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Risks and Benefits of Selective Serotonin Reuptake Inhibitors in the Treatment of Depression
Abstract
Depression is a common, life-disrupting, potentially lethal illness that can affect both sexes and all ages. Its peak onset is in the early adult years. It is more common than hypertension in primary care practice. Recent studies show that fewer than 1 in 20 depressed patients are correctly diagnosed and adequately treated. Depression periodically destroys the productivity of those with the condition, and depressed patients have a worse quality of life than patients with debilitating, chronic conditions such as arthritis, hypertension, diabetes mellitus and back pain. Suicide occurs in as many as 15% of patients with depression, especially those with recurrent episodes and hospitalisations, and may even occur in those with in subsyndromal depression. Suicide is one of the leading causes of death, and individuals who complete suicide have usually experienced mood disorders, mainly depression. Current data support a decreased frequency of suicidal ideation with all antidepressants, including selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs). Modern pharmacotherapy is the cornerstone for effective treatment of depression. As they are well tolerated, even in the presence of comorbid medical illness, and easier to manage, SSRIs enhance compliance. A fully adequate antidepressant dosage is suitable for patients of all ages and can be used by non-psychiatrist physicians for the treatment of the acute episode, as well as the frequent recurrences that often require long term maintenance antidepressant medication. SSRIs have fewer drug interactions than older antidepressants, and even the SSRI inhibition of hepatic cytochrome P450 enzymes has proven only very infrequently to be of clinical importance. SSRIs also effectively treat anxious depression, dysthymia and atypical depression. Fluoxetine may provide more rapid onset of therapeutic effect because it can be started at closer to its usual full therapeutic dosage than other SSRIs or older antidepressants. SSRIs, in particular fluoxetine, are more suitable for use as long-term maintenance therapy in these chronic relapsing diseases. These factors and the high efficacy rate, increased safety in overdose, reduced incidence of adverse effects (mostly decreasing with time) and superiority in ease of maintaining patients in adequate treatment plans provides fluoxetine with an overall superior therapeutic profile.
... Patients who required ≥ 2 units of PRBCs had a longer median hospital stay than those who did not receive ≥ 2 units of PRBCs (8 [5-10.1] vs 4 [ [3][4][5]; P < 0.0001). Conclusion and Relevance: Receiving SADs in the perioperative period is associated with a higher transfusion requirement in patients undergoing orthopedic surgery. ...
... Selective serotonin reuptake inhibitors (SSRIs) and, serotonin and norepinephrine reuptake inhibitors (SNRIs) are the mainstay of treatment currently in use for major depression, anxiety disorders, obsessive-compulsive disorders, and posttraumatic stress disorder. 1 Antidepressants are one of the most widely prescribed therapeutic drug classes in the United States. 2 Serotonergic antidepressants (SADs) are the preferred first line of medication for depression because of their higher tolerability and lower toxicity compared with the older tricyclic antidepressants 3,4 ; however, SADs are associated with several adverse effects, including nausea, agitation, insomnia, and sexual dysfunction. Overdosing can cause life-threatening serotonin syndrome or abruptly discontinuing them can cause antidepressant discontinuation syndrome. ...
Background
The use of serotonergic antidepressants (SADs) is associated with an increase in bleeding, and their exposure during the perioperative period increases the potential bleeding risk in patients undergoing surgical operations.
Objective
The purpose of this study was to compare the rates of bleeding between patients on perioperative SADs and those not on SADs in patients undergoing orthopedic surgical procedures.
Methods
A retrospective cohort study was conducted with patients who were admitted to a single tertiary care county teaching hospital for orthopedic surgery. Outcomes evaluated were requirements of ≥ 2 units of packed red blood cells (PRBCs) and length of hospital stay for those requiring ≥ 2 units of PRBCs.
Results
Of 273 patients, a significantly higher percentage of patients who received SADs required ≥ 2 units of PRBCs (19.3% vs 6.9%; P = 0.0049). Patients who required transfusion had a higher median (interquartile range [IQR]) age (79 [64-84.6] vs 65 [59-75]; P < 0.0001). The risk of requiring ≥ 2 units of PRBCs transfusion was greater for individuals having an anemia comorbidity (odds ratio [OR], 4.55; 95% CI, 1.95-10.62, P = 0.0004). Patients who required ≥ 2 units of PRBCs had a longer median hospital stay than those who did not receive ≥ 2 units of PRBCs (8 [5-10.1] vs 4 [3-5]; P < 0.0001).
Conclusion and Relevance
Receiving SADs in the perioperative period is associated with a higher transfusion requirement in patients undergoing orthopedic surgery. Clinicians should be aware of this increased risk for patients who are taking SADs while undergoing surgical procedures.
... The improved side-effect profile is reflected in the better compliance seen even in the controlled studies. In addition, SSRIs have fewer drug interactions than traditional antidepressants, they are more suitable for use in long-term maintenance therapy, and are associated with fewer deaths from overdosage (Mourilhe et al., 1998;Montgomery, 2000;Cipriani et al., 2003). ...
... In particular, Stokes and Holtz (1997) highlight that fluoxetine can reduce healthcare costs by 'reducing the need of physician contact because of increased compliance, by reducing premature patient discontinuation, thereby yielding fewer relapses, less recurrence, and less reutilisation of mental health services'. Sources: Adapted from Stokes and Holtz (1997); Mourilhe et al. (1998); Stewart (1998); Montgomery (2000); Cipriani et al. (2003) Pharmacological considerations suggest that SSRIs are a heterogeneous class (Cipriani et al., 2003). There are differences in both their primary pharmacological action (ie selective and potential inhibition of serotonin reuptake) and their secondary action (blockade of norepinephrine and dopamine reuptake). ...
... Despite this lack of knowledge, prescription rates of antidepressants to children and adolescents are increasing; with 17.6% in The Netherlands alone in the period from 2005 to 2012 (Bachmann et al., 2016). Earlier evidence suggested that antidepressant exposure in adulthood is safe and does not have any long-term consequences (Mourilhe and Stokes, 1998), and it is therefore generally assumed that the same applies for children and adolescents. However, this assumption has been challenged as evidence accumulated that the developing brain responds differently to psychotropic drugs than the adult brain (Andersen and Navalta, 2004). ...
Preclinical studies have demonstrated that antidepressant treatment in juvenile rodents affect the ontogeny of the serotonin system. However, whether early antidepressant use has similar effects on the development of the serotonin system in humans remains unknown. Therefore, we investigated whether effects of selective serotonin reuptake inhibitor (SSRI) treatment on the serotonin system are modulated by age. With pharmacological Magnetic Resonance Imaging the cerebral blood flow (CBF) response to an acute citalopram challenge was measured, as a proxy for serotonin function. Fifty-one females with major depressive disorder or anxiety disorder were stratified into three groups: 1) those treated with SSRIs <23 years of age, 2) those treated with SSRIs >23 years of age, and 3) those that were never treated with SSRIs. Additionally, a group of 14 healthy controls was included. CBF decreased after a citalopram challenge in the amygdala, hippocampus and orbitofrontal cortex across the whole sample. However, in contrast to preclinical studies, we did not find any age-dependent effect of SSRI exposure on the CBF response. In view of recent concerns on potential adverse effects of SSRIs administered to children, future studies are needed to replicate our negative findings in larger samples sizes and potentially in a prospective design.
... TCAs have also been reported to block muscarinic, alpha1 adrenergic and histaminic receptors. However, these molecules may lead to occurrence of different side effects in patients as summarised in Table 2. Mourilhe [20] have reported that the Selective serotoninreuptake inhibitors (SSRIs) may block the reuptake of 5HT and increase synaptic 5HT transmission. The SSRIs have very little or insignificant effect on the reuptake of other neurotransmitters. ...
... Citalopram (Cit), fluoxetine (Fle), and fluvoxamine (Fla) are antidepressant drugs in the class of selective serotonin reuptake inhibitors (SSRIs). The main mechanism of action of SSRIs involves controlled serotonin reuptake inhibition at the presynaptic nerve terminal, which is as effective as traditional tricyclic antidepressants (TCAs) in monotherapy for treating major depression [1], but exhibits a much more favorable side-and toxic-effect profile. Thus, SSRIs have become widely prescribed medications for treating depression and psychiatric disorders. ...
Dispersive liquid–liquid microextraction was combined with acetonitrile stacking in capillary electrophoresis for the identification of three selective serotonin reuptake inhibitors (citalopram, fluoxetine, and fluvoxamine) in human fluids such as urine and plasma. Parameters that affect the extraction and stacking efficiency, such as the type and volume of the extraction and disperser solvent, extraction time, salt addition for dispersive liquid–liquid microextraction, and sample matrices, pH, and concentration of the separation buffer for stacking, were investigated and optimized. Under optimum conditions, the enrichment factors were in the range of 1195–1441. Limits of detection ranged from 1.4 to 1.7 nM for the target analytes. Calibration graphs displayed satisfied linearity with R2 greater than or equal to 0.9978, and relative standard deviations of the peak area analysis were in the range of 2.9–5.0% (n = 3). The recoveries of all tricyclic antidepressant drugs from urine and plasma were in the range of 77–117 and 79–106%, respectively. The findings of this study show that dispersive liquid–liquid microextraction acetonitrile-stacking capillary electrophoresis is a rapid and convenient method for identifying tricyclic antidepressant drugs in urine and plasma. This article is protected by copyright. All rights reserved
... Fluoxetine (FLX) belongs to a class of new antidepressants which act by selective inhibition of serotonin re-uptakes [1]. It has been shown that FLX has comparable efficacy to traditional tricyclic antidepressants but causes fewer anticholinergic side effects and is remarkably safer in the likelihood of an overdose [2]. The therapeutic dose can vary from 20 to 60 mg per day depending on the patient which about 11% of the dose is excreted unchanged in the urine [3]. ...
... For example, SSRIs block the reuptake of 5-hydroxytryptamine receptors (5HT) and increase synaptic 5HT transmission. 15 Although SSRIs lack any muscarinic and histaminergic receptor activity, some SSRIs like paroxetine can worsen cognitive impairment because of their anticholinergic activity 16 and are considered as potentially inappropriate for elderly patients with dementia and cognitive impairment. 17 However, a recent study did not find any higher risk of dementia among depressed elderly nursing home patients using paroxetine when compared with the other SSRIs. ...
Background:
Past literature suggests that the use of second-generation antidepressants improves cognition in depressed elderly patients.
Objective:
This study assessed the comparative cognitive profile of commonly used second-generation antidepressant classes in elderly residents with depression.
Methods:
A multiple propensity score adjusted retrospective cohort study was conducted using 2007-2010 Medicare Part D claims and Minimum Data Set (MDS). Elderly nursing home residents (65 years or older) with depression using a new prescription of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tetracyclics constituted the study cohort. The outcome of interest was cognition, measured using the MDS Cognition Scale. Cognition was measured at each quarterly assessment after antidepressant initiation for a maximum of 1 year. The propensity score-adjusted repeated-measures mixed model was used to evaluate the comparative profile of SSRIs, SNRIs, and tetracyclics with respect to cognition.
Results:
The study cohort comprised 1518 elderly nursing home residents. Of these, 1081 received SSRIs (71.21%), 320 received tetracyclics (21.08%), and 117 received SNRIs (7.71%). The propensity score-adjusted repeated-measures mixed model did not show any statistically significant difference in cognition with the use of SSRIs (β = -0.14; 95% CI = -0.53, 0.25) or tetracyclics (β = -0.36; 95% CI = -0.80, 0.08) when compared with SNRIs, after controlling for other factors.
Conclusions:
The cognitive effect of SSRIs, SNRIs, and tetracyclics was similar in elderly nursing home residents with depression. Further studies are needed to evaluate the long-term cognitive effects of second-generation antidepressants in this vulnerable population.
... La terapia conductual y cognitiva se consideran más efectivas que las de orientación no directiva o analítica y ayudan a reintegrar al paciente a su ambiente social y prevenir recaídas (34) TRATAMIENTO FARMACOLÓGICO La mayoría de los antidepresivos han demostrado su efectividad en la población anciana. El antidepresivo ideal para usar en ancianos debiera no ser cardiotóxico, carecer de efectos ortoestáticos, tener un bajo poder sedativo, no interferir en la memoria y no provocar alteraciones funcionales (35) . ...
RESUMEN. La depresión es un síndrome geriátrico frecuente que produce alto grado de incapacidad y aumenta la mortalidad (directamente e indirectamente por comorbilidad con otras enfermedades) en la población geriátrica. Altera la calidad de vida del que la sufre y es, además, un problema social y de salud pública. La prevalencia varía según el medio en el que la estudiemos y según los instrumentos diagnósticos que usemos. La depresión del anciano tiene formas peculiares de presentación (depresión menor, depresión de inicio tardío) y, a veces, pueden predominar síntomas físicos o cognitivos. Algunas veces aparecen lesiones orgánicas en el sustrato de la depresión ("depresión vascular"). La terapia antidepresiva en ancianos es frecuentemente complicada por comorbilidad de enfermedades médicas, la polifarmacia y por el aumento de sensibilidad a los efectos de los fármacos. Los antidepresivos inhibidores selectivos de la recaptación de serotonina aportan seguridad, eficacia y reducción de efectos adversos, siendo el grupo de elección en el tratamiento de la depresión en el anciano. Palabras clave : Depresión geriátrica. Diagnóstico de depresión. Alteraciones cognitivas. Antidepresivos. 1. INTRODUCCIÓN. EPIDEMIOLOGÍA. La depresión constituye uno de los síndrome psiquiátricos más frecuentes e incapacitantes entre la población geriátrica. Los trastornos depresivos son un importante problema de salud pública, ya que, entre otros factores, aumentan con la edad (1) Los trastornos del estado de ánimo y fundamentalmente la depresión tienen una elevada prevalencia (en base a su alta incidencia, recurrencia aumentada y tendencia a la cronicidad) y conllevan alta morbilidad tanto directa como indirecta (comorbilidad con otros procesos) (2) Los estudios epidemiológicos sobre prevalencia de las diferentes alteraciones depresivas varían según el instrumento diagnóstico utilizado, sea la entrevista psiquiátrica o la aplicación de escalas orientativas (3) , y según el grupo poblacional al que se estudie : ancianos en la comunidad, ancianos institucionalizados en residencias o ancianos hospitalizados. En lo que coinciden la mayoría de estudios y autores es que los trastornos afectivos del anciano están infradiagnosticados e infratratados. Si se analizan estudios sobre depresión mayor en ancianos en la comunidad que usan para el diagnóstico instrumentos estructurados administrados por especialistas, suelen arrojar tasas de prevalencia significativamente menores (1-3 %) que estudios que usan instrumentos dimensionales de screening como la Geriatric Depression Scale (GDS) (4) , la Center for Epidemiologic Studies Depression Scale (CES-D) (5) o la escala de Koenig (6) que se basa en la presencia de más o menos síntomas de los llamados "depresivos".
