesterase inhibitors (ChEI) showed a small effect on working memory (k = 6, Hedges’ g = 0.26, p = 0.03). Other sub-analyses were positively nonsignificant, which may partly be due to the low number of studies we could include per neurotransmitter system. Overall, this meta-analysis showed few favorable effects of cognitive enhancers for patients with schizophrenia, partly due to lack of power. There is a lack of studies involving agents acting on other than glutamatergic and cholinergic systems, especially of those targeting the dopaminergic system.
... Emphasising the translational relevance of the alterations in functional connectivity seen in the subchronic PCP model, the global network alterations seen in the model are consistent with the altered neural systems connectivity, including reduced hippocampal-PFC and thalamic connectivity, seen in patients with schizophrenia (Micheloyannis et al. 2006;Liu et al. 2008;Godsil et al. 2013;Anticevic et al. 2014). Moreover, the potential translational relevance and the utility of these alterations as biomarkers in the drug validation process is supported by evidence that these alterations in functional connectivity, including hippocampal-PFC and thalamo-PFC connectivity, are amenable to pharmacological correction by a drug, modafinil, known to have procognitive effects in both the subchronic PCP model and patients with schizophrenia (Goetghebeur and Dias 2009;Dawson et al. 2012;Scoriels et al. 2013). In addition, modafinil both increases PFC cerebral metabolism in schizophrenia patients and reverses the hypofrontality seen in the PCP model (Spence et al. 2005;Dawson et al. 2012), supporting PFC hypometabolism (hypofrontality) as a biomarker for the cognitive flexibility deficit seen in the disorder. ...
Schizophrenia is considered to develop as a consequence of genetic and environmental factors impacting on brain neural systems and circuits during vulnerable neurodevelopmental periods, thereby resulting in symptoms in early adulthood. Understanding of the impact of schizophrenia risk factors on brain biology and behaviour can help in identifying biologically relevant pathways that are attractive for informing clinical studies and biomarker development. In this chapter, we emphasize the importance of adopting a reciprocal forward and reverse translation approach that is iteratively updated when additional new information is gained, either preclinically or clinically, for offering the greatest opportunity for discovering panels of biomarkers for the diagnosis, prognosis and treatment of schizophrenia. Importantly, biomarkers for identifying those at risk may inform early intervention strategies prior to the development of schizophrenia.
... The effect of modafinil (MOD), a wake-promoting drug, was also researched in the CSD treated mice as positive control. Cognitive enhancement effects of MOD have been studied extensively in human volunteers and rodents using different memory tasks such as spatial working, short-term and long-term memory (Scoriels et al., 2013;Sase et al., 2012;Wadhwa et al., 2015). In agreement, our results verified that MOD significantly improved the learning and memory function of CSD mice in behavioral tests, and showed antioxidant activity. ...
Sleep deprivation (SD) negatively caused cognitive deficit, which was associated with oxidative stress induced damage. Ginsenoside Rh2 had the ability to protect against damage caused by reactive oxygen species in vitro, showing antioxidant property. Therefore, it was hypothesized that Ginsenoside Rh2 could prevent SD-induced cognitive deficit via its antioxidant properties. In this study, the effect of Ginsenoside Rh2 on memory impairment induced by sleep deprivation was investigated. The mice were sleep deprived continuously for 14 days using our self-made Sleep Interruption Apparatus (SIA). Ginsenoside Rh2 was administered intraperitoneally at two doses (20 and 40 μmol/kg) for 20 days. Thereafter, behavioral studies were conducted to test the learning and memory ability using object location recognition (OLR) experiment and passive avoidance (PA) test. Additionally, the oxidative stress parameters in the serum and the brain tissues (cortex and hippocampus) were assessed, including the superoxide dismutase (SOD) enzyme activity, the total antioxidant reactivity (TAR), the malondialdehyde (MDA) level, the glutathione (GSH) level, and the lipid peroxidation (LPO) content. The results revealed that SD impaired both spatial and non-spatial memory (P < 0.05). Treatment with Ginsenoside Rh2 at both doses prevented memory impairment induced by SD. Moreover, Ginsenoside Rh2 normalized the reduction of SOD and TAR activities in the serum (P < 0.01) and the decrease of GSH content in both the cortex and hippocampus (P < 0.05) induced by SD. Furthermore, Ginsenoside Rh2 significantly decreased the MDA level in the serum (P < 0.05) and the LPO content in both the cortex and hippocampus (P < 0.05) compared to SD group. In conclusion, sleep deprivation impaired both spatial and non-spatial memory and Ginsenoside Rh2 reversed this impairment, probably by preventing the oxidative stress damage in the body, including the serum and brain during sleep deprivation.
... A parent compound of CE-123, modafinil (Fig. 1) is a wake-promoting drug approved for the treatment of narcolepsy, sleep apnea and shift-work sleep disorders [19]. Modafinil has gained increasing interest for its cognitive enhancing properties in healthy individuals [20,21] and individuals with some cognitive dysfunctions, including attention deficit hyperactivity disorder (ADHD) [22] and schizophrenia [23]. Despite a weak binding potential for DAT, modafinil occupies more than 50% of DAT at therapeutic doses [24], that makes modafinil a candidate for off-prescription use for cognitive enhancement. ...
Dopamine reuptake inhibitors have been shown to improve cognitive parameters in various tasks and animal models. We recently reported a series of modafinil analogues, of which the most promising, 5-((benzhydrylsulfinyl)methyl) thiazole (CE-123), was selected for further development. The present study aims to characterize pharmacological properties of CE-123 and to investigate the potential to enhance memory performance in a rat model. In vitro transporter assays were performed in cells expressing human transporters. CE-123 blocked uptake of [3H] dopamine (IC50 = 4.606 µM) while effects on serotonin (SERT) and the norepinephrine transporter (NET) were negligible. Blood-brain barrier and pharmacokinetic studies showed that the compound reached the brain and lower elimination than R-modafinil. The Pro-cognitive effect was evaluated in a spatial hole-board task in male Sprague-Dawley rats and CE-123 enhances memory acquisition and memory retrieval, represented by significantly increased reference memory indices and shortened latency. Since DAT blockers can be considered as indirect dopamine receptor agonists, western blotting was used to quantify protein levels of dopamine receptors D1R, D2R and D5R and DAT in the synaptosomal fraction of hippocampal subregions CA1, CA3 and dentate gyrus (DG). CE-123 administration in rats increased total DAT levels and D1R protein levels were significantly increased in CA1 and CA3 in treated/trained groups. The increase of D5R was observed in DG only. Dopamine receptors, particularly D1R, seem to play a role in mediating CE-123-induced memory enhancement. Dopamine reuptake inhibition by CE-123 may represent a novel and improved stimulant therapeutic for impairments of cognitive functions.
... The eugeroic agent, modafinil (8 mg/kg), was the only compound to cause significant improvements in sensitivity, d′, a common index of sustained, focused attentional performance in the CPT paradigm, but did so only in control rats. Modafinil has shown mixed effects for cognitive enhancements in healthy human subjects but generally improves performance on tests of sustained and focused attention at more difficult task parameters using low to moderate doses (Scoriels et al. 2013;Battleday and Brem 2015). While the majority of studies using young, healthy rodents in the 5-CSRTT has found either no effect or reductions in attentional accuracy and/or inhibitory control (Milstein et al. 2003;Waters et al. 2005;Liu et al. 2010), such results may be explained by the use of higher dose ranges (>30 mg/kg) and/or insufficient task difficulty. ...
Rationale:
Impairments in attention and inhibitory control are endophenotypic markers of neuropsychiatric disorders such as schizophrenia and represent key targets for therapeutic management. Robust preclinical models and assays sensitive to clinically relevant treatments are crucial for improving cognitive enhancement strategies.
Objectives:
We assessed a rodent model with neural and behavioral features relevant to schizophrenia (gestational day 17 methylazoxymethanol acetate treatment (MAM-E17)) on a novel test of attention and executive function, and examined the impact of putative nootropic drugs.
Methods:
MAM-E17 and sham control rats were trained on a novel touchscreen-based rodent continuous performance test (rCPT) designed to closely mimic the human CPT paradigm. Performance following acute, systemic treatment with an array of pharmacological compounds was investigated.
Results:
Two cohorts of MAM-E17 rats were impaired on rCPT performance including deficits in sensitivity (d') and increased false alarm rates (FARs). Sulpiride (0-30 mg/kg) dose-dependently reduced elevated FAR in MAM-E17 rats whereas low-dose modafinil (8 mg/kg) only improved d' in sham controls. ABT-594 (5.9-19.4 μg/kg) and modafinil (64 mg/kg) showed expected stimulant-like effects, while LSN2463359 (5 mg/kg), RO493858 (10 mg/kg), atomoxetine (0.3-1 mg/kg), and sulpiride (30 mg/kg) showed expected suppressant effects on performance across all animals. Donepezil (0.1-1 mg/kg) showed near-significant enhancements in d', and EVP-6124 (0.3-3 mg/kg) exerted no effects in the rCPT paradigm.
Conclusion:
The MAM-E17 model exhibits robust and replicable impairments in rCPT performance that resemble attention and inhibitory control deficits seen in schizophrenia. Pharmacological profiles were highly consistent with known drug effects on cognition in preclinical and clinical studies. The rCPT is a sensitive and reliable tool with high translational potential for understanding the etiology and treatment of disorders affecting attention and executive dysfunction.
... Given the inconsistency of findings concerning modafinil in schizophrenia (Scoriels et al. 2012(Scoriels et al. , 2013Michalopoulou et al. 2015;Vreeker et al. 2015) the present study was mounted to test whether phase of illness was critical for the action of cognitive enhancers. We also compared cognitive assessment batteries' sensitivities. ...
Background:
Cognitive deficits in schizophrenia have major functional impacts. Modafinil is a cognitive enhancer whose effect in healthy volunteers is well-described, but whose effects on the cognitive deficits of schizophrenia appear to be inconsistent. Two possible reasons for this are that cognitive test batteries vary in their sensitivity, or that the phase of illness may be important, with patients early in their illness responding better.
Methods:
A double-blind, randomised, placebo-controlled single-dose crossover study of modafinil 200 mg examined this with two cognitive batteries [MATRICS Consensus Cognitive Battery (MCCB) and Cambridge Neuropsychological Test Automated Battery (CANTAB)] in 46 participants with under 3 years' duration of DSM-IV schizophrenia, on stable antipsychotic medication. In parallel, the same design was used in 28 age-, sex-, and education-matched healthy volunteers. Uncorrected p values were calculated using mixed effects models.