... Therefore, targeted population and age are also two factors that result in distinct pathogenic conditions which result in different reactions against therapies because of the pathophysiological effects on drugs' efficacy and undesirable side effects. Indeed, nowadays, depression and anxiety disorder treatments increasingly use selective serotonin reuptake inhibitors (SSRIs) (Murray et al., 2004;Zito et al., 2002) and among all the SSRI only fluoxetine is registered for the treatment of major depressive disorder (MDD) for children over eight years old and this, in spite of the limited data we have regarding its effects on the late developing brain during the Prediger et al. (2012) adolescence period (Klomp et al., 2012), whereas we know more about Long-term (side-) effects of fluoxetine in both adulthood (Benmansour et al., 1999;Cipriani et al., 2007;Mourilhe and Stokes, 1998;Racagni and Popoli, 2008;Schule, 2007) and perinatal periods (Alwan and Friedman, 2009;Borue et al., 2007;Homberg et al., 2011;Oberlander et al., 2006). Nevertheless, in 2004 we have seen a black box warning, from both the Food and Drug Administration (FDA) and European Medicines Agency (EMA), drawing attention to the side-effects associated with the SSRI use and that have been shown for children, adolescents and young adults, the most serious are higher occurrence of psychiatric and/or behavioral adverse events such as sleep disturbances and agitation (Bridge et al., 2007;Hammad et al., 2006;Wilens et al., 2002;Wohlfarth et al., 2006), moreover, adolescence has a critical importance for 'neuronal imprinting' effects in which long term drug exposure effects are expressed in adult life. ...
Psychiatric disorders are often considered as simple imbalances between a limited number of cerebral neurotransmitters. In fact, it is more complicated than this “simple approach” and each psychiatric disorder constitutes network dysfunction within which several agents and factors are implicated. Thus, the therapeutical perspectives and implications are as vast and as numerous as the diversity of those network dysfunctions. Furthermore, the description of factors influencing diseases prognoses and treatment efficacy indicates new elements to consider both in therapies and drug researches.
... During the literature survey, it was also found that along with its benefits, paroxetine do possess some serious health risks. Patients with depression are at a high risk of suicide attempts (5). The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) published a letter for patients, prescribers and parents that paroxetine should not be prescribed to children. ...
Paroxetine is a potent selective serotonin reuptake inhibitor used for the treatment of depression and related mood disorders.
A micellar liquid chromatographic method was developed for the determination of paroxetine in serum and urine. Detection of
paroxetine was carried out using a C18 column and a mobile phase of 0.15 M sodium dodecyl sulfate, 6% 1-pentanol at pH 3 (buffer
salt 0.01 M NaH2PO4) running under isocratic mode at 1.0 mL/min and electrochemical detection at 0.8 V. The analyte was eluted without interferences
in <15 min. The proposed methodology was validated under the guidelines of the International Conference on Harmonization of
Technical Requirements for Registration of Pharmaceuticals for Human Use in matrix in terms of specificity, linearity (r2 > 0.9999; 0.5–5 μg/mL range), accuracy (88–97.5%, recovery), repeatability (RSD < 0.54%), intermediate precision (RSD < 0.54%),
limit of detection and quantification (0.001 and 0.005 μg/mL, respectively) and robustness (RSD < 3.63%). Developed method
was successfully applied to real blood and urine samples as well as in spiked serum and urine samples. The developed method
was specific, rapid, precise, reliable, accurate, inexpensive and then suitable for routine analysis of paroxetine in monitorized
samples.
... SSRIs have also been associated with increased anxiety, agitation, and insomnia in a small percentage of patients. 51 Paroxetine may be associated with daytime somnolence in approximately 20% of the patients, while fluoxetine is more likely to cause agitation and insomnia. Other side effects that are common with paroxetine include headache, dry mouth, insomnia, asthenia, sweating, constipation and tremor. ...
... At present, fluoxetine is the only SSRI registered for treatment of major depressive disorder in children over 8 years old. Long-term (side-) effects of this drug are well studied in adulthood (Benmansour et al., 1999;Cipriani et al., 2007;Mourilhe and Stokes, 1998;Racagni and Popoli, 2008;Schule, 2007), as well as in the perinatal period (Alwan and Friedman, 2009;Borue et al., 2007;Morrison et al., 2005;Oberlander et al., 2006;Olivier et al., 2011) in both animals and humans. Yet, limited data exists on its effects on the late developing brain, i.e. during (pre)adolescence. ...
With the growing prevalence of psychotropic drug prescriptions among children and adolescents, the need for studies on lasting effects of drug exposure on the developing brain rises. Fluoxetine is the only selective serotonin reuptake inhibitor (SSRI) officially registered to treat major depressive disorder in children. Although various (pre)clinical studies have assessed the (long-term) effects of fluoxetine exposure in the perinatal period and in adulthood, limited data is available on its effects on the developing brain later in life, i.e. during adolescence.
The present study aimed at investigating the effects of age following chronic SSRI treatment on the central serotonin (5-HT) system. To this end, pharmacological MRI (phMRI) was performed in chronic fluoxetine-treated (5 mg/kg, oral gavage for 3 weeks) juvenile (PND25) and adult rats (PND65) after a 1-week washout period, using an acute fluoxetine challenge (5 mg/kg, i.v.) to trigger the 5-HT system.
We observed a diminished brain response to the acute challenge in adult treated animals when compared to control animals, whereas this response was increased in juvenile treated rats. As a result, a significant age by treatment interaction effect was seen in several (subcortical) 5-HT related brain regions.
An opposite effect of chronic fluoxetine treatment was seen in the developing brain compared to that in matured brain, as assessed non-invasively using phMRI. These findings most likely reflect neuronal imprinting effects of juvenile SSRI treatment and may underlie emotional disturbances seen in animals and children treated with this drug. Also, our findings suggest that phMRI might be ideally suited to study this important issue in the pediatric population.
The discovery and development of effective medicines for the treatment of psychiatric disorders such as schizophrenia and depression has been heralded as one of the great medical achievements of the past century. Indeed, the profound impact of these medicines on our understanding of the pathophysiology underlying these diseases, the treatment of psychiatric patients and even our social perception of mental illnesses cannot be underestimated. However, there is still an urgent medical need for even more effective, safe and well-tolerated treatments. For example, currently available treatments for schizophrenia address mainly the positive symptoms and largely neglect the negative symptoms and cognitive disfunction which greatly impact overall morbidity. Similarly, whilst the current first line antidepressants show significantly improved side effect profiles compared to the first generation therapies, there still up to 40% of patients who are treatment resistant, and even in the patient population which responds well, the onset of action is slow at typically 2-3 weeks. The aim of this book is to provide the first point of call for those involved or just interested in this rapidly expanding and increasingly fragmented field of research and drug discovery. The editors will combine their wide ranging experience and extensive network of contacts with leading scientists and opinion leaders in this field to provide an authoritative reference text covering the evolution, major advances, challenges and future directions in drug discovery and medicinal chemistry for major psychiatric disorders.
Chronic pain and anxiety symptoms are frequently encountered clinically, but the neural circuit mechanisms underlying the comorbid anxiety symptoms in pain (CASP) in context of chronic pain remain unclear. Using viral neuronal tracing in mice, we identified a previously unknown pathway whereby glutamatergic neurons from layer 5 of the hindlimb primary somatosensory cortex (S1) (Glu), a well-known brain region involved in pain processing, project to GABAergic neurons in the caudal dorsolateral striatum (GABA). In a persistent inflammatory pain model induced by complete Freund's adjuvant injection, enhanced excitation of the Glu→GABA pathway was found in mice exhibiting CASP. Reversing this pathway using chemogenetic or optogenetic approaches alleviated CASP. In addition, the optical activation of Glu terminals in the cDLS produced anxiety-like behaviors in naive mice. Overall, the current study demonstrates the putative importance of a novel Glu→GABA pathway in controlling at least some aspects of CASP.
Envenomations are a particular type of toxic exposure resulting from human contact with biologic substances produced in specialized glands or tissues from animals, usually by cutaneous or transdermal injection. The poisoned pregnant woman poses particular challenges to the emergency room physicians, toxicology experts, and obstetrician. The emergency treatment and stabilization of the mother should take priority over the monitoring and treatment of the fetus. Up to a certain extent, although the pregnant patient goes through an acute episode of overdose or poisoning during pregnancy, the fetus might continue to be exposed to the toxic agent and environment, sometimes for several weeks. Poisoning during pregnancy represents one‐third of a percent of all toxic exposures reported in the United States. The chapter presents toxicology, short‐term problems, long‐term problems and maternal considerations for acetaminophen, amphetamines, antidepressants, carbon monoxide, cocaine, ethanol, iron and organophosphates.
Depression is nowadays a major contributor to global burden of disease. The most commonly prescribed drugs influence monoaminergic pathways, mainly concentrating on serotonin. Unfortunately, there are several drawbacks associated with these drugs, namely late onset of action, risk of suicide and adverse effects: mainly nausea, vomiting and sexual dysfunction. Therefore there is still need for new drugs with possibly high efficacy and fewer side effects. In this paper selected compounds which inhibit serotonin reuptake by acting on the serotonin transporter (SERT) and various serotoninergic receptors are presented. We also discuss the ways in which their mechanism of action can be modified to improve pharmacological profile. Here, we focus on describing drugs' potency, efficacy and adverse effects. Additional applications, apart from depression, are also discussed.
DefinitionsScope of the ProblemEvaluation of the Poisoned Pregnant PatientSpecific AgentsEnvenomations During PregnancySummary
Die Hauptgruppe der serotonin-selektiven Antidepressiva stellen die serotonin-selektiven Rückaufnahme-Inhibitoren (Wiederaufnahmehemmer) (SSRI)dar. In deutschsprachigen Ländern derzeit verfügbare Substanzen sind>
Citalopram/Escitalopram
Fluoxetin
Fluvoxamin
Paroxetin
Sertralin
A sensitive and rapid method based on alcohol-assisted dispersive liquid-liquid microextraction followed by high-performance liquid chromatography for the determination of fluoxetine in human plasma and urine samples was developed. The effects of six parameters on the extraction recovery were investigated and optimized utilizing Plackett-Burman design and Box-Benken design, respectively. According to the Plackett-Burman design results, the volume of disperser solvent, extraction time, and stirring speed had no effect on the recovery of fluoxetine. The optimized conditions included a mixture of 172 μL of 1-octanol as extraction solvent and 400 μL of methanol as disperser solvent, pH of 11.3 and 0% w/v of salt in the sample solution. Replicating the experiment in optimized condition for five times, gave the average extraction recoveries equal to 90.15%. The detection limit of fluoxetine in human plasma was obtained 3 ng/mL, and the linearity was in the range of 10-1200 ng/mL. The corresponding values for human urine were 4.2 ng/mL with the linearity range from 10 to 2000 ng/mL. Relative standard deviations for intra and inter day extraction of fluoxetine were less than 7% in five measurements. The developed method was successfully applied for the determination of fluoxetine in human plasma and urine samples. This article is protected by copyright. All rights reserved.
BACKGROUND. Guidelines for recognition and management of depression in primary care provide a framework for detailed exploration of physician practice patterns. METHODS. Our objective was to explore physician diagnosis and management approaches to depressive disorders according to type (major vs minor) and presenting complaint (difficulty sleeping and concentrating vs headache). The participants were community primary care internists and family physicians in northern New England, Washington, and Alabama (N = 149) who were randomly assigned to receive a visit from an unannounced actor portraying a standardized patient in 1 of 2 depression scenarios: (A) insomnia and poor concentration meeting Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R) criteria for major depressive disorder; or (B) tension headaches meeting the criteria for minor depression. RESULTS. All physicians who were assigned to the standardized patients presenting with scenario A recognized depression, and 49% (38 of 78) of those assigned to scenario B patients diagnosed depression. Of those recognizing depression, 72% and 42% queried patients about anhedonia and mood, respectively. For both scenarios, if fewer than 2 DSM-III-R criteria were explored, depression was not diagnosed. Management for scenario A was compatible with Agency for Health Care Policy and Research guidelines, including the prescription of an antidepressant (94%), scheduling of a follow-up visit within 2 weeks (61%), and exploration of suicidal ideation (69.4%). For scenario B, management included over-the-counter analgesics for the headache (84%), exercise (63%), prescription for an antidepressant (53%), recommendation for ongoing counseling (100%), and follow-up within 2 weeks (42%). CONCLUSIONS. Major depression is recognized in primary care at a very high rate. Guidelines for recognizing and managing depression are often followed in primary care. Patients' presentations of depression influence its recognition and management.
DefinitionsScope of the problemEvaluation of the poisoned pregnant patientSPECIFIC AGENTSAcetaminophenAmphetaminesAntidepressantsAspirinBarbituratesBenzodiazepinesCarbon monoxideCocaineEthanolIronOrganophosphates (and carbamates)Envenomations during pregnancySummaryReferences
Background and aim:Sexual dysfunction could be most important side effect of selective serotonin reuptake inhibitors (SSRIs). Sexual dysfunction is common among both men and women with major depressive disorder. Propose of this study is to evaluate the effect of SSRIs drug on sexual tendency and ability. Method:Present study was conducted during November 211to January 2012. Sample consisted of 584 subjects. All patients attending psychiatry clinic. 247subjects used SSRIs drug and 337 subjects used other psychiatry drugs. Results:Results of the research indicated that out of 247subjects used SSRIs drug 93people(38%) did not show drug side effects, but from other subjects; 60people (24%) reduced sexual tendency, 25people(10%) total disruption of sexual tendency, 33people(13%) lack of sexual tendency before onset of treatment, 10 people (4%) reduced sexual tendency before beginning of treatment, 10people(4%) increased sexual tendency, 7 people (3%) lack of satisfaction, 2people(0.08%) reduced or delayed satisfaction were reported. Discussion and Conclusion: The results of studies investigating correlation of SSRIs drugs and Sexual Dysfunction, which there are significant relation between consumption of SSRIs drugs and reduce or disruption of sexual tendency that may be one the most important problem among the couples.
Fast release capsules, containing sertraline hydrochloride, pregelatinized maize starch and microcrystalline cellulose were formulated. For this purpose, different technological assays were elaborated being the formulation 2 selected as the better technological variant. Dry powders were filled into hard gelatin capsules. From this formulation were derived capsules with satisfactory technological properties. The quantification of sertraline through HPLC UV detection method was validated for accuracy, precision, linearity and selectivity. The method was linear over the concentration range 0.5 to 0.75 mg/mL and was shown to be highly reproducible. It could be used, without any interference of capsule excipients, for determination of sertraline from solid dosage form. Hard capsules showed an adequate stability during 24 months demonstrating the feasibility from the process of production of this formulation. Parameters, f1 and f2, were used to confirm similarity of dissolution, in deaerated distilled water, of test formulation and capsules of Prosertin as reference product.
IntroductionThe occurrence of female sexual dysfunction (FSD) in patients with major depressive disorder (MDD) receiving selective serotonin reuptake inhibitors (SSRIs) treatment gives negative impacts on patients' quality of life and causes treatment discontinuation. We aimed to investigate whether genetic polymorphism of identified candidate gene is associated with FSD in our study population. Methods
This is a cross-sectional study. A total of 95 female patients with MDD who met the criteria of the study were recruited and were specifically assessed on the sexual function by trained psychiatrists. Patients' DNA was genotyped for BDNF Val66Met polymorphism using real-time polymerase chain reaction. ResultsThe prevalence of FSD in this study is 31.6%. In the FSD group, patients with problematic marriage were significantly more frequent compared with patients who did not have problematic marriage (P=0.009). Significant association was detected in the lubrication domain with BDNF Val66Met polymorphism (P=0.030) using additive genetic model, with even stronger association when using the recessive model (P=0.013). DiscussionThis study suggested that there was no significant association between BDNF Val66Met with FSD. However, this polymorphism is significantly associated with lubrication disorder in patients treated with SSRIs.
Paroxetine is a selective serotonin reuptake inhibitor (SSRI), with antidepressant and anxiolytic activity.
In 6- to 24-week well designed trials, oral paroxetine 10 to 50 mg/day was significantly more effective than placebo, at least as effective as tricyclic antidepressants (TCAs) and as effective as other SSRIs and other antidepressants in the treatment of major depressive disorder. Relapse or recurrence over 1 year after the initial response was significantly lower with paroxetine 10 to 50 mg/day than with placebo and similar to that with imipramine 50 to 275 mg/day.
The efficacy of paroxetine 10 to 40 mg/day was similar to that of TCAs and fluoxetine 20 to 60 mg/day in 6- to 12-week trials in patients aged ≥60 years with major depression. Paroxetine 10 to 40 mg/day improved depressive symptoms to an extent similar to that of TCAs in patients with comorbid illness, and was more effective than placebo in the treatment of dysthymia and minor depression.
Paroxetine 20 to 60 mg/day was more effective than placebo after 8 to 12 weeks’ treatment of obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder (social phobia), generalised anxiety disorder (GAD) and post-traumatic stress disorder (PTSD). Improvement was maintained or relapse was prevented for 24 weeks to 1 year in patients with OCD, panic disorder, social anxiety disorder or GAD. The efficacy of paroxetine was similar to that of other SSRIs in patients with OCD and panic disorder and similar to that of imipramine but greater than that of 2′chlordesmethyldiazepam in patients with GAD.
Paroxetine is generally well tolerated in adults, elderly individuals and patients with comorbid illness, with a tolerability profile similar to that of other SSRIs. The most common adverse events with paroxetine were nausea, sexual dysfunction, somnolence, asthenia, headache, constipation, dizziness, sweating, tremor and decreased appetite.
In conclusion, paroxetine, in common with other SSRIs, is generally better tolerated than TCAs and is a first-line treatment option for major depressive disorder, dysthymia or minor depression. Like other SSRIs, paroxetine is also an appropriate first-line therapy for OCD, panic disorder, social anxiety disorder, GAD and PTSD. Notably, paroxetine is the only SSRI currently approved for the treatment of social anxiety disorder and GAD, which makes it the only drug of its class indicated for all five anxiety disorders in addition to major depressive disorder. Thus, given the high degree of psychiatric comorbidity of depression and anxiety, paroxetine is an important first-line option for the treatment of major depressive disorder, OCD, panic disorder, social anxiety disorder, GAD and PTSD.
Pharmacodynamic Properties
Paroxetine is a potent and selective inhibitor of presynaptic serotonin reuptake and enhances serotonergic neurotransmission by prolonging serotonin activity at its postsynaptic receptors. Paroxetine is a moderate inhibitor of noradrenaline (norepinephrine) and a weak inhibitor of dopamine transporters in human brain tissue in vitro.
In healthy volunteers, paroxetine 30 mg/day has a suppressant effect on rapid eye movement (REM) sleep; it reduces the number of REM phases and prolongs REM latency. However, available data on sleep efficiency are equivocal. Although there were no significant changes associated with sleep efficiency in one study, it was significantly lowered compared with baseline values in another study.
Paroxetine 20 mg/day had little appreciable effect on psychomotor activity in healthy volunteers, and paroxetine 30 mg/day did not potentiate alcohol-induced psychomotor impairment. Paroxetine 40 mg/day was associated with minimal psychomotor impairment and less impairment than that seen with amitriptyline, amylobarbitone (amylobarbital), doxepin, haloperidol, lorazepam, oxazepam or trazodone.
Paroxetine 30 mg/day was not associated with any clinically significant haemodynamic or electrophysiological effects in healthy volunteers. At a dosage of 20 mg/day it reduced platelet activation in patients with depression and ischaemic heart disease and normalised platelet activation in patients with major depression.
Pharmacokinetic Properties
The pharmacokinetic parameters of paroxetine show wide interindividual variability. Paroxetine is well absorbed after oral administration, and absorption is not affected by the presence of food or antacids. Steady state was reached after 7 to 14 days in healthy volunteers administered paroxetine 30 mg/day. A maximum plasma concentration (Cmax) of 62 μg/L was reached after 5 to 6 hours. Paroxetine has a large volume of distribution (3 to 12 L/kg) after an intravenous bolus of 5 to 10mg; only about 1% of the administered dose remains free in the plasma. Paroxetine has been found in human breast milk after oral administration.
Paroxetine is extensively metabolised in the liver to inactive glucuronide and sulphate metabolites. It is primarily metabolised by the cytochrome P450 (CYP) 2D6 isoenzyme in extensive metabolisers; saturation of this enzyme results in accumulation of the drug after repeated administration or high dosages. The elimination half-life of paroxetine is approximately 21 hours. 62% of the administered dose is excreted in the urine and 36% in the faeces; <2% of the drug is excreted unchanged.
In elderly individuals the plasma concentration of the drug at steady state was increased and the elimination half-life was prolonged in comparison with younger individuals. In individuals with renal impairment [creatinine clearance <1.8 L/h (<30 ml/min)], mean Cmax was 4-fold that of healthy volunteers. In patients with hepatic impairment and in individuals with creatinine clearance 1.8 to 3.6 L/h (30 to 60 ml/min), Cmax and area under the plasma concentration-time curve were increased 2-fold.
Paroxetine, like fluoxetine and sertraline, is highly plasma protein bound and has the potential for drug-drug interactions with other highly protein-bound drugs. All selective serotonin reuptake inhibitors (SSRIs) inhibit CYP enzymes, which potentially results in drug interactions with agents metabolised by these enzymes; paroxetine, like fluoxetine, is a potent inhibitor of CYP2D6 and thus has the potential for interactions with other SSRIs, certain tricyclic antidepressants (TCAs), antipsychotics and antiarrhythmics.
Therapeutic Use in Adult Patients with Psychiatric Disorders
Major Depressive Disorder:Paroxetine 10 to 50 mg/day, in short- to medium- term (6- to 24-week) well designed trials, has shown significantly superior effi-cacy to that of placebo, and similar efficacy to TCAs (amitriptyline 50 to 250 mg/day, imipramine 50 to 275 mg/day, lofepramine 140 to 210 mg/day), all other investigated SSRIs (fluoxetine 20 to 80 mg/day, sertraline 50 to 200 mg/day, fluvoxamine 50 to 200 mg/day), and all other antidepressant comparators (maprotiline 50 to 100 mg/day, mianserin 60 mg/day, mirtazapine 30 to 45 mg/day, nefazodone 200 to 600 mg/day, tianeptine 37.5 mg/day, trazodone 146.1 to 154.3 mg/day and venlafaxine 75 mg/day) in the treatment of adult in- or outpatients with mainly moderate to severe major depressive disorder. Baseline Hamilton Depression Rating Scale (HDRS) or Montgomery and Åsberg Rating Scale (MÅDRS) scores were reduced by 31 to 47% with paroxetine and 11 to 27% with placebo (p ≤ 0.05). The decreases from baseline HDRS or MÅDRS scores were similar with paroxetine to those with the TCAs amitriptyline (39 to 68 vs 44 to 71%), imipramine (31 to 63% vs 25 to 59%) and lofepramine (57 vs 54%), and the SSRIs fluoxetine (48 to 67% vs 45 to 68%), sertraline (64 and 66% vs 68 and 73%) and fluvoxamine (50 and 53% vs 47 and 55%). Response rates (defined as 50% reduction in MADRS or HDRS score from baseline) were similar with paroxetine to those with TCAs (60 to 74% with paroxetine vs 65 to 87% with amitriptyline, 63% with paroxetine vs 54% with lofepramine and 71% with paroxetine vs 60% with imipramine) and SSRIs (58 to 77% with paroxetine vs 57 to 78% with fluoxetine, 69 and 77% with paroxetine vs 72 and 86% with sertraline, and 53% with paroxetine vs 50% with fluvoxamine).
The incidence of relapse or recurrence over 1 year of extended treatment after the initial response was significantly lower with paroxetine 10 to 50 mg/day (10 to 17%) than with placebo (49%; p < 0.05) and similar to that with imipramine 50 to 275 mg/day (4 to 14%).
In elderly patients (≥60 years of age) with depression, baseline HDRS scores were reduced to a similar extent with paroxetine 10 to 40 mg/day to those with amitriptyline 50 to 150 mg/day (65 and 61% vs 63 and 55%, respectively), nortriptyline (plasma concentrations 50 to 150 μg/L) [55 vs 60%], doxepin ≤200 mg/day (53 vs 47%) and clomipramine 25 to 75 mg/day (70 vs 70%). Baseline HDRS scores were decreased by 31% with paroxetine 20 to 40 mg/day and 20% with fluoxetine 20 to 60 mg/day. The response rates (percentage of patients with a 50% reduction in HDRS baseline score) were 64 and 76% with paroxetine versus 58 and 86% with amitriptyline, 65% with paroxetine versus 72% with clomipramine and 38% with paroxetine versus 17% with fluoxetine (p < 0.05). Furthermore, 66% of paroxetine and 78% of nortripty line recipients metresponse criteria defined as HDRS score ≤10.
Paroxetine 10 to 40 mg/day prevented the development of depression when administered for 2 weeks prior to and 12 weeks during treatment with high-dose interferon-α in patients with malignant melanoma; the incidence of major depression [Diagnostic and Statistical Manual (DSM)-IV criteria] at the end of treatment was 11% with paroxetine and 45% with placebo (p < 0.05).
The addition of the β-blocker pindolol 7.5 to 15 mg/day for 4 to 6 weeks to treatment with paroxetine 20 mg/day significantly shortened the time to antidepressant response in comparison with the addition of placebo in patients with major depressive disorder. The addition of paroxetine 20 mg/day or amitriptyline 75 mg/day to long-term lithium treatment (serum concentrations 0.5 to 0.8 mmol/L) in patients with breakthrough episodes of major depression resulted in response rates of 79 and 39%, respectively, after 4 weeks (p < 0.05 for paroxetine vs amitriptyline), with no significant differences after 6 weeks, in a well designed trial.
In well designed trials, baseline MÅDRS scores were reduced by 45 and 42%, respectively, in patients with dementia receiving paroxetine 20 to 40 mg/day or imipramine 25 to 100 mg/day, by 44 and 40%, respectively, in patients with cancer receiving paroxetine 20 to 40 mg/day or amitriptyline 75 to 150 mg/day, and by 45% each in paroxetine 20 to 40 mg/day or amitriptyline 75 to 150 mg/day recipients with rheumatoid arthritis. Reductions in HDRS of 50, 81 and 41%, respectively, were observed in patients with HIV infection receiving paroxetine 10 to 40 mg/day, imipramine 50 to 200 mg/day or placebo; 54 and 61 % of paroxetine 10 to 40 mg/day or nortriptyline (plasma concentrations 50 to 150 μg/L) recipients with ischaemic heart disease had a reduction in HDRS scores from baseline.
There were no significant differences in antidepressant efficacy between treatment groups in 6 to 12 week, randomised, double-blind trials involving patients with depression and anxiety; MADRS scores were decreased from baseline by 83% with paroxetine 20 mg/day versus 76% with fluoxetine 20 mg/day, by 58% with paroxetine 20 to 40 mg/day versus 57% with clomipramine 25 to 150 mg/day, and by 58% with paroxetine 20 mg/day versus 57% with tianeptine 37.5 mg/day. Decreases from baseline HARS or Clinical Anxiety Scale scores (measures of anxiolytic activity) were similar for paroxetine and the comparator drugs [85 vs 75% (paroxetine vs fluoxetine); 53 vs 53% (paroxetine vs clomipramine); and 52 vs 52% (paroxetine vs tianeptine)].
Dysthymia and Minor Depression: Paroxetine (up to 40 mg/day) and psychotherapy [problem solving treatment — primary care (PST-PC)] have been compared with placebo for the treatment of dysthymia and minor depression in large randomised trials in adults ≥60 years of age and patients aged 18 to 59 years. Paroxetine was effective in the treatment of both conditions, but was not significantly different from PST-PC. These multicentre trials were of identical design and there was ≈50% division between patients with dysthymia and minor depression. All patients aged 60 years or older showed improvement over 11 weeks: paroxetine was significantly more effective than placebo (p = 0.004) in the intent-to-treat analysis of the change in the 20-item Hopkins Symptom Checklist Depression Scale, and produced a slightly greater rate of symptom resolution compared with placebo from weeks 2 through 11. The effects on depressive symptoms were similar in patients with dysthymia and those with minor depression. In the trial in younger patients, all three groups showed a significant decline in depressive symptoms over 11 weeks and there were no significant differences between interventions or when groups were analysed by diagnosis. Remission rates (HDRS ≤6 or 7) in patients with dysthymia receiving paroxetine or PST-PC were significantly greater than in placebo recipients but did not differ across treatment groups in patients with minor depression.
Anxiety Disorders:
Obsessive-Compulsive Disorder (OCD): Paroxetine 20 to 60 mg/day significantly improved symptoms of Diagnostic and Statistical Manual third edition revised (DSM-III-R) defined OCD compared with placebo in two well controlled 12-week trials. Preliminary data (presented in an abstract) indicate that improvement relative to placebo was observed with the 40 and 60 mg/day dosages but not the 20 mg/day dosage. Fewer paroxetine than placebo recipients relapsed and the mean time to relapse was significantly greater with active treatment than with placebo in a 12-month study.
Paroxetine recipients (evaluable n = 198) experienced a similar reduction in the symptoms of OCD to that observed in clomipramine recipients (evaluable n = 94) in a well controlled, 12-week trial, and the reduction in symptoms was similar with paroxetine to that observed with fluvoxamine and citalopram in a small (n = 30), single-blind trial of 10 weeks’ duration.
Panic Disorder: Compared with placebo, paroxetine 20 to 60 mg/day significantly improved panic disorder (across multiple assessment parameters) in short-term (10- to 12-week) double-blind, randomised trials involving 120 to 278 (ITT) patients, with paroxetine being effective in all five domains (panic attacks, anxiety, phobia, well-being and disability). In the fixed dosage trial, results were significant for the higher dosage of paroxetine (40 mg/day) only. In addition, paroxetine 20 to 60 mg/day relative to placebo reduced the occurrence of panic attacks for up to 36 weeks in a double-blind extension phase in one trial.