Results:
In patients, modafinil significantly improved CANTAB Paired Associate Learning, non-significantly improved efficiency and significantly slowed performance of the CANTAB Stockings of Cambridge spatial planning task. There was no significant effect on any MCCB domain. In healthy volunteers, modafinil significantly increased CANTAB Rapid Visual Processing, Intra-Extra Dimensional Set Shifting and verbal recall accuracy, and MCCB social cognition performance. The only significant differences between groups were in MCCB visual learning.
Conclusions:
As in earlier chronic schizophrenia studies, modafinil failed to produce changes in cognition in early psychosis as measured by MCCB. CANTAB proved more sensitive to the effects of modafinil in participants with early schizophrenia and in healthy volunteers. This confirms the importance of selecting the appropriate test battery in treatment studies of cognition in schizophrenia.
... In addition to its primary effects on dopamine and noradrenaline, modafinil also modulates GABA, glutamate, serotonin, histamine and orexin (Minzenberg & Carter, 2007). It is thought that the cognitiveenhancing and task-related motivational effects of modafinil include actions on glutamate, noradrenaline and dopamine (Müller et al., 2004;Porsdam Mann & Sahakian, 2015;Scoriels et al., 2013). Other drugs with purported cognition enhancing effects include acetylcholinesterase inhibitors such as donepezil, that are used to treat Alzheimer's disease , beta-blockers such as propranolol (Maher, 2008;Schelle et al., 2015) and atomoxetine, a highly selective noradrenaline reuptake inhibitor also used to treat ADHD (Graf et al., 2011). ...
Today, there is continued, and in some cases growing, availability of not only psychoactive substances, including treatments for mental health disorders such as cognitive enhancers, which can enhance or restore brain function, but also ‘recreational’ drugs such as novel psychoactive substances (NPS). The use of psychoactive drugs has both benefits and risks: whilst new drugs to treat cognitive symptoms in neuropsychiatric or neurodegenerative disorders could have great benefits for many patient groups, the increasing ease of accessibility to recreational NPS and the increasing lifestyle use of cognitive enhancers by healthy people means that the effective management of psychoactive substances will be an issue of increasing importance. Clearly, the potential benefits of cognitive enhancers are large and increasingly relevant, particularly as the population ages, and for this reason, we should continue to devote resources to the development of cognitive enhancers as treatments for neurodegenerative diseases and psychiatric disorders, including Alzheimer's disease, attention deficit hyperactivity disorder and schizophrenia. However, the increasing use of cognitive enhancers by healthy individuals raises safety, ethical and regulatory concerns, which should not be ignored. Similarly, understanding the short‐ and long‐term consequences of the use of NPS, as well as better understanding the motivations and profiles of users could promote more effective prevention and harm reduction measures.
Linked Articles
This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc
... One example is the description of the mode of action of modafinil, which in the most recent version of the NbN is described as a dopamine (DA) reuptake inhibitor and wakefulness-promoting agent. However, the pharmacological action of modafinil is more complex, involving also a reuptake inhibiting effect for noradrenaline (Minzenberg & Carter, 2008) as well as modulating GABA, serotonin, histamine and orexin (Scoriels et al. 2013), and besides promoting wakefulness, it also has various effects on memory, emotional and motivational processes. However, the NbN is explicitly designed to be extended, updated and adapted; currently, it is automatically updated twice a year. ...
Neuroscience-based Nomenclature: improving clinical and scientific terminology in research and clinical psychopharmacology - A. B. Brühl, B. J. Sahakian
... Another noteworthy medication is modafinil which was shown to improve cognition in depression as adjunctive treatment (DeBattista et al. 2004). One of the proposed mechanisms of modafinil's pro-cognitive effect is through augmenting glutamatergic transmission in hippocampus (Scoriels et al. 2013). Modafinil augmentation showed beneficial effects on mood and fatigue (Goss et al. 2013) which may make its use more favourable for patients with persistent cognitive dysfunction. ...
Cognitive dysfunction in depression is associated with poorer clinical outcomes and impaired psychosocial functioning. However, most treatments for depression do not specifically target cognition. Neurocognitive deficits such as memory and concentration problems tend to persist after mood symptoms recover. Improving cognition in depression requires a better understanding of brain systems implicated in depression. A comprehensive approach is warranted for refined methods of assessing and treating cognitive dysfunction in depression.
... One such assay is the attentional set-shifting task (ASST) paradigm, which aims to evaluate alterations in a specific aspect of executive control and cognitive flexibility, namely attentional set-shifting abilities. This assay has successfully demonstrated improvement of the extra-dimensional shift with several pharmacological interventions in patients with schizophrenia or schizophrenia-like rodent models including erythropoietin (Ehrenreich et al., 2007;Goetghebeur et al., 2010), sertindole (Gallhofer et al., 2007;Goetghebeur and Dias, 2009) and modafinil (Goetghebeur and Dias, 2009;Morein-Zamir et al., 2007;Scoriels et al., 2012Scoriels et al., , 2013Turner et al., 2004). ...
Central nervous system pharmacological research and development has reached a critical turning point. Patients suffering from disorders afflicting the central nervous system are numerous and command significant attention from the pharmaceutical industry. However, given the numerous failures of promising drugs, many companies are no longer investing in or, indeed, are divesting from this therapeutic area. Central nervous system drug development must change in order to develop effective therapies to treat these patients. Preclinical research is a cornerstone of drug development; however, it is frequently criticised for its lack of predictive validity. Animal models and assays can be shown to be more predictive than reported and, on many occasions, the lack of thorough preclinical testing is potentially to blame for some of the clinical failures. Important factors such as translational aspects, nature of animal models, variances in acute versus chronic dosing, development of add-on therapies and understanding of the full dose–response relationship are too often neglected. Reducing the attrition rate in central nervous system drug development could be achieved by addressing these important questions before novel compounds enter the clinical phase. This review illustrates the relevance of employing these criteria to translational central nervous system research, better to ensure success in developing new drugs in this therapeutic area.
... We are also studying an active comparison agent: single doses of modafinil administered prior to the learning session. Modafinil is a wake agent used to treat sleep disorders, which offers cognitive enhancing effects among both sleep deprived and non-sleep deprived individuals [17][18][19][20][21], presumably by increasing glutamatergic and dopaminergic neuronal activation in the hippocampus and in the prefrontal cortex respectively [22]. There is some evidence for more reliable cognitive benefits with 100 mg modafinil compared to 200 mg modafinil in non-sleep deprived healthy adults [23]; hence, single doses of 100 mg modafinil was selected for the current study. ...
Despite the lack of guidance available for practitioners, extensive polypharmacy has become the primary method of treating patients with severe and chronic mood, anxiety, psychotic or behavioral disorders. This ground-breaking new book provides an overview of psychopharmacology knowledge and decision-making strategies, integrating findings from evidence-based trials with real-world clinical presentations. It adopts the approach and mind-set of a clinical investigator and reveals how prescribers can practice 'bespoke psychopharmacology', tailoring care to the individualized needs of patients. Practitioners at all levels of expertise will enhance their ability to devise rationale-based treatments, targeting manifestations of dysfunctional neural circuitry and dimensions of psychopathology that cut across conventional psychiatric diagnoses. Presented in a user-friendly, practical, full-colour layout and incorporating summary tables, bullet points, and illustrative case vignettes, it is an invaluable guide for all healthcare professionals prescribing psychotropic medications, including psychiatry specialists, primary care physicians, and advanced practice registered nurses.
Major depressive disorder (MDD) is the leading cause of disability globally in both developed and developing nations. The staggering economic costs attributable to MDD are largely a consequence of impairment in role function. Evidence indicates that disturbance in the domain of cognitive function in individuals with MDD is the principal determinant of health outcome. This is the first book to comprehensively explore the domain of cognition in MDD. The literature describing cognitive dysfunction is reviewed with particular focus on clinical determinants, pathophysiology and causative factors. The patient subpopulations most susceptible are defined. A summary of contemporary assessment tools for research and clinical purposes is provided. Multimodality treatments and prevention strategies are described. This book is an invaluable resource for psychiatrists, neuropsychologists and other members of the mental health team, as well as for policy makers, vocation rehabilitation experts, disability providers and other stakeholders interested in improving health outcomes in MDD.
Major depressive disorder (MDD) is the leading cause of disability globally in both developed and developing nations. The staggering economic costs attributable to MDD are largely a consequence of impairment in role function. Evidence indicates that disturbance in the domain of cognitive function in individuals with MDD is the principal determinant of health outcome. This is the first book to comprehensively explore the domain of cognition in MDD. The literature describing cognitive dysfunction is reviewed with particular focus on clinical determinants, pathophysiology and causative factors. The patient subpopulations most susceptible are defined. A summary of contemporary assessment tools for research and clinical purposes is provided. Multimodality treatments and prevention strategies are described. This book is an invaluable resource for psychiatrists, neuropsychologists and other members of the mental health team, as well as for policy makers, vocation rehabilitation experts, disability providers and other stakeholders interested in improving health outcomes in MDD.
Major depressive disorder (MDD) is the leading cause of disability globally in both developed and developing nations. The staggering economic costs attributable to MDD are largely a consequence of impairment in role function. Evidence indicates that disturbance in the domain of cognitive function in individuals with MDD is the principal determinant of health outcome. This is the first book to comprehensively explore the domain of cognition in MDD. The literature describing cognitive dysfunction is reviewed with particular focus on clinical determinants, pathophysiology and causative factors. The patient subpopulations most susceptible are defined. A summary of contemporary assessment tools for research and clinical purposes is provided. Multimodality treatments and prevention strategies are described. This book is an invaluable resource for psychiatrists, neuropsychologists and other members of the mental health team, as well as for policy makers, vocation rehabilitation experts, disability providers and other stakeholders interested in improving health outcomes in MDD.
Major depressive disorder (MDD) is the leading cause of disability globally in both developed and developing nations. The staggering economic costs attributable to MDD are largely a consequence of impairment in role function. Evidence indicates that disturbance in the domain of cognitive function in individuals with MDD is the principal determinant of health outcome. This is the first book to comprehensively explore the domain of cognition in MDD. The literature describing cognitive dysfunction is reviewed with particular focus on clinical determinants, pathophysiology and causative factors. The patient subpopulations most susceptible are defined. A summary of contemporary assessment tools for research and clinical purposes is provided. Multimodality treatments and prevention strategies are described. This book is an invaluable resource for psychiatrists, neuropsychologists and other members of the mental health team, as well as for policy makers, vocation rehabilitation experts, disability providers and other stakeholders interested in improving health outcomes in MDD.