The drug at a dosage of 20 to 60 mg/day was at least as effective as clomipramine 50 to 150 mg/day in the treatment of panic disorder in two well controlled 12-week trials and had similar efficacy to clomipramine in a long-term (36-week) extension phase in one trial. In addition, paroxetine (but not clomipramine) was significantly more effective at reducing the occurrence of panic attacks to zero than cognitive-behavioural therapy in one of the short-term trials. Paroxetine (up to 50 mg/day) appeared to reduce the symptoms of DSM-IV diagnosed panic disorder to a similar extent to citalopram (up to 50 mg/day) in a small (evaluable n = 45) trial, although there was a trend towards a higher proportion of paroxetine than citalopram recipients being free of panic attacks at study end (60 days).
Social Anxiety Disorder (Social Phobia): Paroxetine 20 to 50 mg/day significantly improved the severity of anxiety compared with placebo in patients with social anxiety disorder (evaluable n = 92 to 360) in five well controlled, 12-week trials. A greater proportion of those receiving paroxetine (43 to 70.5%) than placebo (8.3 to 47.8%) were much or very much improved on the Clinical Global Impression-Improvement (CGI-I) scale (p < 0.0001 to p < 0.05) and, in most cases, there were significantly greater reductions in Liebowitz Social Anxiety Scale total scores from baseline in paroxetine (27.5 to 47.4%) than placebo (11.0 to 25.1%) recipients (p < 0.0001 to p < 0.05). Abstract reports from an extension study and a long-term relapse prevention trial indicate that the efficacy of paroxetine in the treatment of patients with social anxiety disorder may be sustained for up to 36 weeks.
Generalised Anxiety Disorder (GAD): Paroxetine 20 to 50 mg/day significantly improved symptoms of anxiety (measured using HARS total score) compared with placebo in two 8-week, randomised, double-blind trials involving 324 (ITT) and 426 (evaluable) outpatients. In a third 8 week trial, the reduction in HARS total score from baseline was numerically greater with paroxetine 20 to 50 mg/day than with placebo. The drug at a dosage of 20 mg/day demonstrated similar efficacy to imipramine 50 to 100 mg/day but greater efficacy than 2′chlordesmethyldiazepam 3 to 6 mg/day in the treatment of GAD in a small (evaluable n = 63) randomised trial. In addition, significantly fewer paroxetine (10.9%) than placebo (39.9%) recipients relapsed during a 32 week relapse prevention study.
Post-Traumatic Stress Disorder (PTSD): Paroxetine 20 to 50 mg/day significantly improved symptoms of PTSD from baseline (p < 0.001) as assessed by the Clinician Administered PTSD Scale and increased the proportion of responders (much or very much improved on CGI-I) [both p < 0.001] compared with placebo in two randomised, double-blind trials of 12 weeks’ duration. Significant improvements with paroxetine relative to placebo were observed across all three symptom clusters (re-experiencing, avoidance and hyperarousal) and in both male and female patients. In addition, treatment benefit was observed across all trauma types.
Tolerability
In patients receiving paroxetine for various psychiatric disorders the most common adverse events occurring with an incidence of ≥5% included nausea, sweating, headache, dizziness, somnolence, constipation, asthenia and sexual dysfunction. In general, these adverse events were mild and events such as nausea and dizziness were transient.
Sexual dysfunction is common to all SSRIs. In patients with depression administered paroxetine 20 to 50 mg/day, the incidence of abnormal ejaculation was approximately 13%. In patients with OCD, social anxiety disorder, GAD or panic disorder the incidence ranged from 21 to 28% with paroxetine 10 to 60 mg/day.
A meta-analysis of 39 studies including over 3700 patients confirmed a significantly lower incidence of adverse events and a trend towards a lower withdrawal rate due to adverse events with paroxetine than with TCAs such as amitriptyline, imipramine, maprotiline and clomipramine.
Paroxetine appeared to have similar tolerability to fluoxetine, fluvoxamine and sertraline in randomised, double-blind trials of 6 weeks’ to 6 months’ duration. The overall incidence of adverse events with paroxetine was similar to that with the other SSRIs with which it was compared and there were no consistent statistically significant differences between paroxetine and the various SSRIs with regards to individual adverse events. Large, placebo-controlled, active-comparator trials are required to further clarify the relative tolerability of SSRIs.
Upon discontinuation of treatment with an SSRI, some patients may experience mild to moderate, self-limiting discontinuation symptoms (e.g. dizziness, paraesthesia, headache and vertigo). As with other SSRIs, slow tapering of the paroxetine dosage over several weeks minimises the extent of these symptoms.
Dosage and Administration
The information in this section is based on the US and UK prescribing information. Paroxetine tablets should be administered once daily, preferably in the morning with or without food, and should be swallowed whole rather than chewed. The recommended initial dosage for all indications except panic disorder is 20 mg/day; in the latter condition the initial dosage should be 10 mg/day. If efficacy is not achieved, paroxetine should be increased at weekly intervals in 10mg increments to a maximum dosage of between 50 and 60 mg/day depending on the condition being treated and local recommendations. Reliable studies of long-term (>1 year) maintenance therapy with paroxetine are not available but, as many of the conditions which respond to the drug are chronic, it is reasonable to consider continuing extended treatment of responding patients, with periodic reassessment and possible adjustment of dosage. The UK guidelines and WHO recommendations suggest that patients should receive treatment for at least 4 to 6 months after recovery from depression, and perhaps longer for OCD and panic disorder. As with many psychoactive medications, abrupt discontinuation should be avoided.
In elderly or debilitated patients or those with severe kidney or hepatic impairment, the recommended initial dosage of paroxetine is 10 mg/day. The dosage may be increased if indicated but should not exceed 40 mg/day.
Serotonin syndrome (which includes changes in mental status, agitation, myoclonus, hyperreflexia, diaphoresis, hyperthermia, and incoordination) may occur with the concomitant use of an SSRI and a monoamine oxidase inhibitor (MAOI). Therefore, paroxetine should not be administered in combination with an MAOI or for at least 14 days after discontinuation of treatment with an irreversible MAOI and at least 1 day after discontinuation of treatment with a reversible MAOI. Paroxetine should be discontinued for at least 1 day before the initiation of therapy with a reversible MAOI and for at least 2 weeks before beginning treatment with other MAOIs.
Caution is advised when paroxetine is coadministered with drugs that are metabolised by CYP2D6 [e.g. antidepressants (nortriptyline, amitriptyline, imipramine, desipramine and fluoxetine), phenothiazines, and type C antiarrhythmics (e.g. propafenone, flecainide and encainide)] or that inhibit this enzyme (e.g. quinidine). In particular, the coadministration of paroxetine and thioridazine is contraindicated. In addition, the concomitant use of paroxetine and tryptophan is not recommended and caution is advised when paroxetine is coadministered with warfarin, sumatriptan, lithium or digoxin.
The safety of paroxetine in pregnancy has not been established and the drug should only be used during pregnancy if the benefits to the mother outweigh the possible risk to the foetus. Paroxetine is secreted in breast milk and discontinuation of breast feeding should be considered in this situation. The safety and effectiveness of paroxetine in paediatric populations has not been established.
A comparative study was made between two designs of paroxetine-selective electrodes: a polyvinyl chloride membrane (liquid inner contact) called electrodes PME1 and PME2 and a solid contact called electrodes CWE1 and CWE2 based on paroxetine-phosphotungstate and paroxetine-phosphomolybdate as ion exchangers. The four electrodes, PME1, PME2, CWE1 and CWE2, show linearity over the concentration range from 1 × 10−5 to 1 × 10−2 M, with slopes of 56.7, 54.4, 59.8 and 55.3 mV/decade, meanwhile the limits of detection were 2.5 × 10−6, 4 × 10−6, 5.6 × 10−6 and 6.2 × 10−6 M, respectively. PME1 and PME2 showed better limit of detection than electrodes CWE1 and CWE2. The present electrodes show clear discrimination of Prx.HCl from several inorganic, and organic species. The sensors were applied efficiently for determination of Prx.HCl in its pharmaceutical preparations using standard addition and the calibration curve methods.
Major unipolar depression is a significant global health problem, with the highest incident risk being during adolescence. A depressive illness during this period is associated with negative long-term consequences including suicide, additional psychiatric comorbidity, interpersonal relationship problems, poor educational performance and poor employment attainment well into adult life. Despite previous safety concerns, selective serotonin reuptake inhibitors (SSRIs) remain a key component of the treatment of moderate to severe depression episodes in adolescents. The impact of SSRIs on the developing adolescent brain, however, remains unclear. In this review we first consider what is currently known about the developing brain during adolescence and how these development processes may be affected by a depressive illness. We then review our understanding of the action of SSRIs, their effects on the brain and how these may differ between adults and adolescents. We conclude that there is currently little evidence to indicate that the human adolescent brain is at developmental risk from SSRIs. Furthermore, there is no clear-cut evidence to support the concerns of marked suicidal adverse side effects accruing in depressed adolescents being treated with SSRIs. Neither, however, is there irrefutable evidence to dismiss all such concerns. This makes SSRI prescribing a matter of medical judgement, ensuring the benefits outweigh the risks for the individual patients, as with so much in therapeutics. Overall, SSRIs show clinical benefits that we judge to outweigh the risks to neurodevelopment and are an important therapeutic choice in the treatment of moderate to severe adolescent depression.
© The Author(s) 2015.
Selective serotonin reuptake inhibitors (SSRIs) are used widely for the treatment of depression and anxiety disorders, and different SSRIs have different licence indications. They prevent the reuptake of serotonin in the synapse between nerve cells; they should be used with caution in children and adolescents owing to the possible side-effect of an increase in suicidal behaviour, particularly in this age group. They are generally safe in overdose, however. SSRIs have a number of side-effects, which are largely self-limiting, and a number of drug interactions of note, with both prescribed, over-the-counter and herbal preparations. This article examines to mode of action of SSRIs, prescribing issues, adverse effects and licencing issues.
Three types of ion-selective electrodes: PVC membrane, modified carbon paste (CPE), and coated graphite electrodes (CGE) have been constructed for determining paroxetine hydrochloride (Prx). The electrodes are based on the ion pair of paroxetine with sodium tetraphenylborate (NaTPB) using dibutyl phthalate as plasticizing solvent. Fast, stable and potentiometric response was obtained over the concentration range of 1.1×10−5–1×10−2 mol L−1 with low detection limit of 6.9×10−6 mol L−1 and slope of a 56.7±0.3mV decade−1 for PVC membrane electrode, the concentration range of 2×10−5–1×10−2 mol L−1 with low detection limit of 1.2×10−5 mol L−1 and slope of a 57.7±0.6 mV decade−1 for CPE, and the concentration range of 2×10−5–1×10−2 mol L−1 with low detection limit of 8.9×10−6 mol L−1 and slope of a 56.1±0.1 mV decade−1 for CGE. The proposed electrodes display good selectivity for paroxetine with respect to a number of common inorganic and organic species. The electrodes were successfully applied to the potentiometric determination of paroxetine hydrochloride in its pure state, its pharmaceutical preparation, human urine and plasma.
Citalopram, paroxetine and fluoxetine are selective serotonin reuptake inhibitor (SSRIs) currently used in the treatment of psychiatric disorders. We present an analytical method using micellar liquid chromatography to quantify these three drugs in pharmaceutical formulations, plasma and urine. The resolution was performed using a mobile phase of 0.075 M SDS – 6% (v/v) butanol buffered at pH 7 running through a C18 column under isocratic mode at 1 mL/min at 25 °C. The analytes were eluted in less than 20 min. The fluorescence detection was programmed at the maximum excitation (236, 295 and 230 nm) and emission (310, 350 and 305 nm) wavelengths for citalopram, paroxetine and fluoxetine, respectively. The experimental procedure was expedited to 1/5 dilution of the sample in the micellar mobile phase and filtration, thus avoiding clean-up and extraction steps. An aliquot of 20 μL was injected after 80 min of preparation, to obtain maximum sensitivity. The method was validated according to the guidelines of the Food and Drug Administration (FDA) in terms of calibration range (20–500 ng/mL; r2 > 0.999), sensitivity, accuracy (91.3–103.2%), precision (<9.3%), and robustness (<6.1%). The suitability of the method was successfully evaluated by analyzing plasma and urine samples from patients treated with SSRIs and checking the content of the active principle in tablets. Thus, the method can be applied to pharmacokinetics studies and in forensic cases, as well as in quality control of commercial pharmaceutical formulations.
Serotonergic antidepressants (SADs) are associated with increased bleeding risk.
To develop optimal guidelines for the usage of antidepressants in the perioperative period, this review of the bleeding risk associated with SADs was conducted.
A total of 10 original articles describing the relationship between SAD use and perioperative bleeding published in English before June 2013 were selected and reviewed.
A total of 6 studies showed positive associations between SAD use and perioperative bleeding. In particular, SAD use before orthopedic or breast surgery was associated with a tendency toward increased intraoperative or postoperative bleeding (i.e., increased need for transfusion during surgery, greater amount of intraoperative blood loss, bleeding events requiring intervention, or reoperation owing to postoperative bleeding). However, 3 studies among SAD users undergoing coronary artery bypass grafting and 1 study in SAD users undergoing facial surgery did not report an increased risk for postoperative bleeding.
The risks and benefits of SAD use should be weighed in all patients undergoing surgical operations. Physicians may consider planned discontinuation of SADs 2 weeks before the operation in patients with a high risk of bleeding but in the stable phase of depression. SAD discontinuation syndrome should be managed appropriately. If, despite the expected exacerbation of depression after discontinuation of antidepressants, discontinuation of SADs is nonetheless required because of the patient's clinical risk of bleeding, changing to an antidepressant that does not, or less potently, inhibits serotonin reuptake (e.g., bupropion or mirtazapine) can be considered.
A polypropylene (PP) sheet was successfully applied as an extracting medium for trace enrichment of fluoxetine (FLX) from urine samples, followed by high performance liquid chromatography–fluorescence detection (HPLC-FD). The extraction medium was a square, 1 × 1 cm, piece of polypropylene membrane sheet which was conditioned in methanol. The extraction process was conveniently carried out using a 5 mL urine sample. After extraction, the PP sheet was withdrawn and transferred to a glass vial for performing the desorption process using 210 µL organic solvent. After complete drying, the residue was dissolved in 50 µL of methanol and an aliquot of 20 µL was, finally, injected into the HPLC system. Some important extraction parameters such as desorption solvent, pH, ionic strength, desorption and extraction time were investigated and optimized. The linearity was studied by preconcentration of 5 mL of urine sample spiked with a standard solution of fluoxetine at the concentration range of 10-100 µ g L. The coefficient of determination was satisfactory (r > 0.99). The relative standard deviations (RSD %) value under the optimized condition was found to be 10.3%. The limit of detection (LOD) and limit of quantification (LOQ) were 1.9 and 6.4 µ g L, respectively. The developed method showed to be simple, sensitive and adequate for the trace determination of fluoxetine in urine media.
BACKGROUND AND OBJECTIVE: Antidepressant drugs are frequently used in deliberate self-poisoning resulting in a major risk for the patients due to their cardiac and central-nervous toxicity. In the present study the cases of intoxications consulting our Poison Center should be analysed illustrating recent results and trends about self-poisoning with antidepressants. PATIENTS AND METHODS: During the study period from 1995 to 2001 35 394 inquiries concerning deliberate self-poisoning were registered in our Poison Center. The substance used, age and gender of the patient as well as the degree of the observed symptoms were documented. Thereby, antidepressant drugs were grouped in tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI) and other antidepressants. RESULTS: The use of antidepressants in deliberate self-poisoning continuously increased during the study period from 17.3 % to 22.9 % with SSRI and other antidepressants being observed more frequently as compared to TCA. Antidepressant drugs were mainly used from female patients and in the age group between 35 and 54 years. Antidepressant drugs caused severe intoxications and deaths more frequently as the remainder substances with TCA showing higher rates of complications as compared to SSRI and other antidepressants. CONCLUSIONS: In recent years, an increasing importance of antidepressant drugs in deliberate self-poisoning was determined particularly concerning female and middle-aged patients. Due to the changing prescribing patterns larger numbers of intoxications with SSRI and other antidepressants were observed representing an advantage with respect to the reduced rate of complications known for these substances as compared to TCA. Nevertheless, the averagely more severe symptoms present in the three groups of antidepressants in comparison to the remainder drug overdoses demonstrated the need for hospitalization and monitoring of intoxications with antidepressants. Language: de
A simple and rapid TLC method using densitometric detection was developed for the simultaneous analysis of four SSRI antidepressants: citalopram, sertraline, fluoxetine, and fluvoxamine. The analytes were separated on silica gel 60 F254s TLC plates using a mobile phase composed of acetone-benzene-ammonia (50:45:5, v/v/v). Densitometric detection and quantification were carried out in the reflectance mode at 240 nm. The calibration curve was linear in the range of 500–5000 ng per spot for all analyzed compounds. The limit of detection was 40 ng per spot for citalopram and 50 ng per spot for fluoxetine, fluvoxamine, and sertraline, respectively. Statistical analysis proves that the method is both precise and accurate. The proposed method was successfully applied for the determination of citalopram and fluoxetine in their pharmaceutical formulations, with recoveries ranging from 98.7–101.9% of the labeled amount of the compounds. Finally, the reported method was also applied to the analysis of antidepressants in real biological samples.
Several strategies were applied in order to find a simple electrophoretic method for the investigation of five selective serotonin reuptake inhibitors (SSRI) (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline). Variation of the pH and of the ionic strength of the background electrolyte (BGE) were studied, but did not enable separation of the analytes. A micellar electrokinetic chromatography (MEKC) strategy for the simultaneous separation of the five SSRIs was developed involving a sodium dodecylsulfate (SDS) MEKC system. The electroosmotic flow (EOF) and the migration of the analytes were determined for separation buffers of several surfactant concentrations and organic modifier percentages. The most favourable MEKC system consisted of 20 mmol/L SDS in a phosphate buffer (pH 7.5) with 30% methanol; the separation was carried out using an uncoated fused-silica capillary, a separation voltage of 25 kV with currents typically less than 40 μA, and spectrophotometric detection at 200 nm. Full separation of the mixture with baseline resolution of all analytes was obtained.
Many antidepressants inhibit serotonin or norepinephrine reuptake or both to achieve their clinical effect. The selective serotonin reuptake inhibitor class of antidepressants (SSRIs) includes citalopram, escitalopram (active enantiomer of citalopram), fluoxetine, fluvoxamine, paroxetine, and sertraline. The SSRIs are as effective as tricyclic antidepressants in treatment of major depression with less significant side effects. As a result, they have become the largest class of medications prescribed to humans for depression. They are also used to treat obsessive-compulsive disorder, panic disorders, alcoholism, obesity, migraines, and chronic pain. An SSRI (fluoxetine) has been approved for veterinary use in treatment of canine separation anxiety. SSRIs act specifically on synaptic serotonin concentrations by blocking its reuptake in the presynapse and increasing levels in the presynaptic membrane. Clinical signs of SSRI overdose result from excessive amounts of serotonin in the central nervous system. These signs include nausea, vomiting, mydriasis, hypersalivation, and hyperthermia. Clinical signs are dose dependent and higher dosages may result in the serotonin syndrome that manifests itself as ataxia, tremors, muscle rigidity, hyperthermia, diarrhea, and seizures. Current studies reveal no increase in appearance of any specific clinical signs of serotonin toxicity with regard to any SSRI medication. In people, citalopram has been reported to have an increased risk of electrocardiographic abnormalities. Diagnosis of SSRI poisoning is based on history, clinical signs, and response to therapy. No single clinical test is currently available to confirm SSRI toxicosis. The goals of treatment in this intoxication are to support the animal, prevent further absorption of the drug, support the central nervous system, control hyperthermia, and halt any seizure activity. The relative safety of the SSRIs in overdose despite the occurrence of serotonin syndrome makes them more desirable than other antidepressants. The prognosis in animals that receive treatment is excellent. In one retrospective study, there were no deaths in 313 SSRI-poisoned dogs. No characteristic or classic histopathologic lesions result from SSRI toxicosis. Differential diagnoses for SSRI overdose must include ingestions of other serotonergic medications such as phenylpiperidine opioids (fentanyl and tramadol), mirtazapine, buspirone, amitraz, and chlorpheniramine.
To evaluate a clinical population of dogs exposed to selective serotonin reuptake inhibitor (SSRI) antidepressant medications and describe the clinical findings, epidemiological characteristics, outcome, and prognosis.
Retrospective study (February 1, 2005–August 31, 2010).
Animal poison control helpline.
Three hundred thirteen dogs with presumed SSRI toxicosis.
None.
Dogs with presumptive SSRI medication toxicosis identified by a review of the electronic database of Pet Poison Helpline, an animal poison control center, were evaluated. No clinical signs were reported in 76.3% (239/313) of cases. The remaining 23.6% (74/313) of cases demonstrated the following clinical signs: neurological 79.7% (59/74), gastrointestinal 25.6% (19/74), cardiovascular 9.5% (7/74), respiratory 8.2% (6/74), and thermoregulatory 6.7% (5/74). Of the dogs exhibiting neurological signs, 62.7% (37/59) showed depression, 37.2% (22/59) showed hyperactivity, 10.1% (6/59) exhibited ataxia, and 1.7% (1/59) showed other miscellaneous signs (eg, hyperesthesia). There was a significant difference between the dose ingested by symptomatic and asymptomatic dogs for fluoxetine (P = 0.0039), but not with any other SSRI. Ninety-four patients were confirmed to have received veterinary care. In cases where duration of veterinary care was determined (55/313), 67.2% (37/55) of dogs were hospitalized and 32.7% (18/55) treated as outpatients. The average duration of hospitalization was 18.5 hours, excluding outpatient visits. Of those patients that had complete follow-up information available (136/313), overall survival was 100%.
The overall prognosis for animals with SSRI toxicosis is excellent with veterinary attention. Central nervous system depression was the most common clinical sign associated with SSRI toxicosis.
This chapter discusses antidepressants and antipsychotics. Neuropsychiatric conditions have a point prevalence of 10% for adults. Worldwide, about 450 million people are estimated to be suffering from neuropsychiatric conditions (such as depression, schizophrenia, bipolar disorders, anxiety and related disorders, dementia, epilepsy, and substance abuse). Many of these conditions require medication with psychotropic drugs. The distribution is equal between men and women, with the exception of depression (more women) and substance misuse (more men). The prevalence and severity of these conditions and the urgent need for treatment have recently been surveyed. The figures differ strongly from country to country. The chapter describes most of the analytical techniques that are still used or have been used for the bio-analysis of antidepressants and antipsychotics. These analyses are normally done in serum or plasma for therapeutic drug monitoring (TDM, serum level determination for dose control) or clinical toxicology and in whole blood for postmortem determinations. There are several effective methods for the determination of antidepressants and antipsychotics in body fluids. Every laboratory—with its own experiences, apparatus, skills, and objective and subjective preferences—has to make its own choice for its optimal methods.
A specific and sensitive direct-injection high performance liquid chromatography atmospheric pressure chemical ionization
tandem mass spectrometry (HPLC-APCI-MS-MS) method has been developed for the rapid identification and quantitative determination
of citalopram, fluvoxamine, and paroxetine in human plasma. After dilution with 0.1% formic acid, plasma samples were injected
into the LC-MS-MS system. Proteins and other large biomolecules were removed during an on-line sample cleanup step. The inter-
and intra-assay coefficients of variation for all compounds were <11%. The total analysis time was 6 min per sample. The proposed
method permits direct analysis of plasma samples without time-consuming sample preparation.
In this paper, we evaluate the factors affecting the accuracy achievable in localization of an endoscopic wireless capsule as it passes through the digestive system of the human body. Using a three-dimension full electromagnetic wave simulation model, we obtain bounds on the capsule-location estimation errors when the capsule is in each of three individual organs: stomach, small intestine and large intestine. The simulations assume two different external sensor arrays topologies. We compare these performance bounds and draw the conclusion that location-estimation errors are different for different organs and for various topologies of the external sensor arrays.
A simple and fast capillary gas chromatographic method with flame ionisation detection (FID) has been developed for the analysis of fluoxetine, fluvoxamine, citalopram, sertraline and paroxetine in their pharmaceutical preparations, using clomipramine as internal standard in order to achieve quantification. The reported method is the first screening one that allows the determination of the five selective serotonin reuptake inhibitors by GC, permitting also to avoid prederivatization for the first time and it is even a pioneering work including an extensive analytical validation and robustness treatment on placebo pharmaceutical formulations too. Optimal conditions for the quantitative gas capillary separation were investigated: column head pressure (100 kPa), injector and detector (FID) temperatures (210 and 260 °C), time and temperature for the splitless step (0.80 min and 80 °C, respectively), volume injected (2 μL) and oven temperature program, providing analysis times shorter than 7 min. Aspects such as stability of solutions, linearity, accuracy, precision, detection and quantitation limits are examined on a selected placebo in order to validate this method. Peak purity is assessed using mass-selective detection (DMS). The robustness of this method was evaluated using the Plackett–Burman fractional factorial experimental design with a matrix of 15 experiments and the statistical treatment proposed by Youden and Steinner. The scope of the validated method is proved in the analysis of almost existing pharmaceutical preparations, with recoveries between 98.5% and 102.4% with regard to their nominal contents. Finally, the proposed method could be also a very successfully option for the analysis of these SSRIs in real urine samples introducing a previous solid phase extraction-preconcentration step.
This paper deals with the wear and creep resistance of a new composite material consisting of high density polyethylene (HD-PE) reinforced by continuous ultra high molecular weight polyethylene (UHMWPE) fibres.Unidirectional PE/PE laminates with fibre contents between 0%and 50% by volume were produced via hot pressing of HD-PE powder impregnated UHMWPE fibres. Flat specimens were tested in a ball-on-prism tribometer with polished steel balls. The penetration of the steel balls into the composite specimen was measured continuously. Creep deformation and material removal by wear were separated.The results were compared with the neat UHMWPE (good wear resistance but poor creep resistance and mechanical properties) and HD-PE (better creep resistance but poor wear resistance). The composites were found to combine the good wear resistance of UHMWPE with a superior creep resistance and mechanical properties. Further work is needed to improve the homogeneity of the composites in order to reduce the scatter of the wear results.
A previous study suggested an increased risk of preeclampsia among women treated with selective serotonin reuptake inhibitors (SSRIs). Using population-based health-care utilization databases from British Columbia (1997-2006), the authors conducted a study of 69,448 pregnancies in women with depression. They compared risk of preeclampsia in women using SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs) between gestational weeks 10 and 20 with risk in depressed women not using antidepressants. Among prepregnancy antidepressant users, the authors compared the risk in women who continued antidepressants between gestational weeks 10 and 24 with the risk in those who discontinued. Relative risks and 95% confidence intervals were estimated. The risk of preeclampsia in depressed women not treated with antidepressants (2.4%) was similar to that in women without depression (2.3%). Compared with women with untreated depression, women treated with SSRI, SNRI, and TCA monotherapy had adjusted relative risks of 1.22 (95% confidence interval (CI): 0.97, 1.54), 1.95 (95% CI: 1.25, 3.03), and 3.23 (95% CI: 1.87, 5.59), respectively. Within prepregnancy antidepressant users, the relative risk for preeclampsia among continuers compared with discontinuers was 1.32 (95% CI: 0.95, 1.84) for SSRI, 3.43 (95% CI: 1.77, 6.65) for SNRI, and 3.26 (95% CI: 1.04, 10.24) for TCA monotherapy. Study results suggest that women who use antidepressants during pregnancy, especially SNRIs and TCAs, have an elevated risk of preeclampsia. These associations may reflect drug effects or more severe depression.
This article reviews recent developments in the pharmacotherapy of mood disorders. Pharmacotherapy is the best studied and most widely validated approach for acute phase treatment and prevention of relapse-recurrence for patients with major depression, dysthymia, and bipolar affective disorder. Antidepressants are also the mainstay of inpatient treatment and, when considered together with electroconvulsive therapy, represent the first line of treatment for the most severe and incapacitating forms of depression. Similarly, pharmacotherapy with mood stabilizers is the first line of treatment for bipolar depression and mania. Despite such efficacy, problems associated with pharmacotherapy include acceptability, tolerability, adherence, incomplete remission, and high rates of recurrence after drug discontinuation. Moreover, a small subset of patients do not respond to multiple medication trials.
Objective.
—A consensus conference on the reasons for the undertreatment of depression was organized by the National Depressive and Manic Depressive Association (NDMDA) on January 17-18, 1996. The target audience included health policymakers, clinicians, patients and their families, and the public at large. Six key questions were addressed: (1) Is depression undertreated in the community and in the clinic? (2) What is the economic cost to society of depression? (3) What have been the efforts in the past to redress undertreatment and how successful have they been? (4) What are the reasons for the gap between our knowledge of the diagnosis and treatment of depression and actual treatment received in this country? (5) What can we do to narrow this gap? (6) What can we do immediately to narrow this gap?
The course of illness of 431 subjects with major depression participating in the National Institute of Mental Health Collaborative Depression Study was prospectively observed for 5 years. Twelve percent of the subjects still had not recovered by 5 years. There were decreasing rates of recovery over time. For example, 50% of the subjects recovered within the first 6 months, and then the rate of recovery declined markedly. Instantaneous probabilities of recovery reflect that the longer a patient was ill, the lower his or her chances were of recovering. For patients still depressed, the likelihood of recovery within the next month declined from 15% during the first 3 months of follow-up to 1% to 2% per month during years 3, 4, and 5 of this follow-up. The severity of current psychopathology predicted the probability of subsequent recovery. Subjects with moderately severe depressive symptoms, minor depression, or dysthymia had an 18-fold greater likelihood of beginning recovery within the next week than did subjects who were at full criteria for major depressive disorder. Many subjects who did not recover continued in an episode that looked more like dysthymia than major depressive disorder.