Major depressive disorder (MDD) is the leading cause of disability globally in both developed and developing nations. The staggering economic costs attributable to MDD are largely a consequence of impairment in role function. Evidence indicates that disturbance in the domain of cognitive function in individuals with MDD is the principal determinant of health outcome. This is the first book to comprehensively explore the domain of cognition in MDD. The literature describing cognitive dysfunction is reviewed with particular focus on clinical determinants, pathophysiology and causative factors. The patient subpopulations most susceptible are defined. A summary of contemporary assessment tools for research and clinical purposes is provided. Multimodality treatments and prevention strategies are described. This book is an invaluable resource for psychiatrists, neuropsychologists and other members of the mental health team, as well as for policy makers, vocation rehabilitation experts, disability providers and other stakeholders interested in improving health outcomes in MDD.
Major depressive disorder (MDD) is the leading cause of disability globally in both developed and developing nations. The staggering economic costs attributable to MDD are largely a consequence of impairment in role function. Evidence indicates that disturbance in the domain of cognitive function in individuals with MDD is the principal determinant of health outcome. This is the first book to comprehensively explore the domain of cognition in MDD. The literature describing cognitive dysfunction is reviewed with particular focus on clinical determinants, pathophysiology and causative factors. The patient subpopulations most susceptible are defined. A summary of contemporary assessment tools for research and clinical purposes is provided. Multimodality treatments and prevention strategies are described. This book is an invaluable resource for psychiatrists, neuropsychologists and other members of the mental health team, as well as for policy makers, vocation rehabilitation experts, disability providers and other stakeholders interested in improving health outcomes in MDD.
Modafinil (MOD, 2‐diphenyl‐methyl‐sulphinil‐2‐acetamide) is stimulant-like medicine used for the treatment of narcolepsy. Off-label uses include improving cognitive ability in the course of other diseases. This review aims to discuss findings demonstrating the memory and learning enhancing activity of MOD in experimental and clinical studies. We included behavioral evaluations alongside the effects of MOD at the cellular and molecular level. MOD in different animal disease models exerted beneficial effects on induced memory and learning impairment, which in some cases were accompanied by modulation of neurotransmitter pathways or neuroplastic capabilities, reducing oxidative stress, or expression of synaptic proteins. Individuals treated with MOD showed improvement of declined memory and learning skills in different conditions. In some participants, these effects were associated with regulation of brain activity, also confirmed by functional magnetic resonance imaging. Presented herein, data support the use of MOD in the treatment of memory and learning deficits in various disease conditions.
Substantial evidence, composed of drug mechanisms of action, in vivo testing, and epidemiological data, exists to support clinical testing of FDA-approved drugs for repurposing to the treatment of Alzheimer’s disease (AD). Licensed compound investigation can often proceed at a faster and more cost-effective manner than un-approved compounds moving through the drug pipeline. As the prevalence of AD increases with life expectancy, the current rise in life expectancy amalgamated with the lack of an effective drug for the treatment of AD unnecessarily burdens our medical system and is an urgent public health concern. The unfounded reluctance to examine repurposing existing drugs for possible AD therapy further impedes the possibility of improving the quality of patient lives with a terminal disease. This review summarizes some evidence which exists to suggest certain already-approved drugs may be considered for the treatment of AD and will perhaps encourage physicians to off-label prescribe these safe therapeutics.
Background:
People with schizophrenia have a range of different symptoms, including positive symptoms (hallucinations and delusions), negative symptoms (such as social withdrawal and lack of affect), and cognitive impairment. The standard medication for people with schizophrenia is antipsychotics. However, these medications may not be effective for all symptoms of schizophrenia, as cognitive and negative symptoms are usually hard to treat. Additional therapies or medications are available for the management of these symptoms. Modafinil, a wakefulness-promoting agent most frequently used in narcolepsy or shift work sleep disorder, is one intervention that is theorised to have an effect of these symptoms.
Objectives:
The primary objective of this review was to assess the effects of modafinil for people with schizophrenia or related disorders.
Search methods:
On 27 April 2015, 24 May 2017, and 31 October 2019, we searched the Cochrane Schizophrenia Group's register of trials, which is based on regular searches of CENTRAL, MEDLINE, Embase, AMED, BIOSIS, CINAHL, PsycINFO, PubMed, and registries of clinical trials. There are no language, time, document type, or publication status limitations for the inclusion of records in the register.
Selection criteria:
We selected all randomised controlled trials comparing modafinil with placebo or other treatments for people with schizophrenia or schizophrenia-spectrum disorders.
Data collection and analysis:
We independently extracted data from the included studies. We analysed dichotomous data using risk ratios (RR) and 95% confidence intervals (CI). We analysed continuous data using mean difference (MD) with a 95% CI. We used a random-effects model for the meta-analysis. We used GRADE to complete a 'Summary of findings' table and assessed risk of bias for the included studies.
Main results:
Eleven studies including a total of 422 participants contributed to data analyses. Most studies had a small population size (average 38 people per study) and were of short duration. We also detected a high risk of bias for selective outcome reporting in just under 50% of the trials. We therefore rated the overall methodological quality of the included studies as low. We considered seven main outcomes of interest: clinically important change in overall mental state, clinically important change in cognitive functioning, incidence of a clinically important adverse effect/event, clinically important change in global state, leaving the study early for any reason, clinically important change in quality of life, and hospital admission. All studies assessed the effects of adding modafinil to participants' usual antipsychotic treatment compared to adding placebo to usual antipsychotic treatment. Six studies found that adding modafinil to antipsychotic treatment may have little or no effect on overall mental state of people with schizophrenia, specifically the risk of worsening psychosis (RR 0.91, 95% CI 0.28 to 2.98; participants = 209; studies = 6, low-quality evidence). Regarding the effect of modafinil on cognitive function, the trials did not report clinically important change data, but one study reported endpoint scores on the MATRICS Consensus Cognitive Battery (MCCB): in this study we found no clear difference in scores between modafinil and placebo treatment groups (MD -3.10, 95% CI -10.9 to 4.7; participants = 48; studies = 1, very low-quality evidence). Only one study (N = 35) reported adverse effect/event data. In this study one serious adverse event occurred in each group (RR 0.84, 95% CI 0.06 to 12.42; participants = 35; studies = 1, very low-quality evidence). One study measured change in global state using the Clinical Global Impression - Improvement Scale. This study found that adding modafinil to antipsychotic treatment may have little or no effect on global state (RR 6.36, 95% CI 0.94 to 43.07, participants = 21; studies = 1, very low-quality evidence). Nine studies found that modafinil has no effect on numbers of participants leaving the study early (RR 1.26, 95% CI 0.63 to 2.52 participants = 357; studies = 9, moderate-quality evidence). None of the trials reported clinically important change in quality of life, but one study did report quality of life using endpoint scores on the Quality of Life Inventory, finding no clear difference between treatment groups (MD -0.2, 95% CI -1.18 to 0.78; participants = 20; studies = 1, very low-quality evidence). Finally, one study reported data for number of participants needing hospitalisation: one participant in each group was hospitalised (RR 0.84, 95% CI 0.06 to 12.42; participants = 35; studies = 1, very low-quality evidence).
Authors' conclusions:
Due to methodological issues, low sample size, and short duration of the clinical trials as well as high risk of bias for outcome reporting, most of the evidence available for this review is of very low or low quality. For results where quality is low or very low, we are uncertain or very uncertain if the effect estimates are true effects, limiting our conclusions. Specifically, we found that modafinil is no better or worse than placebo at preventing worsening of psychosis; however, we are uncertain about this result. We have more confidence that participants receiving modafinil are no more likely to leave a trial early than participants receiving placebo. However, we are very uncertain about the remaining equivocal results between modafinil and placebo for outcomes such as improvement in global state or cognitive function, incidence of adverse events, and changes in quality of life. More high-quality data are needed before firm conclusions regarding the effects of modafinil for people with schizophrenia or related disorders can be made.
Drug abuse and addiction are overwhelming health problems mainly during adolescence. Based on a previous study of our research group, the rats that received modafinil (MD) during the adolescence showed less preference for amphetamine (AMPH) in adulthood. Our current hypothesis is that MD will show beneficial effects against AMPH preference and abstinence symptoms during adolescence, a critical lifetime period when drug hedonic effects are more pronounced. We investigated the influence of MD pretreatment on AMPH preference in conditioned place preference (CPP) paradigm in adolescent rats and anxiety-like symptoms during drug withdrawal (48 h after the last AMPH dose) in elevated plus maze (EPM) task. Besides that, oxidative and molecular status were evaluated in the ventral tegmental area (VTA) and striatum. Our findings showed, as it was expected, that adolescent animals developed AMPH preference together with anxiety-like symptoms during the drug withdrawal while the MD pretreatment prevented those behaviors. Besides promoting benefits on reward parameters, MD was able to preserve VTA and striatum from oxidative damages. This was observed by the increased catalase activity and reduced generation of reactive species and lipid peroxidation, which were inversely modified by AMPH exposure. At molecular level, MD exerted an interesting modulatory activity on the VTA and induced an up-regulation in striatal dopaminergic targets (TH, DAT, D1R and D2R). So far, during the adolescence, MD presented beneficial behavioral outcomes that could be attributed to its modulatory activity on the striatal dopaminergic system in an attempt to maintain the adequate dopamine levels.
Objective:
Negative symptoms and cognitive deficits are main features of schizophrenia but with limited treatment options. Earlier studies have suggested that central nervous system (CNS) stimulants have a small effect on these domains, but with inconclusive results. As the first study to date, we aimed to investigate whether CNS stimulants improve naturalistic outcomes (psychiatric admissions and antipsychotic use) in patients with schizophrenia.
Methods:
By using extensive health registers all patients with schizophrenia and their use of CNS stimulants in Denmark were identified. Two models were used to investigate the effectiveness of CNS stimulants in patients with schizophrenia between 1995 and 2014; a mirror-image model with 605 individuals, using paired t tests and Wilcoxon signed rank tests, and a follow-up study with 789 individuals, using a conditional risk-set model.
Results:
CNS stimulants use was associated with a reduction in number of psychiatric admissions from 3.43 (95% CI = 2.86 to 4.01) to 2.62 (95% CI = 1.99 to 3.25) (P = .009), with a more pronounced reduction for women (mean difference: -1.37, 95% CI = -2.34 to -0.40, P = .006). Psychiatric bed-days were reduced by 40 (95% CI = 24.5 to 55.6, P < .001) for individuals with at least 1 admission before CNS stimulant use. In addition, the total amount of antipsychotic use (Defined Daily Dose [DDD]) was reduced (P = .001). The Hazard rate ratio in psychiatric admissions between women taking CNS stimulants compared to women not taking CNS stimulants was 0.77 (95% CI = 0.67 to 0.88).
Conclusion:
CNS stimulants may have clinical potentials for improving functional outcomes in patients with schizophrenia and randomized clinical studies evaluating this topic are warranted.
Study Objectives
To assess the effect of 200 mg of modafinil compared to placebo on alertness, neurobehavioral performance, and executive function during 4 consecutive simulated night shifts.
Design
Double-blind, randomized, parallel groups.
Setting
Sleep research facility.
Participants
32 male and female volunteers between the ages of 18 and 55 years.
Interventions
200 mg of modafinil or placebo given nightly on the 4 consecutive simulated night shifts.
Measurements and Results
Subjects were randomly assigned to 1 of the 2 treatment conditions, following medical, psychiatric, and polysomnographic screening. On 4 consecutive nights, subjects took study drug at 2200, and then from about 2300 to 0730 participated in a simulated night shift that included the Maintenance of Wakefulness Test, Psychomotor Vigilance Test, Digit Symbol Substitution Test, measures of subjective alertness, and multiple executive-function measures. At 0800, daytime sleep periods were recorded polysomnographically for 6 to 8 hours. Alertness—as measured by the MWT, vigilance and reaction time as indexed by Psychomotor Vigilance Test lapses, and slowest 10% of reaction times—and 3 executive-function tasks showed significant enhancement with modafinil versus placebo. Subjective sleepiness at night and some performance measures did not show consistent treatment differences. Daytime sleep showed minimal differences between conditions.
Conclusions
The physiologic sleepiness and neurobehavioral deficits that occurred during the hours of a typical night shift were clearly attenuated by modafinil. Modafinil also had beneficial effects on some measures of executive function.
Much experimental and clinical data suggest
that the pharmacological profile of modafinil, a newly discovered
waking substance, differs from those of amphetamine
and methylphenidate, two classical psychostimulants. The
brain targets on which modafinil acts to induce wakefulness,
however, remain unknown. A double-blind study using the
protooncogene c-fos as experimental marker in the cat was,
therefore, carried out to identify the potential target neurons
of modafinil and compare them with those for amphetamine
and methylphenidate. Cats were sacrificed after a single oral
administration of amphetamine, methylphenidate, or modafinil
at equivalent doses for wake induction (1, 2.5, or 5 mgykg,
respectively) and brain sections examined for Fos by immunocytochemistry.
Administration of either amphetamine or
methylphenidate evoked Fos-like immunoreactivity in a large
number of neurons in the striatum and whole cortex, especially
in the caudate nucleus and mediofrontal cortex, which
are known to be dopaminergic targets. In contrast, administration
of modafinil resulted in the labeling of few cells in these
structures, but did induce marked Fos labeling in neurons of
the anterior hypothalamic nucleus and adjacent areas. These
results provide evidence for the potential brain targets of
modafinil, which differ from those of amphetamine or methylphenidate,
and suggest that modafinil induces wakefulness
by mechanisms distinct from those of the two stimulants.
Schizophrenia is characterized by reality distortion, psychomotor poverty and cognitive disturbances. These characteristics contribute to a lesser social functioning and lower quality of life in patients with schizophrenia. It has been suggested that modafinil and its isomer armodafinil as an add-on strategy to antipsychotic treatment in patients with schizophrenia may improve cognitive functioning, attenuate fatigue, inactiveness and other negative functions as well as weight gain. In this paper we review the literature relevant to the question of whether modafinil and armodafinil are beneficial as add-on therapy in antipsychotic-treated patients with schizophrenia. A total of 15 articles were included in this review; of the 15 articles, 10 were randomized controlled trials (RCTs). Evidence for the use of modafinil or armodafinil as add-on therapy to antipsychotic drugs to alleviate fatigue, sleepiness and inactivity is inconclusive. One cohort study and one out of two single-dose crossover RCTs in which modafinil addition was studied could demonstrate a positive effect. All five RCTs of modafinil (three RCTs) and armodafinil (two RCTs) addition with a longer study duration could not demonstrate a positive effect. With respect to cognitive disturbances, animal models of cognitive deficits show clear improvements with modafinil. In RCTs with a treatment duration of 4 weeks or more, however, no positive effect could be demonstrated on cognitive functioning with modafinil and armodafinil addition. Yet, four single-dose crossover RCTs of modafinil addition show significant positive effects on executive functioning, verbal memory span, visual memory, working memory, spatial planning, slowing in latency, impulse control and recognition of faces expressing sadness and sadness misattribution in the context of disgust recognition. The addition of modafinil or armodafinil to an antipsychotic regime, despite theoretical and preclinical considerations, has not been proved to enhance cognitive function, attenuate fatigue, enhance activity, improve negative symptoms and reduce weight in patients with schizophrenia.
Rationale
The discriminative stimulus properties of the atypical antipsychotic drug (APD) clozapine (CLZ) have recently been studied in C57BL/6 mice, a common background strain for genetic alterations. However, further evaluation is needed to fully characterize CLZ’s discriminative cue in this strain of mice.
Objectives
The objectives of the study were to confirm the previous findings using a shorter pretreatment time and to further characterize the receptor mechanisms mediating the discriminative stimulus properties of CLZ by testing APDs, selective ligands, and N-desmethylclozapine (CLZ’s major metabolite) in C57BL/6 mice.
Materials and methods
C57BL/6 male mice were trained to discriminate 2.5 mg/kg CLZ (s.c.) from vehicle in a two-lever drug discrimination task.
Results
Generalization testing with CLZ yielded an ED50 = 1.19 mg/kg. Substitution testing with APDs showed that the atypical APDs quetiapine, sertindole, zotepine, iloperidone, and melperone fully substituted for CLZ (≥80% CLZ-appropriate responding), but aripiprazole did not. The typical APDs chlorpromazine and thioridazine substituted for CLZ (fluphenazine and perphenazine did not). The serotonin (5-HT) 2A antagonist M100907 and the α1-adrenoceptor antagonist prazosin fully substituted for CLZ. The H1 histaminergic antagonist pyrilamine, dopamine agonist amphetamine, and the selective serotonin reuptake inhibitor fluoxetine did not substitute for CLZ. While N-desmethylclozapine did not substitute for CLZ when tested alone, N-desmethylclozapine plus a low dose of CLZ combined in an additive manner produced full substitution.
Conclusions
CLZ’s discriminative cue in C57BL/6 mice is a “compound” cue mediated in part by antagonism of 5-HT2A and α1 receptors.
This study evaluated (a) whether chronic, medicated schizophrenia patients show deficits in emotion recognition compared to nonpatients, and (b) whether deficits in emotion recognition are related to poorer social competence. Two emotion recognition tests developed by S. L. Kerr and J. M. Neale (1993) and Benton's Test of Facial Recognition (A. Benton, M. VanAllen, K. Hamsher, & H. Levin, 1978) were given to patients with chronic schizophrenia and nonpatient controls. Patients' social skills, social adjustment, and symptomatology were assessed. Like Kerr and Neale's unmedicated patients, these patients performed worse than controls on both emotion recognition tests and the control test. For patients, facial perception was related to the chronicity of illness and social competence. Chronicity of illness may contribute to face perception deficits in schizophrenia, which may affect social competence. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Modafinil is a waking drug prescribed to narcolepsy patients, but its usage among healthy individuals is increasing to enhance their alertness or to mitigate fatigue. This study was conducted to investigate practical use and toxic effects on neuro-immune interaction of modafinil.
This study reviewed the significance of psychoactive drugs, and discussed the benefits and risks of the application of modafinil, which seems to be ideal as an anti-psychotic or anti-fatigue agent.
Modafinil is known to have less or no adverse effects than those found in traditional psychostimulants such as amphetamine, methylphenidate or cocaine. It can be applied as an anti-psychotic or anti-fatigue agent. However, the waking mechanism of modafinil is yet to be fully revealed. Recent studies reported that modafinil may be subject to abuse and addiction. In addition prolonged sleeplessness induces stress responses and impairs immune function.
Modafinil can be used by anyone, who wishes to work late, stay awake, enhance their cognitive reactions, or brighten their moods. Users may already be under a great level of stress, i.e. cancer patients or soldiers in a battle field. A psychoneuroimmunological approach is thus needed to investigate the multi-functional effects of modafinil.
Selective serotonin reuptake inhibitors (SSRIs) are typically thought to have a delay of several weeks in the onset of their clinical effects. However, recent reports suggest they may have a much earlier therapeutic onset. A reduction in amygdala responsivity has been implicated in the therapeutic action of SSRIs.
To investigate the effect of a single dose of an SSRI on the amygdala response to emotional faces.
Twenty-six healthy volunteers were randomised to receive a single oral dose of citalopram (20 mg) or placebo. Effects on the processing of facial expressions were assessed 3 h later using functional magnetic resonance imaging.
Volunteers treated with citalopram displayed a significantly reduced amygdala response to fearful facial expressions compared with placebo.
Such an immediate effect of an SSRI on amygdala responses to threat supports the idea that antidepressants have an earlier onset of therapeutically relevant effects than conventionally thought.
Individuals who are methamphetamine dependent exhibit higher rates of cognitive dysfunction than healthy people who do not use methamphetamine, and this dysfunction may have a negative effect on the success of behavioral treatments for the disorder. Therefore, a medication that improves cognition, such as modafinil (Provigil), may serve as a useful adjunct to behavioral treatments for methamphetamine dependence. Although cognitive-enhancing effects of modafinil have been reported in several populations, little is known about the effects of modafinil in methamphetamine-dependent individuals. We thus sought to evaluate the effects of modafinil on the cognitive performance of methamphetamine-dependent and healthy individuals.
Seventeen healthy subjects and 24 methamphetamine- dependent subjects participated in this randomized, double-blind, placebo-controlled, crossover study. Effects of modafinil (200 mg, single oral dose) were assessed on participants' performance on tests of inhibitory control, working memory, and processing speed/attention.
Across subjects, modafinil improved performance on a test of sustained attention, with no significant improvement on any other cognitive tests. However, within the methamphetamine-dependent group only, participants with a high baseline frequency of methamphetamine use demonstrated a greater effect of modafinil on tests of inhibitory control and processing speed than those participants with low baseline use of methamphetamine.
Although modafinil produced limited effects across all participants, methamphetamine-dependent participants with a high baseline use of methamphetamine demonstrated significant cognitive improvement on modafinil relative to those with low baseline methamphetamine use. These results add to the findings from a clinical trial that suggested that modafinil may be particularly useful in methamphetamine-dependent subjects who use the drug frequently.