Depression is unfortunately a very common illness; it is extremely unpleasant for sufferers and for their relatives and friends, and is associated with a substantial morbidity and mortality. The lifetime risk of developing depression was estimated by Boyd & Weissman (1981) as between 8% and 12% for men and between 20% and 26% for women. Estimates of point-prevalence vary, but a review of published studies suggests a level of 8.4% for men and 14.8% for women. A difference in prevalence of depression between men and women, with a twofold increase in women, appears to be well established. Recent evidence suggests, however, that the incidence of depression in men is rather more common than was previously thought: some apparent sex differences in frequency may be accounted for by a difference in coping with, and expression of, depressive symptoms (Angst & Dobler-Mikola, 1984). What is clear from the epidemiological studies in ‘normal’ populations is that much depressive illness remains untreated.
All existing treatments for depression, in particular the tricyclic antidepressants (TCAs), have drawbacks. Since the TCAs, for example, are associated with rather unpleasant and sometimes dangerous side-effects, which reduce compliance and compromise treatment, the search for new antidepressants with less unwanted effects and if possible greater efficacy remains an important goal. A recent trend in antidepressant research has been to develop compounds with specific pharmacological actions, which are selective for one of the amine systems. Currently, a number of specific 5-HT reuptake inhibitors are being developed, and some of these are now in clinical use.
• One hundred nineteen patients who met specific criteria for atypical depression completed six weeks of double-blind, randomly assigned treatment with phenelzine sulfate, imipramine hydrochloride, or placebo. The overall response rates were 71% with phenelzine, 50% with imipramine, and 28% with placebo. Phenelzine was widely superior to placebo and also showed superiority to imipramine. Phenelzine superiority appeared even greater after an additional six-week continuation phase. Imipramine was only moderately effective in this atypical depressive sample. Unexpectedly, the superiority of either phenelzine or imipramine to placebo was largely confined to patients in subsets of the study sample who were prospectively judged to also have a history of spontaneous panic attacks and/or show hysteroid dysphoric features. This is consonant with some but not other recent findings and requires replication. Overall, the concept of atypical depression as a subtype that is preferentially responsive to monoamine oxidase inhibitors is supported.
• The course of illness of 431 subjects with major depression participating in the National Institute of Mental Health Collaborative Depression Study was prospectively observed for 5 years. Twelve percent of the subjects still had not recovered by 5 years. There were decreasing rates of recovery over time. For example, 50% of the subjects recovered within the first 6 months, and then the rate of recovery declined markedly. Instantaneous probabilities of recovery reflect that the longer a patient was ill, the lower his or her chances were of recovering. For patients still depressed, the likelihood of recovery within the next month declined from 15% during the first 3 months of follow-up to 1 % to 2% per month during years 3, 4, and 5 of this follow-up. The severity of current psychopathology predicted the probability of subsequent recovery. Subjects with moderately severe depressive symptoms, minor depression, or dysthymia had an 18-fold greater likelihood of beginning recovery within the next week than did subjects who were at full criteria for major depressive disorder. Many subjects who did not recover continued in an episode that looked more like dysthymia than major depressive disorder.
Paroxetine is a new selective serotonin reuptake inhibitor which has been extensively evaluated as an antidepressant in clinical trials and a large computerzed safety database has been accumulated. A comprehensive review of data on dosage supports the recommendation that 20 mg paroxetine daily is the optimal therapeutic dose for most patient. When compared to active controls-mainly tricyclic antidepressants-paroxetine was found to have a different adverse-event profile with fewer anticholinergic, cardiovascular and nervous system events but more gastrointestinal events, particularly nausea. However, these events were not severe and did not usually lead to discontinuation of treatment. The adverse events reported with paroxetine were most likely to occur early in the course of treatment and there was no evidence of any increase in events in the elderly or with longer-term treatment. Paroxetine was not associated with excess of death from any cause, suicides, suicide attempts or serious life-threatening events. No clinically significant drug-related abnormalities were reported in laboratory monitoring, including liver function tests, in short-or long-term use. Finally, and importantly for an antidepressant, paroxetine appears relatively safe in overdose.
A post-hoc analysis of nine controlled antidepressant trials examined the intensity of the initial anxiety and agitation of depressed patients improved by SSRIs compared with depressed patients improved by norepinephrine (NK) reuptake inhibitors, mixed NE/serotonin reuptake inhibitors and placebo. We report that SSKI responders were more anxious-agitated than NE reuptake inhibitor responders, suggesting a preferential efficacy of SSRIs in agitated depression.
Objective.
—To compare pregnancy outcome following first-trimester fluoxetine (Prozac) exposure with pregnancy outcome in two matched control groups. Fluoxetine is a new antidepressant used by many young women. Currently, no published data exist on its safety in pregnancy.Design.
—We prospectively collected and followed up 128 pregnant women exposed to a mean daily dose of 25.8 mg (±13 mg) of fluoxetine during the first trimester and compared pregnancy outcome with two matched groups of women exposed during the first trimester of pregnancy to either nonteratogens or tricyclic antidepressants.Results.
—Rates of major malformations were comparable within the three groups and did not exceed those expected in the general population. Women treated with fluoxetine had a tendency for increased risk for miscarriage when compared with women exposed to nonteratogens (relative risk, 1.9; 95% confidence interval, 0.92 to 3.92). The rate of miscarriages in the fluoxetine group was comparable with the tricyclic group (13.5% and 12.2% vs 6.8% in the nonteratogens).Conclusions.
—Our study suggests that the use of fluoxetine during embryogenesis is not associated with an increased risk of major malformations. Women exposed to both fluoxetine and tricyclic antidepressants tended to report higher rates of miscarriage; further studies will be needed to confirm this observation and to separate the effects of the psychiatric condition from the associated drugs. Long-term studies will be warranted to rule out potential developmental teratology of fluoxetine, which affects a central nervous system neurotransmitter.(JAMA. 1993;269:2246-2248)
• We conducted a randomized 3-year maintenance trial in 128 patients with recurrent depression who had responded to combined short-term and continuation treatment with imipramine hydrochloride and interpersonal psychotherapy. A five-cell design was used to determine whether a maintenance form of interpersonal psychotherapy alone or in combination with medication could play a significant role in the prevention of recurrence. A second question was whether maintaining antidepressant medication at the dosage used to treat the acute episode rather than decreasing to a "maintenance" dosage would provide prophylaxis superior to that observed in earlier trials in which a maintenance dosage strategy was employed. Survival analysis demonstrated a highly significant prophylactic effect for active imipramine hydrochloride maintained at an average dose of 200 mg and a modest prophylactic effect for monthly interpersonal psychotherapy. We conclude that active imipramine hydrochloride maintained at an average dose of 200 mg is an effective means of preventing recurrence and that monthly interpersonal psychotherapy serves to lengthen the time between episodes in patients not receiving active medication.
Objective.
—To determine if the diagnosis of major depression in patients hospitalized following myocardial infarction (Ml) would have an independent impact on cardiac mortality over the first 6 months after discharge.Design.
—Prospective evaluation of the impact of depression assessed using a modified version of the National Institute of Mental Health Diagnostic Interview Schedule for major depressive episode. Cox proportional hazards regression was used to evaluate the independent impact of depression after control for significant clinical predictors in the data set.Setting.
—A large, university-affiliated hospital specializing in cardiac care, located in Montreal, Quebec.Patients.
—All consenting patients (N=222) who met established criteria for Ml between August 1991 and July 1992 and who survived to be discharged from the hospital. Patients were interviewed between 5 and 15 days following the MI and were followed up for 6 months. There were no age limits (range, 24 to 88 years; mean, 60 years). The sample was 78% male.Primary Outcome Measure.
—Survival status at 6 months.Results.
—By 6 months, 12 patients had died. All deaths were due to cardiac causes. Depression was a significant predictor of mortality (hazard ratio, 5.74; 95% confidence interval, 4.61 to 6.87; P=.0006). The impact of depression remained after control for left ventricular dysfunction (Killip class) and previous Ml, the multivariate significant predictors of mortality in the data set (adjusted hazard ratio, 4.29; 95% confidence interval, 3.14 to 5.44; P=.013).Conclusion.
—Major depression in patients hospitalized following an Ml is an independent risk factor for mortality at 6 months. Its impact is at least equivalent to that of left ventricular dysfunction (Killip class) and history of previous Ml. Additional study is needed to determine whether treatment of depression can influence post-MI survival and to assess possible underlying mechanisms.(JAMA. 1993;270:1819-1825)
Objective.
—Suicide by drug overdose is a major public health problem, and antidepressant medications are the most common agent involved. European studies suggest differences in the rates of suicide by overdose among antidepressants, but no reports have been published for the United States. We estimated the comparative risks of suicide attempts and suicides, and the relative risk of fatality in the event of an overdose for the major antidepressants currently marketed in the United States.Data Sources.
—Information regarding suicide attempts and suicides by antidepressant overdose was obtained from the published reports of the Drug Abuse and Warning Network and the annual report of the American Association of Poison Control Centers, and corrected for differences in total annual prescriptions using data from the National Prescription Audit.Results.
—The risk of a suicide attempt did not appear to differ among antidepressants. The tricyclic antidepressants were associated with a higher rate of death in the event of an overdose than the newer nontricyclic antidepressants in both the annual report of the American Association of Poison Control Centers and the Drug Abuse and Warning Network data. The chance of death after an overdose was greater for desipramine hydrochloride than for other tricyclics.Conclusion.
—The higher risk of suicide with tricyclics vs nontricyclics may be explained by a higher rate of death from overdose rather than more suicide attempts. Tricyclics carry the risk of greater cardiotoxicity. The basis for the even higher rate of death/overdose of desipramine is not known and requires further research. If these findings are replicated in a case-control study design, they have important implications for the choice of an antidepressant for the depressed patient at risk for suicidal behavior.(JAMA. 1992;268:3441-3445)
DEPRESSION in the aging and the aged is a major public health problem. It causes suffering to many who go undiagnosed, and it burdens families and institutions providing care for the elderly by disabling those who might otherwise be able-bodied. What makes depression in the elderly so insidious is that neither the victim nor the health care provider may recognize its symptoms in the context of the multiple physical problems of many elderly people. Depressed mood, the typical signature of depression, may be less prominent than other depressive symptoms such as loss of appetite, sleeplessness, anergia, and loss of interest in, and enjoyment of, the normal pursuits of life. There is a wide spectrum of depressive symptoms as well as types of available therapies.
Because of the many physical illnesses and social and economic problems of the elderly, individual health care providers often conclude that depression is a normal consequence
The pharmacokinetics and clinical properties of clomipramine, the classic 5-HT uptake inhibiting antidepressant is well known. Within the last years, several new and more selective serotonin uptake inhibitors have been introduced in clinical practice, including trazodone, citalopram, paroxetine, femoxetine, fluvoxamine and fluoxetine. They differ by their chemical structure, and therefore, important differences can be expected with respect to their metabolism and kinetics in man. In this presentation, the following points will be addressed: Present knowledge about their metabolism and their kinetics, taking into account that most of them are racemates, whose clinical role is only partially understood, including that of the metabolites. It will further be examined whether they are candidates for a genetic polymorphism of metabolism of the debrisoquine-spartein-dextromethorphan type. This may e.g. be suspected for fluoxetine which interferes strongly with the metabolism of tricyclic antidepressants. Finally, data of the literature will be analysed about a possible relationship between the clinical efficacy of these drugs and their plasma levels, including those of their active metabolites.
• The incidence of suicidal acts was studied in 68 depressed patients and related to the level of 5-hydroxyindoleacetic acid (5HIAA) in the cerebrospinal fluid. The distribution of 5-HIAA levels was bimodal. Patients in the low 5-HIAA mode (below 15 ng/ml) attempted suicide significantly more often than those in the high mode, and they used more violent means. Two of the 20 patients in the low mode, and none of the 48 patients in the high mode died from suicide.
• Utilization of health and mental health services by noninstitutionalized persons aged 18 years and older is examined based on interviews with probability samples of 3,000 to 3,500 persons In each of three sites of the National Institute of Mental Health Epidemiologic Catchment Area (ECA) program: New Haven, Conn, Baltimore, and St Louis. In all three ECAs, 6% to 7% of the adults made a visit during the prior six months for mental health reasons; proportions were considerably higher among persons with recent DSM-III disorders covered by the Diagnostic Interview Schedule (DIS) or severe cognitive impairment. Between 24% and 38% of all ambulatory visits by persons with DIS disorders were to mental health specialists. In seeking mental health services, men were more likely to turn to the specialty sector than to the generalist; women used both sectors about equally. The aged infrequently received care from mental health specialists. Visits for mental health reasons varied considerably depending on specific types of DIS disorder.
• After conducting a randomized, 3-year maintenance trial in 128 patients with recurrent depression who had responded to combined short-term and continuation treatment with imipramine hydrochloride and interpersonal psychotherapy, we asked those individuals who survived the 3-year trial receiving active medication (with or without psychotherapy) to continue in a 2-year additional randomized trial of active medication vs placebo. The question was whether maintaining antidepressant medication at the dosage used to treat the acute episode beyond 3 years would continue to provide a significant prophylactic effect compared with medication discontinuation after the 3 years of effective maintenance treatment. Survival analysis demonstrated a highly significant continued prophylactic effect for active imipramine hydrochloride treatment maintained at an average dose of 200 mg. We conclude that active imipramine treatment is an effective means of preventing recurrence beyond 3 years and that patients with previous episodes less than 21/2 years apart, therefore, merit continued prophylaxis for at least 5 years.
• We investigated the effectiveness of two brief psychotherapies, interpersonal psychotherapy and cognitive behavior therapy, for the treatment of outpatients with major depressive disorder diagnosed by Research Diagnostic Criteria. Two hundred fifty patients were randomly assigned to one of four 16-week treatment conditions: interpersonal psychotherapy, cognitive behavior therapy, imipramine hydrochloride plus clinical management (as a standard reference treatment), and placebo plus clinical management. Patients in all treatments showed signifi-cant reduction in depressive symptoms and improvement in functioning over the course of treatment. There was a consistent ordering of treatments at termination, with imipramine plus clinical management generally doing best, placebo plus clinical management worst, and the two psychotherapies in between but generally closer to imipramine plus clinical management. In analyses carried out on the total samples without regard to initial severity of illness (the primary analyses), there was no evidence of greater effectiveness of one of the psychotherapies as compared with the other and no evidence that either of the psychotherapies was significantly less effective than the standard reference treatment, imipramine plus clinical management.
Comparing each of the psychotherapies with the placebo plus clinical management condition, there was limited evidence of the specific effectiveness of interpersonal psychotherapy and none for cognitive behavior therapy. Superior recovery rates were found for both interpersonal psychotherapy and imipramine plus clinical management, as compared with placebo plus clinical management. On mean scores, however, there were few significant differences in effectiveness among the four treatments in the primary analyses. Secondary analyses, in which patients were dichotomized on intial level of severity of depressive symptoms and impairment of functioning, helped to explain the relative lack of significant findings in the primary analyses. Significant differences among treatments were present only for the subgroup of patients who were more severely depressed and functionally impaired; here, there was some evidence of the effectiveness of interpersonal psychotherapy with these patients and strong evidence of the effectiveness of imipramine plus clinical management. In contrast, there were no significant differences among treatments, including placebo plus clinical management, for the less severely depressed and functionally impaired patients.