Modafinil (MOD) is a wake-promoting drug with pro-cognitive properties. Despite its increasing use, the neuronal substrates of MOD action remain elusive. In particular, animal studies have highlighted a putative role of diencephalic areas as primary neuronal substrate of MOD action, with inconsistent evidence of recruitment of fronto-cortical areas despite the established pro-cognitive effects of the drug. Moreover, most animal studies have employed doses of MOD of limited clinical relevance. We used pharmacological magnetic resonance imaging (phMRI) in the anesthetized rat to map the circuitry activated by a MOD dose producing clinically relevant plasma exposure, as here ascertained by pharmacokinetic measurements. We observed prominent and sustained activation of the prefrontal and cingulate cortex, together with weaker but significant activation of the somatosensory cortex, medial thalamic domains, hippocampus, ventral striatum and dorsal raphe. Correlation analysis of phMRI data highlighted enhanced connectivity within a neural network including dopamine projections from the ventral tegmental area to the nucleus accumbens. The pro-arousing effect of MOD was assessed using electroencephalographic recording under anesthetic conditions comparable to those used for phMRI, together with the corresponding Fos immunoreactivity distribution. MOD produced electroencephalogram desynchronization, resulting in reduced delta and increased theta frequency bands, and a pattern of Fos induction largely consistent with the phMRI study. Altogether, these findings show that clinically relevant MOD doses can robustly activate fronto-cortical areas involved in higher cognitive functions and a network of pro-arousing areas, which provide a plausible substrate for the wake-promoting and pro-cognitive effects of the drug.
To investigate the effect of modafinil 200 mg on the performance of a cohort of healthy male doctors after 1 night of supervised sleep deprivation.
Sleep-deprived and fatigued doctors pose a safety risk to themselves and their patients. Yet, because of the around-the-clock nature of medical practice, doctors frequently care for patients after periods of extended wakefulness or during circadian troughs. Studies suggest that a group of substances may be capable of safely and effectively reversing the effects of fatigue. However, little work has been done to investigate their role within our profession.
We conducted a parallel, double-blind, randomized, and placebo-controlled study to investigate the effect of pharmacological enhancement on performance doctors. Thirty-nine healthy male resident doctors received either lactose placebo (n = 19) or modafinil 200 mg (n = 20) after 1 night of sleep deprivation. A selection of CANTAB neuropsychological tests was used to assess higher cognitive function. Clinical psychomotor performance was assessed using the Minimally Invasive Surgical Trainer Virtual Reality. Assessments were carried out between 6.00 AM and approximately 8.00 AM.
Modafinil improved performance on tests of higher cognitive function; participants in the modafinil group worked more efficiently when solving working memory (F1,38 = 5.24, P = 0.028) and planning (F1,38 = 4.34, P = 0.04) problems, were less-impulsive decision makers (F1,37 = 6.76, P = 0.01), and were more able to flexibly redirect their attention (F1,38 = 4.64, P = 0.038). In contrast, no improvement was seen in tests of clinical psychomotor performance.
Our results suggest that fatigued doctors might benefit from pharmacological enhancement in situations that require efficient information processing, flexible thinking, and decision making under time pressure. However, no improvement is likely to be seen in the performance of basic procedural tasks.
Cognitive impairments are important determinants of functional outcome in psychosis, which are inadequately treated by antipsychotic medication. Modafinil is a wake-promoting drug that has been shown to improve attention, memory and executive function in the healthy population and in patients with schizophrenia.
We aimed to establish modafinil's role in the adjunctive treatment of cognitive impairments in the first episode of psychosis, a time when symptoms may be more malleable than at chronic stages of the disease.
Forty patients with a first episode of psychosis participated in a randomised, double-blind, placebo-controlled crossover design study assessing the effects of a single dose of 200 mg modafinil on measures of executive functioning, memory, learning, impulsivity and attention.
Modafinil improved verbal working memory (d = 0.24, p = 0.04), spatial working memory errors (d = 0.30, p = 0.0004) and strategy use (d = 0.23, p = 0.03). It also reduced discrimination errors in a task testing impulsivity. Modafinil showed no effect on impulsivity measures, sustained attention, attentional set-shifting, learning or fluency.
Modafinil selectively enhances working memory in first episode psychosis patients, which could have downstream effects on patients' social and occupational functioning.
Methamphetamine (MA)-dependent individuals exhibit deficits in cognition and prefrontal cortical function. Therefore, medications that improve cognition in these subjects may improve the success of therapy for their addiction, especially when cognitive behavioral therapies are used. Modafinil has been shown to improve cognitive performance in neuropsychiatric patients and healthy volunteers. We therefore conducted a randomized, double-blind, placebo-controlled, cross-over study, using functional magnetic resonance imaging, to examine the effects of modafinil on learning and neural activity related to cognitive function in abstinent, MA-dependent, and healthy control participants. Modafinil (200 mg) and placebo were administered orally (one single dose each), in counterbalanced fashion, 2 h before each of two testing sessions. Under placebo conditions, MA-dependent participants showed worse learning performance than control participants. Modafinil boosted learning in MA-dependent participants, bringing them to the same performance level as control subjects; the control group did not show changes in performance with modafinil. After controlling for performance differences, MA-dependent participants showed a greater effect of modafinil on brain activation in bilateral insula/ventrolateral prefrontal cortex and anterior cingulate cortices than control participants. The findings suggest that modafinil improves learning in MA-dependent participants, possibly by enhancing neural function in regions important for learning and cognitive control. These results suggest that modafinil may be a suitable pharmacological adjunct for enhancing the efficiency of cognitive-based therapies for MA dependence.
The default mode network (DMN) is a functional network which is implicated in a range of cognitive processes. This network is proposed to consist of hubs located in the ventromedial prefrontal cortex (vmPFC), posterior cingulate/retrosplenial cortex (PCC/rSpl), and inferior parietal lobule (IPL), with other midline cortical and temporal lobe nodes connected to these hubs. How this network is modulated by neurochemical systems during functional brain activity is not yet understood.
In the present study, we used the norepinephrine/dopamine transporter inhibitor modafinil to test the hypothesis that this drug modulates the DMN.
Eighteen healthy right-handed adults participated in a double-blind, placebo-controlled study of single oral dose modafinil 200 mg. They performed a simple visual sensorimotor task during slow event-related fMRI. Drug effects were interrogated within the DMN defined by task-induced deactivation (TID) on placebo.
There was a trend toward faster reaction time (RT) on modafinil (Cohen's d = 0.38). Brain regions within the DMN which exhibited significant modafinil-induced augmentation of TID included vmPFC, PCC/rSpl, and left IPL. Across subjects, the modafinil effect on TID in the vmPFC was significantly and specifically associated with drug effects on RT speeding.
Modafinil augments TID in the DMN to facilitate sensorimotor processing speed, an effect which may be particularly dependent on changes in vmPFC activity. This is consistent with the gain control function of catecholamine systems and may represent an important aspect of the pro-cognitive effects of modafinil.
In the present study, we employ mathematical modeling (partial least squares regression, PLSR) to elucidate the functional connectivity signatures of discrete brain regions in order to identify the functional networks subserving PCP-induced disruption of distinct cognitive functions and their restoration by the procognitive drug modafinil.
We examine the functional connectivity signatures of discrete brain regions that show overt alterations in metabolism, as measured by semiquantitative 2-deoxyglucose autoradiography, in an animal model (subchronic phencyclidine [PCP] treatment), which shows cognitive inflexibility with relevance to the cognitive deficits seen in schizophrenia.
We identify the specific components of functional connectivity that contribute to the rescue of this cognitive inflexibility and to the restoration of overt cerebral metabolism by modafinil. We demonstrate that modafinil reversed both the PCP-induced deficit in the ability to switch attentional set and the PCP-induced hypometabolism in the prefrontal (anterior prelimbic) and retrosplenial cortices. Furthermore, modafinil selectively enhanced metabolism in the medial prelimbic cortex. The functional connectivity signatures of these regions identified a unifying functional subsystem underlying the influence of modafinil on cerebral metabolism and cognitive flexibility that included the nucleus accumbens core and locus coeruleus. In addition, these functional connectivity signatures identified coupling events specific to each brain region, which relate to known anatomical connectivity.
These data support clinical evidence that modafinil may alleviate cognitive deficits in schizophrenia and also demonstrate the benefit of applying PLSR modeling to characterize functional brain networks in translational models relevant to central nervous system dysfunction.
Modafinil differs from other arousal-enhancing agents in chemical structure, neurochemical profile, and behavioral effects. Most functional neuroimaging studies to date examined the effect of modafinil only on information processing underlying executive cognition, but cognitive enhancers in general have been shown to have pronounced effects on emotional behavior, too. We examined the effect of modafinil on neural circuits underlying affective processing and cognitive functions. Healthy volunteers were enrolled in this double-blinded placebo-controlled trial (100 mg/day for 7 days). They underwent BOLD fMRI while performing an emotion information-processing task that activates the amygdala and two prefrontally dependent cognitive tasks-a working memory (WM) task and a variable attentional control (VAC) task. A clinical assessment that included measurement of blood pressure, heart rate, the Hamilton anxiety scale, and the profile of mood state (POMS) questionnaire was also performed on each test day. BOLD fMRI revealed significantly decreased amygdala reactivity to fearful stimuli on modafinil compared with the placebo condition. During executive cognition tasks, a WM task and a VAC task, modafinil reduced BOLD signal in the prefrontal cortex and anterior cingulate. Although not statistically significant, there were trends for reduced anxiety, for decreased fatigue-inertia and increased vigor-activity, as well as decreased anger-hostility on modafinil. Modafinil in low doses has a unique physiologic profile compared with stimulant drugs: it enhances the efficiency of prefrontal cortical cognitive information processing, while dampening reactivity to threatening stimuli in the amygdala, a brain region implicated in anxiety.
Models of cognitive control posit a key modulatory role for the pontine locus coeruleus-norepinephrine (LC-NE) system. In nonhuman primates, phasic LC-NE activity confers adaptive adjustments in cortical gain in task-relevant brain networks, and in performance, on a trial-by-trial basis. This model has remained untested in humans. We used the pharmacological agent modafinil to promote low-tonic/high-phasic LC-NE activity in healthy humans performing a cognitive control task during event-related functional magnetic resonance imaging (fMRI). Modafanil administration was associated with decreased task-independent, tonic LC activity, increased task-related LC and prefrontal cortex (PFC) activity, and enhanced LC-PFC functional connectivity. These results confirm in humans the role of the LC-NE system in PFC function and cognitive control and suggest a mechanism for therapeutic action of procognitive noradrenergic agents.
Countries must learn how to capitalize on their citizens' cognitive resources if they are to prosper, both economically and socially. Early interventions will be key.
In first-episode schizophrenia, longer duration of untreated psychosis (DUP) predicts poorer outcomes.
To address whether the relationship between DUP and outcome is a direct causal one or the result of association between symptoms and/or cognitive functioning and social functioning at the same time point.
Symptoms, social function and cognitive function were assessed in 98 patients with first-episode schizphrenia at presentation and 1 year later.
There was no significant clinical difference between participants with short and long DUP at presentation. Linear regression analyses revealed that longer DUP significantly predicted more severe positive and negative symptoms and poorer social function at 1 year, independent of scores at presentation. Path analyses revealed independent direct relationships between DUP and social function, core negative symptoms and positive symptoms. There was no significant association between DUP and cognition.
Longer DUP predicts poor social function independently of symptoms. The findings underline the importance of taking account of the phenomenological overlap between measures of negative symptoms and social function when investigating the effects of DUP.
Theta/alpha spectral powers ratio was used to quantify physiological decrease of vigilance occurring after 5 min recording eyes closed, at different times of the day, in normal volunteers with ‘high alpha’. Maximum decrease of vigilance occurred at about 2 or 4 p.m. Theta/alpha ratio fluctuations were similar on the homologous right and left scalp areas. This ratio is useful in psychopharmacology to quantify the antagonist activity of a CNS stimulant drug on the physiological decrease of vigilance after 5 min as well as the sedative effect of a drug. It allows to follow the kinetics of the drug action at receptor level.
THE antinarcoleptic drug modafinil [(diphenyl-methyl)sulfinyl-2-acetamide; Modiodal] dose-dependently inhibits the activity of GABA neurons in the cerebral cortex and in the nucleus accumbens, as well as in sleep-related brain areas such as the medial preoptic area and the posterior hypothalamus. This study examined the effects of modafinil (30-300 mg/kg, i.p.) on dialysate glutamate and GABA levels in the ventromedial (VMT) and ventrolateral (VLT) thalamus and hippocampal formation (Hip) of the awake rat. The results show a maximal increase in glutamate release in these brain regions at the 100 mg/kg dose, associated with a lack of effect on GABA release. Thus modafinil may increase excitatory glutamatergic transmission in these regions, altering the balance between glutamate and GABA transmission.
Objectives:
Modafinil has recently been approved for the treatment of shift work sleep disorder, making it potentially available for shift-working emergency physicians. The authors' objectives were to determine whether modafinil improved cognitive performance of emergency physicians following overnight shifts and to record symptoms and subjective evaluations of the effect of modafinil on the participants.
Methods:
This was a randomized, double-blind, placebo-controlled crossover study that followed CONSORT guidelines. Participants were assigned to one of two study groups, with study sessions occurring at least seven weeks apart, and received either modafinil or placebo depending on their random allocation. Testing after night shifts included a coding task and an AX version of the Continuous Performance Task, both of which test cognitive function. Participants also completed visual analog scales for three subjective outcomes, and symptoms were elicited.
Results:
Modafinil facilitated performance on long interstimulus-interval AX trials (F [1, 23] = 6.65, p = 0.1) and marginally reduced errors on AY trials in the Continuous Performance Task (F [1, 23] = 3.59, p = 0.07), suggesting facilitation of sustained attention, cognitive control, and working memory. Additionally, modafinil, compared with placebo, facilitated performance on the coding task at the first session. Subjective data from visual analog scales confirmed that modafinil increased perceived alertness during the simulated patient care sessions but worsened sleep onset when opportunities for sleep arose.
Conclusions:
Modafinil increased certain aspects of cognitive function and subjectively improved participants' ability to attend post-night-shift didactic sessions but made it more difficult for participants to fall asleep when opportunities for sleep arose.
The effect of modafinil on endogenous γ-aminobutyric acid (GABA) release in the medial preoptic area (MPA) and posterior hypothalamus (PH) and the role of local 5-HT3 receptors in this effect was investigated in the awake rat using in vivo microdialysis. Modafinil (30–100 mg/kg i.p.) dose-dependently decreased GABA release from the MPA, while only the 100 mg/kg dose markedly reduced GABA release in the PH. The modafinil (100 mg/kg) induced inhibition of GABA release in the MPA and the PH was partially counteracted by the 5-HT3 receptor antagonist MDL72222 (1 μM) when perfused locally alone or together with the non-selective 5-HT receptor antagonist methysergide (1 μM). Thus, the reduction of GABA transmission induced by modafinil in the MPA and in the PH, at least in part, involves local 5-HT3 receptors. The GABA release inhibition by modafinil in the above areas may be relevant for its vigilance promoting action.
The acute or chronic administration of modafinil, (diphenyl-methyl-sulfinyl-2-acetamide, 30 mg/kg s.c.) decreased γ-aminobutyric acid (GABA) outflow from the cerebral cortex of freely moving guinea pigs and rats. In 5,7-dihydroxytryptamine intracerebroventricularly pretreated guinea pigs, the effect of modafinil on GABA outflow was reversed and the noradrenaline cortical levels increased. Prazosin (35,8 ng/kg i.p.) blocked the drug-induced increase in GABA efflux. In vitro experiments, performed in rat cortical slices, showed that modafinil failed to affect [3H]GABA release and uptake as well as glutamic acid decarboxylase activity. In conclusion, our results suggest that the balance between central noradrenaline and 5-hydroxytryptamine transmission is important for the regulation by modafinil of the GABAergic release in the cerebral cortex.
Previous work showed that sleep deprivation (SD) impairs hippocampal-dependent cognitive function and synaptic plasticity, and a novel wake-promoting agent modafinil prevents SD-induced memory impairment in rat. However, the mechanisms by which modafinil prevented REM-SD-induced impairment of brain function remain poorly understood. In the present study, rats were sleep-deprived by using the modified multiple platform method and brain function was detected. The results showed that modafinil treatment prevented REM-SD-induced impairment of cognitive function. Modafinil significantly reduced the number of errors compared to placebo and upregulated synapsin I expression in the dorsal hippocampal CA3 region. A synaptic plasticity-related gene, MMP-9 expression was also upregulated in modafinil-treated rats. Importantly, downregulation of MMP-9 expression by special siRNA decreased synapsin I protein levels and synapse numbers. Therefore, we demonstrated that modafinil increased cognition function and synaptic plasticity, at least in part by increasing MMP-9 expression in REM-SD rats.
In recent years, evidence suggests that modafinil may be useful for certain symptom domains of schizophrenia, especially for the negative and cognitive symptoms. However, the results are not consistent.
This study was designed to investigate the effect of modafinil added to risperidone in patients with chronic schizophrenia in a double blind and randomized clinical trial.
Participants were inpatients males (35) and females (11), ages 20-49 years at two teaching psychiatric hospital in Iran. All patients were in the active phase of the illness and met DSM-IV-TR criteria for schizophrenia. Patients were allocated in a random fashion 23 patients to risperidone 6 mg/day plus modafinil 200 mg/day and 23 patients to risperidone 6 mg/day plus placebo. The principal measure of outcome was the positive and negative syndrome scale (PANSS). Patients were assessed by a psychiatrist at baseline and after 2, 4, 6 and 8 weeks after the start of medication.
The modafinil group had significantly greater improvement in the negative symptoms as well as PANSS total scores over the 8-week trial. Therapy with 200 mg/day of modafinil was well tolerated and no clinically important side effects were observed.
The present study indicates modafinil as a potential adjunctive treatment strategy for treatment of schizophrenia particularly the negative symptoms. Nevertheless, results of larger-controlled trials are needed before recommendation for broad clinical application can be made.
The basis of the unique clinical profile of the antipsychotic clozapine is not yet elucidated. Brain histamine receptors may play a role in schizophrenia and its treatment, but their involvement in the profile of clozapine remained unknown.
We explored the properties of clozapine and its two metabolites, N-desmethylclozapine (NDMC) and clozapine N-oxide, at the four human histaminergic receptors. We compared their active concentrations with their blood concentrations in patients treated by clozapine. We investigated the changes in receptor densities induced in rat brain by repeated administration of a therapeutic dose of clozapine.
Clozapine and NDMC behaved as very potent, and partial, H(1)-receptor inverse agonists, weak, and full, H(2)-receptor inverse agonists, moderate, and protean, H(3)-receptor agonists, and moderate, and partial, H(4)-receptor agonists. Taking into account their micromolar mean blood concentrations found in 75 treated patients, and assuming that they are enriched in human brain as they are in rat brain, a full occupation of H(1)-, H(3)-, and H(4)-receptors, and a partial occupation of H(2) receptors, is expected. In agreement, repeated administration of clozapine at a therapeutic dose (20 mg/kg/day for 20 days) induced an up-regulation of H(1)- and H(2)-receptors in rat brain.
Clozapine and its active metabolite NDMC interact with the four human histamine receptors at clinically relevant concentrations. This interaction may substantiate, at least in part, the atypical antipsychotic profile of clozapine, as well as its central and peripheral side effects such as sedation and weight gain.
Modafinil is an alerting substance that is considered safer than amphetamine with fewer side effects. Although modafinil has been used successfully to treat narcolepsy, relatively little is known about its ability to ameliorate fatigue and declines in mental performance due to sleep deprivation (SD) in a normal population. Forty-one military subjects received either 300 mg of modafinil, 20 mg of d-amphetamine, or placebo on 3 separate occasions during 64 hours of continuous cognitive work and sleep loss. Three drug treatments were given: at 23.30 hours and 05.30 hours during the first and second SD nights, respectively, and once at 15.30 hours during the third day of continuous work. Subjective estimates of mood, fatigue and sleepiness, as well as objective measures of reaction time, logical reasoning and short-term memory clearly showed better performance with both modafinil and amphetamine relative to placebo. Both modafinil and amphetamine maintained or increased body temperature compared to the natural circadian cycle observed in the placebo group. Also, from subject debriefs at the end of the study, modafinil elicited fewer side-effects than amphetamine, although more than the placebo group. Modafinil appears to be a good alternative to amphetamine for counteracting the debilitating mood and cognitive effects of sleep loss during sustained operations.