Supplementing but not supplanting the original series of tricyclic and monoamine oxidase (MAO) inhibitor compounds, a new generation of antidepressant medications has been developed and marketed throughout the past decade. Constituting a more diverse group of drugs than the standard agents, the newer drugs in general have more selective acute biochemical actions (reuptake blockade of a single neurotransmitter, inhibition of 1 subtype of MAO), enabling more precise targeting of symptoms and avoiding common antidepressant-associated side effects, especially anticholinergic and cardiovascular effects. Moreover, a number of recent additions to this group, such as bupropion and ademetionine (S-adenosyl-methionine), incorporate novel mechanisms of action, challenging previous concepts of how antidepressants work, and offering opportunities for research into the pathophysiology of mood disorders. Caution in prescribing the newer antidepressants must be applied, however, as recent experience, e.g. with nomifensine, suggests that unforeseen toxicities may not appear until a medication has been in use for several years.
This study is a comparison across treatment settings of two previously published trials, namely the Danish University Antidepressant Group (DUAG) study on citalopram vs. clomipramine in hospitalized patients with major depression, and the Nordic citalopram vs. imipramine study of depressed patients treated by their family doctors. The Hamilton Depression Scale (HAM-D) had the same level of inter-rater reliability and construct validity in the two settings. Using a HAM-D score of 7 or less as the criterion for full remission, clomipramine was superior to imipramine and citalopram. Using a reduction of the baseline HAM-D score by 50% or more as a response criterion, there were no differences between the three antidepressants after 5 or 6 weeks of treatment. Citalopram showed superior tolerability to the tricyclic antidepressants.
Prescribing patterns of selective serotonin reuptake inhibitors (SSRIs)in the treatment of depression in primary care in the UK were examined in a cross sectional study using a computerised database which provided information from 100 practices (383 general medical practitioners) across the UK. Over a three month period, a total of 2,548 prescriptions were written for these compounds. Differences in the patterns of prescribing between the SSRIs were found, which suggested that substantial upward titration from starting doses occurs with fluvoxamine, paroxetine and sertraline, but not with fluoxetine. A possible explanation for these differences is that an effective dose is reached earlier in treatment with fluoxetine, which mag simplify treatment and improve outcomes. Further studies are required to evaluate the clinical significance of these findings.
The social and economic impact of depression on society at large has only recently been elucidated. The U.S. National Institute of Mental Health (NIMH) Epidemiology Catchment Area (ECA) Program demonstrated that the 1 year prevalence of DSM-III mood disorders was almost 10% in the adult population of the United States—or that in any year over 17 million adults suffer from a major mood disorder. Moreover, data gathered by the Cross-National Collaborative Group suggest further that the incidence of depression is increasing, not only in the United States, but in many countries all over the world. And results from the Medical Outcomes Study, which assessed the level of disability associated with depression compared with other common medical disorders, suggested that patients with major depression and dysthymia suffer greater levels of impairment than patients with hypertension, diabetes, arthritis, lung disease, and GI disorders.
A number of recent investigations have sought to quantify the costs of depression in the United States and the United Kingdom, and found that depression has remarkably high direct and indirect economic costs, comparable to those associated with other major public health problems. This paper reviews depression within this larger framework and evaluates the impact of treatment advances on the costs of depression. Both pharmaceutical-sponsored and non-sponsored cost-benefit analyses reveal that while the classical anti-depressants cost less on a per-pill basis, ultimately treatment may be less expensive with the newer SSRIs because of improved compliance leading to better outcomes. Depression 2:173–177 (1994/1995).
Objective.
—To compare the clinical, functional, and economic outcomes of initially prescribing fluoxetine with outcomes of initially selecting imipramine or desipramine.Design.
—Randomized controlled trial.Setting.
—Primary care clinics of a Seattle, Wash, area staff-model health maintenance organization from 1992 through 1994.Patients.
—A total of 536 adults beginning antidepressant treatment for depression.Intervention.
—Random assignment of initial antidepressant prescription (desipramine, fluoxetine, or imipramine). Subsequent antidepressant treatment (doses, medication changes or discontinuation, specialty referral) was managed by the primary care physician.Main Outcome Measures.
—Assessments after 1, 3, and 6 months examined clinical outcomes (Hamilton Depression Rating Scale and the depression subscale of the Hopkins Symptom Checklist) and quality-of-life outcomes (Medical Outcomes Study SF-36). Medication use and health care costs were assessed using the health maintenance organization's computerized data.Results.
—Patients assigned to receive fluoxetine reported fewer adverse effects, were more likely to continue the original medication, and were more likely to reach adequate doses than patients beginning treatment with either tricyclic drug. The fluoxetine group reported marginally better clinical outcomes after 1 month, but these differences were not statistically significant and disappeared by the 3-month assessment. Quality-of-life outcomes in the 3 groups did not differ. Total health care costs over 6 months were approximately equal for the 3 groups, with higher antidepressant costs in the fluoxetine group balanced by lower outpatient visit and inpatient costs.Conclusions.
—Clinical outcomes, quality-of-life outcomes, and overall treatment costs provide no clear guidance on initial selection of fluoxetine or tricyclic drugs. Thus, patients' and physicians' preferences are an appropriate basis for treatment selection.(JAMA. 1996;275:1897-1902)
To determine the effect of fluoxetine on diazepam's pharmacokinetic and psychomotor responses, single oral doses of 10 mg diazepam were administered to six normal subjects on three occasions, either alone or in combination with 60 mg fluoxetine. Diazepam was given alone, after a single dose of fluoxetine, and after eight daily doses of fluoxetine. Psychometric data showed that fluoxetine had no significant effect on the psychomotor responses to diazepam. However, the pharmacokinetic data indicated a change in diazepam disposition after fluoxetine administration. Diazepam AUC was larger, the half-life was longer, and the plasma clearance was lower after fluoxetine administration, suggesting that fluoxetine inhibited the metabolism of diazepam. The reduced formation of an active metabolite, N-desmethyldiazepam, also suggested that fluoxetine inhibited diazepam's metabolism. The clinical implications of this pharmacokinetic drug-drug interaction are minor because psychomotor responses were unaffected and offsetting changes in the kinetics of diazepam and its metabolite occurred. Dosage modification of either fluoxetine or diazepam is unlikely to be necessary.
Contends that antidepressants should not be stopped immediately if a response is observed but should be continued for a longer period to prevent early relapse. The minimum duration of the continuation phase is discussed. It is noted that in analyzing the efficacy of antidepressants in the continuation or prophylactic phase of treatment, more weight should be given to placebo-controlled studies. A study testing the efficacy of fluoxetine in preventing recurrence of new episodes in 456 patients with major unipolar recurrent depression is presented. 182 of these Ss participated in a 1-yr prophylactic study. Fluoxetine was found to have a highly significant prophylactic efficacy compared with placebo. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
We investigated 243 patients from a series of comparator and/or placebo-controlled, double-blind trials of several mechanistically distinct antidepressants. Data were analyzed for changes in suicidal ideation during trial participation.
Ambulatory referrals with a current DSM-III-R major depression, corroborated by a structured interview, were screened; those fulfilling entrance criteria began a 1-week, single-blind placebo run-in. Pool 1 (placebo comparator) subjects who continued to meet entrance criteria at their baseline visit were blindly randomized to receive either placebo (n = 49) or one of several novel antidepressant drugs (n = 81). Pool 2 subjects (active comparator) were randomized to either a novel antidepressant (n = 66) or a tricyclic antidepressant comparator (n = 57). Trial duration ranged from 5 to 8 weeks. Patient compliance was monitored by a regular pill count from each subject's blister pack.
Analyses were conducted on Pool 1 and Pool 2 separately. Ego-dystonic suicidal preoccupation or acts were not reported in either group. There was a statistically significant treatment difference in Hamilton Depression Rating Scale item 3 mean peak change (Pool 1); patients treated with a novel antidepressant demonstrated a mean decrease in HDRS item 3 (improvement), those patients randomized to placebo experienced a mean score increase (worsening). No statistically significant treatment difference in mean peak change difference factors (CDFs) between the novel antidepressants and conventional tricyclic antidepressant comparators (Pool 2) was observed. A statistically significant correlation between item 3 change and total HDRS-17 change also emerged (both treatments within each pool).
Increased suicidal ideas/behaviors may emerge during depression “treatment.” However, in this study it occurred more frequently among placebo recipients, suggesting a change in suicidal ideation was a reflection of the underlying disease process. Not surprisingly, antidepressants improved suicidal ideation to a greater extent than placebo. Depression 2:73–79 (1994).
The selective serotonin reuptake inhibitors (SSRIs) have the best established tolerance and safety profile of the available antidepressants. Evidence for this conclusion comes from controlled clinical trials, post-marketing surveillance, prescription audits and case reports. Comparative studies are sparse within the class of SSRIs, and methodological differences between studies are problematic, yet certain differences emerge in tolerability when comparing placebo-adjusted incidence rates for the most common adverse events. Fluoxetine commonly produces nervousness, anxiety, insomnia and headache. Sexual dysfunction is more common with sertraline. Dry mouth can occur from paroxetine, and gastrointestinal effects (cramps, diarrhoea) from sertraline. The incidence of nausea appears to be no greater for any particular drug, especially after several weeks of treatment. Hyponatraemia and extrapyramidal side effects are rare events reported with all SSRIs. General guidelines are given for choosing an initial SSRI according to adverse effect profile; however, inter-subject variability exists in the expression of adverse effects, as well as intra-subject variability during treatment, suggesting the development of pharmacodynamic tolerance. Thus, rational selection of an SSRI on the basis of comparative tolerability is possible, but largely empirical without further scientific evidence from clinical trials specifically designed to differentiate drugs according to their adverse effect profile.
The recognition that antidepressants are effective in panic and anxiety disorders had led to the evaluation of drugs selective for serotonin uptake in an attempt to dissect the neurotransmitters responsible for panic disorder. Fluvoxamine is the best studied of the selective serotonin reuptake inhibitors (SSRIs) and recent double-blind studies have confirmed earlier findings showing a reduced number and duration of panic attacks. In addition, fluvoxamine attenuates the ‘accessory symptoms’ of panic disorder such as depression and anxiety. Fluoxetine has only been evaluated in open trials, although these results are generally positive. Paroxetine has shown similar efficacy to clomipramine in a large, controlled study, although the other SSRIs have seldom been investigated. Fluvoxamine lacks the activating properties possessed by some SSRIs and this also makes it a useful candidate for the treatment of anxious depression. The efficacy of fluvoxamine in obsessive-compulsive disorder has been established in several double-blind, placebo-controlled trials. In clinical terms, fluvoxamine is approximately as effective as clomipramine, but with a decidedly better adverse event profile. Fluoxetine has also proved effective in obsessive-compulsive disorder, although a recent meta-analysis suggests that fluvoxamine may be somewhat more effective. The other SSRIs have not been sufficiently well studied to justify conclusive statements.
Although the acute pharmacology properties of antidepressants is predominantly due to their presynaptic action, their therapeutic activity is believed to derive from adaptive post-synaptic changes in monoaminergic neurones. The selective serotonin reuptake inhibitors (SSRIs) exhibit differences in potency at inhibiting serotonin reuptake, although the differences do not correlate with clinical posology. There are also differences in their effects on neurotransmitter receptors; paroxetine has a slight affinity for muscarinic cholinergic receptors whilst citalopram has a slight affinity for histamine-H1 receptors. These properties may be related to clinical adverse effects. The pharmacokinetic profiles of the SSRIs show many differences. Whilst fluvoxamine, paroxetine and citalopram are metabolized to inactive products, fluoxetine is metabolized to norfluoxetine which is pharmacologically active and, like its parent compound, has a long half-life. Fluvoxamine is less protein-bound than the other SSRIs and sertraline is only well absorbed when taken with food. Differences are also apparent in the suitability of individual SSRIs in special patient groups. There has been considerable speculation over the inhibition of cytochrome P450 isoenzymes which are responsible for the metabolism of SSRIs and other drugs. In clinical practice, the differences between the SSRIs in this respect are probably of limited importance. However, it is worthwhile that clinicians be made aware of possible interactions between drugs that act as inhibitors or substrates of the hepatic cytochrome P450 system.
In a double-blind multicentre trial in patients with major depression, the efficacy and the tolerability of sertraline were compared with those of fluoxetine, during an eight-week acute treatment phase followed by a 24-week continuation treatment phase in treatment responders.
A total of 165 patients who met DSM III-R criteria for moderate to severe major depression were randomized to receive either sertraline or fluoxetine for short-term and continuation treatment with initial daily dosages of either 50 mg of sertraline or 20 mg of fluoxetine. In the event of an inadequate response after 4 weeks of double-blind therapy these doses could be doubled.
Both treatment groups demonstrated similar improvements on both the Hamilton Rating Scale for Depression (HAM-D) and the Montgomery and Asberg Depression Rating Scale (MADRS), during the acute phase as well as during the continuation phase. Both sertraline and fluoxetine were well tolerated, the most common side-effects being gastrointestinal symptoms. Significantly more patients in the fluoxetine-treatment group experienced activationg adverse events.
The study demonstrates similar antidepressant efficacy and tolerability for sertraline and fluoxetine in acute and continuation treatment and equivalence of sertraline 50 mg daily with fluoxetine 20 mg daily in the treatment of depression.
Primary affective disorders, depressive or manic episodes in patients who have been psychiatrically well previously, or who have had episodes of mania or depression without other psychiatric illnesses (Robins and Guze, 1969), are associated with high suicide rates. The following data indicate that the suicide risk among these patients is over thirty times greater than that of the population without these disorders, and that the risk of suicide compared to other causes of death may be increased early in the course of the illness.
This article provides estimates of direct treatment costs and indirect costs from lost productivity associated with the morbidity and mortality of depression. Data are based on epidemiologic estimates of the prevalence of major depressive illness and on the number of suicides assumed to be secondary to depression. The number of hospitalizations, hospital days, physician and mental health provider visits, home/nursing home costs, and pharmaceutical costs are estimated. The direct and indirect costs are estimated to be approximately $16.3 billion per year. These economic figures provide a lower-bound estimate of the full economic burden of major depression and further emphasize the need for timely recognition and treatment to potentially minimize the negative impact of the illness on society.
Suicide, attempted suicide, and relapse rates in 519 depressives were examined, comparing the effects of different treatments. After six months, suicide attempts were seen significantly less frequently in the ECT groups (0.8%) than in the antidepressant group (4.2%) or the "adequate" antidepressant subgroup (7.0%) Fewer suicide attempts occurred in the ECT group compared to the antidepressant group among both in those who had attempted suicide prior to admission (0% vs 10%) and in those who had not (1.1% vs 3.6%). A history of attempted suicide showed a greater risk of both suicide (2.9%) in the following year and subsequent suicide attempt (5.9%). A depressive diagnosis may be as good a predictor of suicidal behavior as a history of attempted suicide. Relapse rates did not differ between treatment groups.