We examined the neuronal targets in the rat brain for the novel wakefulness-promoting agent modafinil and for amphetamine using c-Fos immunohistochemistry. Both modafinil and amphetamine induced neuronal expression of c-Fos-like immunoreactivity in the paraventricular nucleus of the hypothalamus, anterior hypothalamus and central nucleus of the amygdala. Modafinil also increased c-Fos-like immunoreactivity in the suprachiasmatic nucleus, while amphetamine had no effect. Brain regions in which amphetamine increased c-Fos-like immunoreactivity, but modafinil had no effect, included frontal cortex, striatum, lateral habenula, supraoptic nucleus and basolateral nucleus of the amygdala. These findings suggest that the mechanism of action of modafinil is different from that of amphetamine and that the neuronal targets for modafinil in the brain include nuclei of the hypothalamus and amygdala.
Clinical studies have indicated that the primary pharmacological activity of modafinil (MOD) is inducing wakefulness; however, the brain targets that underlie its wake-promoting activity have not been described. In the present study, we show that MOD injected into sleep-wake related brain areas promoted alertness. If administered (10, 20, or 30 μg/1 μL) into either anterior hypothalamus (AH) or pedunculopontine tegmental nucleus (PPTg) at 08:00, 12:00 or 16:00 h, MOD enhanced wakefulness whereas diminished slow wave sleep as well as rapid eye movement sleep. In addition, microinjection of MOD (10, 20, or 30 μg/1 μL) either into AH or PPTg after total sleep deprivation prevented the sleep rebound. Taken together, these observations suggest that AH and PPTg play a key role in the wake-inducing effects of MOD and encourage further experimentation to draw a possible mechanism of action.
Modafinil, a psychostimulant, is used in the treatment of narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea. Preclinical and clinical studies suggest that modafinil may have reinforcing effects. However, a possible rewarding property of modafinil has not been fully investigated. In this study, we assessed the potential rewarding property of modafinil using the conditioned place preference (CPP) paradigm in mice. Using radiolabeled ligands, we observed changes in dopamine, glutamate, and GABA receptor binding in the brains of mice after treatment with modafinil. Modafinil produced significant CPP in mice at an intraperitoneal (i.p.) dose of 125 mg kg⁻¹ and prevented normal body weight gain of mice in a dose-dependent manner. A significant reduction in normal body weight gain was observed when mice were administrated 125 mg kg⁻¹ modafinil. In addition, there were widespread changes in receptor binding in the brains of modafinil-treated mice; Dopamine D₁ binding was increased in the caudate putamen, the accumbens, and the substantia nigra, while dopamine D₂ binding was decreased in the caudate putamen and the accumbens. Dopamine transporter (DAT) binding was increased in the prefrontal cortex, the caudate putamen, and the nucleus accumbens. No changes were observed in NMDA and GABA(A) receptor binding. These data indicate that modafinil had a significant rewarding property and could be abused as a recreational drug. Dopamine systems may play a key role in the rewarding property of modafinil.
Emotional impairments are important determinants of functional outcome in psychosis, and current treatments are not particularly effective. Modafinil is a wake-promoting drug that has been shown to improve emotion discrimination in healthy individuals and attention and executive function in schizophrenia. We aimed to establish whether modafinil might have a role in the adjuvant treatment of emotional impairments in the first episode of psychosis, when therapeutic endeavor is arguably most vital.
Forty patients with a first episode of psychosis participated in a randomized, double-blind, placebo-controlled crossover design study testing the effects of a single dose of 200 mg modafinil on neuropsychological performance. Emotional functions were evaluated with the emotional face recognition test, the affective go-no go task, and the reward and punishment learning test. Visual analogue scales were used throughout the study to assess subjective mood changes.
Modafinil significantly improved the recognition of sad facial expressions (z = 2.98, p = .003). In contrast, there was no effect of modafinil on subjective mood ratings, on tasks measuring emotional sensitivity to reward or punishment, or on interference of emotional valence on cognitive function, as measured by the affective go-no go task.
Modafinil improves the analysis of emotional face expressions. This might enhance social function in people with a first episode of psychosis.
Modafinil is a drug used to treat hypersomnolence of narcolepsy. We previously reported that modafinil increases hypothalamic histamine release in rats but did not increase locomotor activity in histamine-depleted mice, suggesting that modafinil-induced locomotor activity involves the histaminergic system. Modafinil is also thought to express its effect through the orexinergic neurons, and orexin increases hypothalamic histamine release. These findings led us to investigate whether modafinil activates the histaminergic system via the orexinergic system. In the present study, we performed in vivo microdialysis and c-Fos immunohistochemistry to investigate whether the orexinergic system mediates the activation of the histaminergic system by modafinil using orexin neuron-deficient mice. Two hours after the injection, modafinil (150 mg/kg) caused a significant increase of histamine release compared to the basal release in wild type mice. However, modafinil had no effect on the histamine release in orexin neuron-deficient mice. By immunohistochemical study, we found that there was no neuronal activation in the tuberomammillary nucleus where the cell bodies of the histaminergic neurons exclusively exist in orexin neuron-deficient mice. These findings indicate that modafinil-induced increment of histamine release requires intact orexinergic neurons.
Modafinil is currently used as a treatment for daytime sleepiness.
The objectives of this study were to explore the dopamine transporter (DAT)-related effects of modafinil on behavior and in vivo neurochemistry in rhesus monkeys (Macaca mulatta).
The effects of modafinil (3.0-10 mg/kg, i.v.) were evaluated on locomotor activity, reinstatement of cocaine-maintained behavior, extracellular dopamine levels in the caudate nucleus, and DAT occupancy in the dorsal striatum. Eight subjects were fitted with a collar-mounted activity monitor to evaluate sleep-activity cycles, with 4 days of baseline recording preceding an injection of saline or modafinil (3.0-10 mg/kg). The effects of modafinil (3.0-10 mg/kg) and cocaine (0.3 mg/kg) on reinstatement of behavior that was previously maintained under a second-order schedule of i.v. cocaine delivery were tested in a separate group of subjects (n = 6). Finally, the effects of modafinil (3.0-10 mg/kg) on extracellular dopamine levels and DAT occupancy in vivo were characterized using microdialysis and positron emission tomography, respectively, in a within-subjects design (n = 4).
Modafinil significantly increased nighttime locomotor activity and reinstated cocaine-maintained behavior but did not affect daytime locomotor activity. Modafinil significantly increased striatal extracellular dopamine levels at a dose that resulted in DAT occupancy of 64.4% (putamen) and 60.2% (caudate).
The behavioral and in vivo dopaminergic effects of modafinil are consistent with the profile of a low potency DAT inhibitor and may indicate potential for abuse at high doses.
Modafinil is a psychostimulant drug used widely for the treatment of narcolepsy, which also has additional positive effects on cognition. Here, we investigate the effects of modafinil on behavioural performance and synaptic plasticity in rats. Improved acquisition in the water maze task was observed in animals that underwent chronic treatment with modafinil. We found that the distance traveled and escape latency were reduced after the first day in chronically-treated rats, compared to controls. Importantly, swim velocity was similar for both groups, excluding pharmacological effects on motor skills. We also found that modafinil increases synaptic plasticity in the dentate gyrus of urethane-anaesthetized rats; modafinil induced a robust augmentation of the population spike, evident after application of 2 bursts of 200 Hz high-frequency stimulation. Furthermore, the modafinil-dependent enhancement of postsynaptic potentials correlated selectively with theta rhythm augmentation. We propose that modafinil may facilitate hippocampal-associated spatial representation via increased theta-related hippocampal plasticity.
Patients with schizophrenia often suffer from cognitive deficits and negative symptoms that are poorly responsive to antipsychotics including clozapine. Clozapine-induced sedation can worsen cognition and impair social and occupational functioning.
To evaluate the efficacy, tolerability, and safety of modafinil for negative symptoms, cognition, and wakefulness/fatigue in DSM-IV-diagnosed schizophrenia patients treated with clozapine.
A double-blind, placebo-controlled, flexible-dosed 8-week pilot trial was conducted between September 2003 and September 2007, adding modafinil up to 300 mg/d to stabilized schizophrenia outpatients receiving clozapine. Psychopathology, cognition, and wakefulness/fatigue were assessed with standard rating scales.
Thirty-five patients were randomly assigned to treatment with study drug and included in the analysis. Modafinil did not reduce negative symptoms or wakefulness/fatigue or improve cognition compared to placebo. Modafinil was well tolerated and did not worsen psychosis.
Results of this pilot trial do not support routine use of modafinil to treat negative symptoms, cognitive deficits, or wakefulness/fatigue in patients on clozapine. However, given our limited power to detect a treatment effect and the clear possibility of a type II error, larger trials are needed to resolve or refute a potential therapeutic effect of uncertain magnitude.
clinicaltrials.gov Identifier: NCT00573417.
We review the modulatory effects of the catecholamine neurotransmitters noradrenaline and dopamine on prefrontal cortical function. The effects of pharmacologic manipulations of these systems, sometimes in comparison with the indoleamine serotonin (5-HT), on performance on a variety of tasks that tap working memory, attentional-set formation and shifting, reversal learning, and response inhibition are compared in rodents, nonhuman primates, and humans using, in a behavioral context, several techniques ranging from microiontophoresis and single-cell electrophysiological recording to pharmacologic functional magnetic resonance imaging. Dissociable effects of drugs and neurotoxins affecting these monoamine systems suggest new ways of conceptualizing state-dependent fronto-executive functions, with implications for understanding the molecular genetic basis of mental illness and its treatment.
A simple and rapid normal-phase HPLC method for enantiospecific separation of a psychostimulant, adrafinil (ADL), and its metabolite modafinil (MDL) in rat serum and urine was developed. The separation was accomplished on a normal-phase polysaccharide stationary phase Chiralcel OJ-H using n-hexane-ethanol (62:38 v/v) as a mobile phase at a flow rate of 1.0 mL/min. Detection was carried out at 225 nm using a photo diode array (PDA) detector. The elution order of the enantiomers was determined by a polarimeter connected in series with the PDA. ADL and its metabolite were recovered from rat serum and urine by solid phase extraction using Oasis HLB cartridges and the mean recoveries were >or=80%. The enantiomers were eluted within 15 min without any interference from endogenous substances. The calibration curves were linear (r(2) > 0.998) in the concentration range of 1.20-500 microg/mL for ADL and MDL. The assay was specific, accurate, precise and reproducible (intra- and inter-day precisions RSDs <7.2%). ADL in rat serum was stable over three freeze-thaw cycles at ambient temperature for 4 h. The method was successfully applied to pharmacokinetic studies of adrafinil after an oral administration to rats.
Modafinil, a wake-promoting drug used to treat narcolepsy, is increasingly being used as a cognitive enhancer. Although initially launched as distinct from stimulants that increase extracellular dopamine by targeting dopamine transporters, recent preclinical studies suggest otherwise.
To measure the acute effects of modafinil at doses used therapeutically (200 mg and 400 mg given orally) on extracellular dopamine and on dopamine transporters in the male human brain.
Positron emission tomography with [(11)C]raclopride (D(2)/D(3) radioligand sensitive to changes in endogenous dopamine) and [(11)C]cocaine (dopamine transporter radioligand) was used to measure the effects of modafinil on extracellular dopamine and on dopamine transporters in 10 healthy male participants. The study took place over an 8-month period (2007-2008) at Brookhaven National Laboratory.
Primary outcomes were changes in dopamine D(2)/D(3) receptor and dopamine transporter availability (measured by changes in binding potential) after modafinil when compared with after placebo.
Modafinil decreased mean (SD) [(11)C]raclopride binding potential in caudate (6.1% [6.5%]; 95% confidence interval [CI], 1.5% to 10.8%; P = .02), putamen (6.7% [4.9%]; 95% CI, 3.2% to 10.3%; P = .002), and nucleus accumbens (19.4% [20%]; 95% CI, 5% to 35%; P = .02), reflecting increases in extracellular dopamine. Modafinil also decreased [(11)C]cocaine binding potential in caudate (53.8% [13.8%]; 95% CI, 43.9% to 63.6%; P < .001), putamen (47.2% [11.4%]; 95% CI, 39.1% to 55.4%; P < .001), and nucleus accumbens (39.3% [10%]; 95% CI, 30% to 49%; P = .001), reflecting occupancy of dopamine transporters.
In this pilot study, modafinil blocked dopamine transporters and increased dopamine in the human brain (including the nucleus accumbens). Because drugs that increase dopamine in the nucleus accumbens have the potential for abuse, and considering the increasing use of modafinil, these results highlight the need for heightened awareness for potential abuse of and dependence on modafinil in vulnerable populations.
Using an in vivo microdialysis technique coupled with HPLC-fluorometry, the release of neuronal histamine from the anterior hypothalamic area was monitored continuously in conscious, freely moving rats under a 12:12 h light:dark cycle. Spontaneous locomotor activity of the rats was measured simultaneously using a locomotor activity counter. Histamine release gradually increased in the second half of the light period (1400-2000) and the average histamine release during the dark period (2000-0800, 0.20 +/- 0.02 pmol/30 min) was significantly higher than that during the light period (0.12 +/- 0.01 pmol/30 min). This clear circadian change in the release suggests that the central histaminergic system is related to the circadian rhythm of rats.
Based on the observations that the psychostimulant drug amphetamine in combination with physiotherapy can promote recovery of brain function after brain injury, we have studied the ability of the vigilance promoting drug Modafinil to counteract 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-(MPTP)-induced degeneration of the nigrostriatal dopamine (DA) neurons of the black mouse. MPTP was given s.c. in a dose of 40 mg/kg and the mice were sacrificed 2 weeks later. The effects of acute and chronic treatment with Modafinil were studied on MPTP-induced DA neurotoxicity. The substantia nigra and neostriatum were taken to both biochemical and histochemical analysis of presynaptic parameters of the nigrostriatal DA neurons, the latter in combination with image analysis. In separate experiments in rats in vivo tests for DA uptake blocking activity were made using intrastriatal microdialysis to study superfusate levels of DA and its metabolites and the 4-alpha-dimethylmetatyramine (H77/77) model to test for a possible ability of Modafinil to protect against H77/77-induced depletion of forebrain DA stores. Chronic treatment with Modafinil in doses of 10 to 100 mg/kg counteracted the MPTP-induced disappearance of nigral TH IR nerve cell body profiles and neostriatal TH IR nerve terminal profiles as evaluated after 2 weeks with image analysis. Chronic treatment with Modafinil (10-100 mg/kg) also dose-dependently counteracted the MPTP-induced disappearance of striatal DA uptake binding sites as evaluated at the same time interval. Also in the dose range 10-100 mg/kg Modafinil counteracts the MPTP-induced depletion of DA stores both in the neostriatum and the substantia nigra. In the acute experiments Modafinil (30 mg/kg) protected against the MPTP-induced depletion of striatal DA, dihydrophenylacetic acid (DOPAC) and homovanillic acid (HVA) levels both when given 15 min before, at the same time and 3 h following the MPTP injection. In the substantia nigra, however, these protective actions of Modafinil were only observed when the drug was coadministered with MPTP. Experiments with microdialysis in intact rats failed to demonstrate any increases of superfusate DA levels in neostriatum with 30 mg/kg of Modafinil. Modafinil in high doses of 2 x 50 mg/kg, however, significantly counteracted the H77/77 induced DA depletion of striatal DA stores. Thus, morphological and biochemical evidence has been obtained that Modafinil in the dose range 10-100 mg/kg protects against MPTP-induced degeneration of the nigrostriatal DA neurons of the black mouse.(ABSTRACT TRUNCATED AT 400 WORDS)
The effects of modafinil on acetylcholine and GABA outflow from the cerebral cortex of awake freely moving guinea pigs provided with an epidural cup were studied. In the dose range of 3-30 mg/kg s.c. modafinil produced a dose dependent significant inhibition of GABA outflow without influencing cortical acetylcholine release. Methysergide (2 mg/kg, i.p.) and ketanserin (0.5 mg/kg, i.p.) but not prazosin (0.14 mg/kg, i.p.) counteracted the inhibitory action of modafinil on cortical GABA outflow. Modafinil both acutely and chronically in the same dose range increased striatal 5-HIAA levels and 5-HT utilization in the rat (acute) and mouse (chronic). The action on cortical GABA release may be dependent on activity at 5-HT2 receptors, since the action of modafinil in this respect is blocked by the non-selective 5-HT antagonist methysergide and the 5-HT2 antagonist ketanserin. The involvement of 5-HT mechanisms in the inhibitory action of modafinil on cortical GABA release is also suggested by the findings that 5-HT metabolism may become increased by modafinil at least in the striatum. The reduction of cortical GABA outflow via 5-HT2 receptors by modafinil is probably related to some of its actions on the central nervous system including behavioural effects.
We have studied the effect of modafinil and amphetamine, two waking drugs, on the electrical activity of central dopaminergic and noradrenergic neurons in the rat. Modafinil (128 mg/kg, i.p.) was unable to modify the firing pattern of these neurons, while amphetamine (2 or 5 mg/kg, i.p.) consistently inhibited their activity. A pretreatment with modafinil did not change thereafter the effect of amphetamine. Contrary to amphetamine, the waking effect of modafinil does not seem to be mediated by the catecholaminergic neuron activity per se.
Theta/alpha spectral powers ratio was used to quantify physiological decrease of vigilance occurring after 5 min recording eyes closed, at different times of the day, in normal volunteers with 'high alpha'. Maximum decrease of vigilance occurred at about 2 or 4 p.m. Theta/alpha ratio fluctuations were similar on the homologous right and left scalp areas. This ratio is useful in psychopharmacology to quantify the antagonist activity of a CNS stimulant drug on the physiological decrease of vigilance after 5 min as well as the sedative effect of a drug. It allows to follow the kinetics of the drug action at receptor level.
Changes in the level of glutamine synthetase (GS), an enzyme chiefly found in glial cells, were investigated in the brains of rats treated with modafinil, an awakening drug interfering with central catecholamine function. Two hours (waking period) and 7 h (recovery period) after intra-peritoneal injection of 128 mg/kg modafinil, a significant increase in the level of GS protein was observed by immunotitration in both the locus coeruleus (+30%) and in the frontoparietal cortex (+50%). No changes were observed with 64 mg/kg of modafinil. GS mRNA was quantified in the entire cortex by Northern blot hybridization using an oligonucleotidic GS cDNA probe. A significant increase in the GS-mRNA level (+70%) was observed in the CX of rats 2 h after injection of 128 mg/kg modafinil; the level tended to return to control values 7 h later during the recovery period. The level of glial acid fibrillary protein (GFAP), an astroglial marker, was unchanged after modafinil treatment. These changes in GS levels after modafinil treatment are discussed in terms of neuron-glia interactions in the regulation of brain metabolism during pharmacologically induced wakefulness, excluding possible stress effects.
Modafinil was compared to the indirect dopaminergic drugs, dexamphetamine and methylphenidate, using in vivo differential normal pulse voltammetry with carbon fibre electrodes located in the caudate nucleus to study extracellular catechol level in anaesthetized mice. Modafinil (16-256 mg kg-1) failed to modify the catechol oxidation peak height (peak 2). Dexamphetamine at low doses (2 and 4 mg kg-1) decreased, while at a higher dose (8 mg kg-1) did not modify peak 2 height. A low dose of methylphenidate (16 mg kg-1) did not display any effect, while higher doses (32 and 64 mg kg-1) increased peak 2 height. Pargyline-induced monoamine oxidase inhibition elicited a rapid and dramatic decrease in peak 2 height (related to the decrease of catechol levels). In these conditions modafinil (64 and 256 mg kg-1) did not modify, while dexamphetamine (2, 4 and 8 mg kg-1) and methylphenidate (16, 32 and 64 mg kg-1) increased peak 2 height in relation to synaptic dopamine level increase. This study, in mice, demonstrated the lack of effects of modafinil on nigro-striatal function, at the pre-synaptic level, as opposed to dexamphetamine and methylphenidate.
Cats were chronically implanted with electrodes for polygraphic recordings and cannulae for intracerebral microinjections in order to study the functional role of histaminergic innervation of the preoptic-anterior hypothalamus in sleep-wake control. alpha-Fluoromethylhistidine (alpha FMH, 50 micrograms in 1 microliter), a specific inhibitor of the histamine-synthesizing enzyme, when injected bilaterally into the preoptic area, where numerous histaminergic fibres and terminal-like structures are present, caused a significant increase in deep slow wave sleep (S2) and paradoxical sleep (PS) and a decrease in wakefulness. In contrast, microinjections of histamine (5 or 30 micrograms in 1 microliter) in the same area dose-relatedly increased wakefulness and decreased both slow wave sleep and paradoxical sleep. The effects of histamine were reduced by pretreatment with mepyramine (1 mg/kg i.p.), a well known histamine H1 receptor antagonist, and were mimicked by a local injection of impromidine (1 microgram in 1 microliter), a potent histamine H2 receptor agonist. Microinjections of mepyramine alone (120 micrograms in 1 microliter) caused an increase in slow wave sleep. These results suggest that preoptic histaminergic innervation is involved in sleep-wake control and that the action might be mediated via both H1 and H2 receptors.