The incidence of suicidal acts was studied in 68 depressed patients and related to the level of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid. The distribution of 5-HIAA levels was bimodal. Patients in the low 5-HIAA mode (below 15 ng/ml) attempted suicide significantly more often than those in the high mode, and they used more violent means. Two of the 20 patients in the low mode, and none of the 48 patients in the high mode died from suicide.
3-(p-Trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine (Lilly 110140) competitively inhibited the uptake of serotonin (5-HT), norepinephrine (NE) and dopamine into synaptosomes of rat brain with Ki values of 5.5 x 10-minus8, 9.5 x 10-minus6 and 1.3 x 10-minus5 M, respectively. Aiming for a more effective inhibitor of 5-HT uptake, we found the trifluoromethyl group in the phenoxy ring was most favorable at the para-position and was better than other substituting groups including fluoro, chloro, methyl and methoxy groups. The N-demethylated (primary amine) and the N.N-diemthylated (tertiary amine) derivatives inhibited the uptake of monoamines with the same effectiveness as Lilly 110140 (a secondary amine). The uptake of 5-HT into synaptosomes was significantly inhibited 15 minutes after an intraperitoneal administration of Lilly 110140. The inhibition persisted for a 24-hour period. NE uptake in vitro maintained a normal rate during the entire time course. Lilly 110140 likewise had no effect on the in vitro and in vivo accumulation of 3-H-tryptophan in the brain. The effect of Lilly 110140 and the tricyclic drug, chlorimipramine, was compared. Although chlorimipramine inhibited the uptake of 5-HT into synaptosomes with same effectiveness as Lilly 110140 in vitro, it reduced the uptake of both 5-HT and NE in vivo. Chlorimipramine exerted its greatest inhibition on the two uptake processes in the 1st hour and none by the 4th hour. Unlike the tricyclic drugs, imipramine, chlorimipramine, desipramine and chlordesipramine, Lilly 110140 and its primary amine derivative did not block the in vivo uptake of NE into rat heart. The present study suggests that Lilly 110140 is a potent and selective inhibitor for uptake of 5-HT into synaptosomes of rat brain.
Depression is a heterogeneous disease state characterised by complex alterations in several CNS neurotransmitter and receptor systems. All antidepressants are thought to act by causing postsynaptic adaptive changes (e.g. in transducers or second messengers) within these systems. Thus, the mechanism of action of selective serotonin reuptake inhibitors (SSRIs) cannot simply be explained in terms of inhibition of serotonin (5-hydroxytryptamine) [5-HT] reuptake. Fluvoxamine, sertraline and fluoxetine downregulate central beta-adrenoceptors, and all SSRIs are believed to normalise central 5-HT1A- and 5-HT2-receptor density and function in patients with depression. SSRIs are as effective as tricyclic antidepressants in the treatment of depression, but have distinct tolerability advantages--they are not associated with anticholinergic adverse effects, cardiotoxicity, sedation or weight gain. However, gastrointestinal reactions (e.g. nausea, diarrhoea/loose stools, constipation) are relatively common during SSRI therapy. Additionally, in contrast to tricyclic antidepressants, SSRI dosage adjustments appear to be unnecessary in elderly depressed patients. Fluvoxamine has a much shorter elimination half-life than fluoxetine and its active metabolite, norfluoxetine, and therefore a reduced potential for drug interactions. Only small amounts of fluvoxamine and fluoxetine, but large quantities of paroxetine, are secreted in breast milk. Furthermore, genetic polymorphism has not been documented for fluvoxamine metabolism, whereas slow and fast metabolisers of paroxetine, and fast metabolisers of fluoxetine have been identified. SSRIs have a better tolerability profile than tricyclic antidepressants, as indicated by lower mean rank scores for behavioural toxicity. Moreover, SSRIs are associated with a much lower incidence of fatal toxicity than tricyclics, and appear to be relatively safe in overdosage.(ABSTRACT TRUNCATED AT 250 WORDS)
Selective serotonin reuptake inhibitors (SSRIs) are a recently developed class of drugs with significantly greater antidepressant efficacy than placebo. Generally, in double-blind comparative trials, all SSRIs demonstrated antidepressant efficacy similar to that of the ‘standard’ tricyclic antidepressants amitriptyline and imipramine; a meta-analysis of controlled trials found the efficacy of the SSRIs to be equivalent to that of the 2 tricyclics. Nevertheless, because of small patient numbers included in most studies that compare SSRIs with other antidepressants, no definitive statements about relative efficacy can be made. In these studies it is simply possible to state that no statistically significant differences were identified between SSRIs and the comparative antidepressants. Importantly, differences in clinical characteristics exist between the SSRIs — differences in elimination half-life (t½β) between fluoxetine and/or its metabolite (total t½β = 330 hours) and other SSRIs (t½β range = 15 to 30 hours), for example. This has implications in terms of potential drug interactions and must be considered when patients have to be switched to treatment with monoamine oxidase inhibitors.
Studies with fluvoxamine have been conducted in both in- and outpatients, whereas trials with other SSRIs have been confined largely to outpatient populations. Fluvoxamine has been associated with a high incidence of nausea (37%), although this may have resulted from high initial dosages (rather than upward dose titration protocols) used in early trials. Of further interest, fluoxetine doses of 20mg may be sufficient to produce a satisfactory antidepressant response, and this SSRI may be particularly useful in patients with chronic retarded depression. More clinical data are required before the efficacy of sertraline and citalopram relative to standard antidepressants can be clearly defined. Preliminary data indicate that SSRIs are effective in the treatment of panic disorder, obsessive-compulsive disorder (OCD), eating (e.g. anorexia and bulimia) and personality disorders (e.g. anger, impulsiveness) and substance abuse (e.g. alcoholism); early results with fluvoxamine in the treatment of panic disorder and OCD, and with fluoxetine in the treatment of bulimia, personality disorders and alcohol abuse, have been encouraging.
SSRIs have a more favourable tolerability profile than tricyclic antidepressants and, unlike the tricyclics, are not associated with anticholinergic adverse effects, sedation, cardiotoxicity or weight gain. SSRIs are associated with a relatively high incidence of nausea, particularly if high doses are used at the start of treatment. However, the incidence of nausea appears to decrease as treatment is continued. Although SSRIs appear to be well tolerated, they are a new drug class and, thus, patients should be monitored carefully for the occurrence of unexpected adverse reactions (e.g. the ‘flu-like’ illness noted in a small number of zimeldine recipients).
Overall, SSRIs have been shown to be effective and safe agents for the treatment of patients with major depressive disorders. These drugs possess tolerability advantages over tricyclic antidepressants, and preliminary evidence suggests that they may have future value in the treatment of panic disorder, OCD, eating and personality disorders, and substance abuse.
Inhibition of human cytochrome P4502D6 (CYP2D6)-catalysed metabolism can lead to clinically significant alterations in pharmacokinetics. Since there is evidence that the selective serotonin reuptake inhibitor (SSRI) class of antidepressant drugs might inhibit CYP2D6, the effects of five SSRIs on human liver microsomal CYP2D6 activity were compared with each other and with three tricyclic antidepressant drugs. On a molar basis, paroxetine was the most potent of the SSRIs at inhibiting the CYP2D6-catalysed oxidation of sparteine (Ki = 0.15 microM), although fluoxetine (0.60 microM) and sertaline (0.70 microM) had Ki values in the same range. Fluvoxamine (8.2 microM) and citalopram (5.1 microM) also inhibited CYP2D6 activity. The major circulating metabolites of paroxetine in man produced negligible inhibition. In contrast, norfluoxetine the active metabolite of fluoxetine, was a potent CYP2D6 inhibitor (0.43 microM). CYP2D6 activity was also diminished by the tricyclic antidepressant drugs clomipramine (2.2 microM), desipramine (2.3 microM) and amitriptyline (4.0 microM). These findings suggest that compounds with SSRI activity are likely to interact with human CYP2D6 in vivo with the potential of causing drug interactions.
The pharmacokinetics and clinical properties of clomipramine, the classic 5-HT uptake inhibiting antidepressant is well known. Within the last years, several new and more selective serotonin uptake inhibitors have been introduced in clinical practice, including trazodone, citalopram, paroxetine, femoxetine, fluvoxamine and fluoxetine. They differ by their chemical structure, and therefore, important differences can be expected with respect to their metabolism and kinetics in man. In this presentation, the following points will be addressed: Present knowledge about their metabolism and their kinetics, taking into account that most of them are racemates, whose clinical role is only partially understood, including that of the metabolites. It will further be examined whether they are candidates for a genetic polymorphism of metabolism of the debrisoquine-spartein-dextromethorphan type. This may e.g. be suspected for fluoxetine which interferes strongly with the metabolism of tricyclic antidepressants. Finally, data of the literature will be analysed about a possible relationship between the clinical efficacy of these drugs and their plasma levels, including those of their active metabolites.
Paroxetine is a selective serotonin reuptake inhibitor that is now licensed in various countries in Europe. It has comparable efficacy with the reference tricyclic antidepressants and is well tolerated with few adverse effects which are usually mild, transient and do not appear to compromise treatment. Paroxetine has a number of advantages as an antidepressant; of particular interest is its ability to improve sleep early in treatment without daytime sedation or interference with psychomotor function. Paroxetine appears effective compared with placebo in different subgroups of depression: it is effective in both endogenous and reactive depression, as well as being effective in moderate and severe depression. Paroxetine appears particularly effective in treating the anxiety associated with depression and has been shown to have greater efficacy than imipramine. There is some evidence that the onset of antidepressant action occurs slightly earlier with paroxetine than with imipramine. As well as being effective in the acute episode, placebo-controlled, long-term data are available indicating paroxetine to be of value in the prevention of depressive relapse.
Paroxetine is a new selective serotonin reuptake inhibitor which has been extensively evaluated as an antidepressant in clinical trials and a large computerized safety database has been accumulated. A comprehensive review of data on dosage supports the recommendation that 20 mg paroxetine daily is the optimal therapeutic dose for most patients. When compared to active controls--mainly tricyclic antidepressants--paroxetine was found to have a different adverse-event profile with fewer anticholinergic, cardiovascular and nervous system events but more gastrointestinal events, particularly nausea. However, these events were not severe and did not usually lead to discontinuation of treatment. The adverse events reported with paroxetine were most likely to occur early in the course of treatment and there was no evidence of any increase in events in the elderly or with longer-term treatment. Paroxetine was not associated with excess of death from any cause, suicides, suicide attempts or serious life-threatening events. No clinically significant drug-related abnormalities were reported in laboratory monitoring, including liver function tests, in short- or long-term use. Finally, and importantly for an antidepressant, paroxetine appears relatively safe in overdose.
Diagnostic criteria, random parallel placebo-controlled study design, and appropriate clinical assessment for both safety and efficacy are all among the essential requirements for the evaluation of a new antidepressant agent. Paroxetine and imipramine were compared for efficacy and safety in a large multicentre, randomized, placebo-controlled, double-blind, parallel design study in the USA. The study involved 717 outpatients with major depressive disorder; after a one-week washout period they were treated for 6 weeks, being assessed at weekly intervals. The results from all six participant centres combined showed that both active drugs were statistically superior to placebo by week 2 and that the antidepressant response was significant for both. Paroxetine was better tolerated than imipramine with fewer dropouts from side effects. This combined study clearly indicated that paroxetine was an effective and well-tolerated antidepressant.
Suicide by drug overdose is a major public health problem, and antidepressant medications are the most common agent involved. European studies suggest differences in the rates of suicide by overdose among antidepressants, but no reports have been published for the United States. We estimated the comparative risks of suicide attempts and suicides, and the relative risk of fatality in the event of an overdose for the major antidepressants currently marketed in the United States.
Information regarding suicide attempts and suicides by antidepressant overdose was obtained from the published reports of the Drug Abuse and Warning Network and the annual report of the American Association of Poison Control Centers, and corrected for differences in total annual prescriptions using data from the National Prescription Audit.
The risk of a suicide attempt did not appear to differ among antidepressants. The tricyclic antidepressants were associated with a higher rate of death in the event of an overdose than the newer nontricyclic antidepressants in both the annual report of the American Association of Poison Control Centers and the Drug Abuse and Warning Network data. The chance of death after an overdose was greater for desipramine hydrochloride than for other tricyclics.
The higher risk of suicide with tricyclics vs nontricyclics may be explained by a higher rate of death from overdose rather than more suicide attempts. Tricyclics carry the risk of greater cardiotoxicity. The basis for the even higher rate of death/overdose of desipramine is not known and requires further research. If these findings are replicated in a case-control study design, they have important implications for the choice of an antidepressant for the depressed patient at risk for suicidal behavior.
Because fluoxetine may be associated with an induction or exacerbation of parkinsonism, caution has been suggested when considering fluoxetine as an antidepressant for patients with Parkinson's disease.
We retrospectively reviewed the medical records of 23 outpatients with Parkinson's disease who were receiving or had received fluoxetine. One author evaluated all patients using the Northwestern University Disability Scale for scoring parkinsonism. Rather than employing a formal depression scale, we assessed depression globally. Concurrent medications were permitted.
Twenty of the 23 patients experienced no worsening of parkinsonism while being treated with up to 40 mg of fluoxetine per day. The other 3 patients' parkinsonism worsened to a mild degree: a 74-year-old man experienced an increase in akinesia, tremor, and rigidity; a 77-year-old man experienced a slight worsening in tremor and rigidity; and a 56-year-old man experienced a decline in gait and akinesia. It was unclear if these declines, which were neither acute nor severe, were due to fluoxetine treatment or the progression of the disease. Signs of parkinsonism in 2 patients appeared to improve during fluoxetine treatment.
Fluoxetine, in doses up to 40 mg/day, does not appear to be associated with exacerbations of parkinsonian signs and symptoms in outpatients with Parkinson's disease. Further investigation of fluoxetine for the treatment of depression in patients with Parkinson's disease is warranted.
Depressive illness among the elderly is an important public health concern. However, treatment of the elderly may be complicated by age-related changes in physiology, general medical status, and susceptibility to side effects. There is therefore a need for improved treatment modalities for depressed elderly patients. Paroxetine is an antidepressant that acts through selective inhibition of serotonin reuptake. It lacks the anticholinergic and cardiovascular side effects of most first- and second-generation antidepressants. The authors present the combined data from two similarly designed comparisons of paroxetine and doxepin in outpatients over 60 years of age with major depression. The results show that paroxetine was an effective as doxepin in alleviating depression as measured on the Hamilton Rating Scale for Depression (HAM-D) total score, the Montgomery and Asberg Depression Rating Scale (MADRS), and the Hopkins Symptom Checklist (SCL) depression factor score. Paroxetine was significantly superior to doxepin on the Clinical Global Impressions (CGI) scale for severity of illness, the HAM-D retardation factor, and the HAM-D depressed mood item. Doxepin produced significantly more anticholinergic effects, sedation, and confusion. Paroxetine was associated with more reports of nausea and headache. These results suggest that paroxetine may be a valuable tool for the treatment of major depression in the elderly.