Selective Serotonin Reuptake Inhibitors

Overview

The seven available agents in the selective serotonin reuptake inhibitor class are citalopram (Lund-beck’s Cipramil, Forest Laboratories’ Celexa, generics) and its single enan-tiomer, escitalopram (Lundbeck’s Cipralex, Forest’s Lexapro); paroxetine (GSK’s Paxil/Seroxat, Novartis’s Frosinor, generics); the controlled-release version of paroxetine (GSK’s Paxil CR); sertraline (Pfizer’s Zoloft); fluoxetine (Eli Lilly’s Prozac, generics); and fluvoxamine (Solvay/Fujisawa’s Luvox, Meiji Seika’s Depromel, generics). This section discusses in detail four of these drugs: escitalopram, paroxetine, sertraline, and fluoxetine.

Mechanism Of Action

Selective serotonin reuptake inhibitors act by selectively inhibiting the presynaptic reuptake of serotonin (5-HT) while exerting little effect on norepinephrine or dopamine uptake. After a serotonergic neuron fires, 5-HT is normally transported back into the presynaptic neuron for repackaging and subsequent re-release. Selective serotonin reuptake inhibitors block the reuptake mechanism and consequently increase the level of 5-HT in the synaptic space surrounding the neuron.

The excess 5-HT activates all 5-HT receptors, both pre- and postsynaptically. The activation of the anxiogenic postsynaptic 5-НТгд receptors by selective serotonin reuptake inhibitors may explain the initial increase in anxiety that selective serotonin reuptake inhibitors cause in some patients, as well as the sexual side effects associated with this class of drugs.

TABLE . Current Therapies Used for Minor Depression

Agent	Company/Brand	Daily Dose	Availability
Selective serotonin reuptake inhibitors
Citalopram	Lundbeck’s Cipramil, Forest Laboratories’ Celexa, generics	20 mg qd	US, France, Germany, Italy, Spain, United Kingdom
Escitalopram	Lundbeck’s Cipralex, Forest Laboratories’ Lexapro	10mg qd	US, France, Germany, Italy, Spain, United Kingdom
Fluoxetine	Eli Lilly’s Prozac, generics	20 mg qd	US, France, Germany, Italy, Spain, United Kingdom
Fluoxetine weekly	Eli Lilly’s Prozac Weekly	90 mg weekly	US
Fluvoxamine	Solvay/Fujisawa’s Luvox, Meiji Seika’s Depromel, generics	100 mg qd	France, Germany, l,Spain, United Kingdom, Japan
Paroxetine	GlaxoSmithKline’s Paxil/Seroxat, Novartis’sFrosinor, generics	20 mg qd	US, France, Germany, Italy, Spain, United Kingdom, Japan
Paroxetine controlled release	GlaxoSmithKline’s Paxil CR	25 mg qd	US
Sertraline	Pfizer’s Zoloft/Lustral/Besitran	100 mg qd	US, France, Germany, Italy, Spain, United Kingdom
Serotonin-norepinephline reuptake inhibitors
Milnacipran	bioMerieux-Pierre Fabre’s Dalcipran/lxel, Asahi Kasei’s Toledomin	50-100 mg bid-tid	France, Japan
Mirtazapine	Organon’sRemeron/Remergil/ Norset/Rexer/Zispin	30 mg qd	US, France, Germany, Italy,Spain, United Kingdom
Venlafaxine	Wyeth’s Effexor/EffexorXR	75-150 mg qd orbid	US, France, Germany, Italy,Spain, United Kingdom
Dopaminergic/noradrenergic agents
Bupropionf	GlaxoSmithKline’s Wellbutrin/Wellbutrin SR/Wellbutrin XL	300 mg bid	US
Tricyclic and tetracyclic antidepressants
Amitriptyline	Roche’s Laroxyl, AstraZeneca’s Elavil, generics	100 mg bid	US, France, Germany, Italy, Spain, United Kingdom, Japan
Clomipramine	Novartis’s Anafranil, generics	100-250 mg bid	US, France, Germany, Italy, Spain, United Kingdom, Japan
Desipramine	Sanofi-Aventis’s Norpramin, Novartis’s Pertofran, generics	100-300 mg	US, France, Germany, Italy
Imipramine	Novartis’s Tofranil, generics	100 mg qd	US, France, Germany, Italy, Spain, United Kingdom, Japan
Maprotiline	Novartis’s Ludiomil, generics	100-200 mg qd or bid	US, France, Germany, Italy, Spain, United Kingdom, Japan
Mian serin	Organon’s Tolvon, generics	30-90 mg qd or bid	France, Germany, l,Spain, United Kingdom, Japan
Nortriptyline	Novartis’s Pamelor, generics	75-100 mg tid or qd	US, Germany, Italy, Spain, United Kingdom, Japan
Opipramol	Novartis’s Insidon, generics	100 mg bid	Germany
Tianeptine	Servier’s Stablon	37.5mgtid	France
Benzodiazepines
Alprazolam	Pfizer’s Xanax, Xanax XR, generics	0.5-3.0 mg tid	US, France, Germany, Italy, Spain, United Kingdom, Japan
Clonazepam	Roche’s Klonopin/Rivatril, generics	1.5-3.0 mg	US, France, Germany, Italy, Spain, United Kingdom, Japan
Diazepam	Roche’s Valium, generics	2-1 Omg bid or qid	US, France, Germany, Italy, Spain, United Kingdom, Japan
Etizolam	Mitsubishi’s Depas, generics	0.5-1 .Omg	Italy, Japan
Lorazepam	Biovail’s Ativan, Wyeth’s Tavor/Wypax, generics	2-3 mg, bid or tid	US, France, Germany, Italy, Spain, United Kingdom, Japan
Psychostimulants
Methylphenidate	Novartis’s Ritalin/Ritaline, Ritalin-SR, Celltech’s Metadate ER, Alza/McNeil Consumer Healthcare/Janssen-Cilag’sConcerta/Concerta XL, Celltech’s Metadate CD, Novartis’s Ritalin-LA, generics	20-80 mg qd-tid	US, France, Germany, Spain, United Kingdom, Japan

Dose shown is the total daily dose.

Drugs with the longest remaining patent life are listed first, followed by those whose patents have expired.

The second-generation antidepressants are also referred to as atypical or heterocyclic antidepressants.

Bupropion has been launched in the United Kingdom, France, Germany, Italy, and Spain under the brand name Zyban for smoking cessation, not depression.

Only a representative sample of tricyclic/tetracyclic antidepressants (tricyclic antidepressants) are included in this table

because of the multitude of agents available; other tricyclic antidepressants include amoxapine (Wyeth’s Asendin, generics),

dothiepin (Knoll’s Prothiaden, generics), doxepin (Roerig’s Sinequan, generics), lofepramine (Merck’s Gamanil, generics), protriptyline (Merck’s Concordin, generics), and trimipramine (Sanofi-Aventis’s Surmontil, generics).

bid = Twice daily;

qd = Once daily;

qid = Four times daily;

tid = Three times daily.

Citalopram and escitalopram show the greatest selectivity for serotonin over norepinephrine, followed by sertraline, paroxetine, fluvoxamine, and fluoxetine, in that order.

Escitalopram

Citalopram’s s-enantiomer, escitalopram (Lundbeck’ s Cipralex, Forest’s Lexapro), was first launched in Switzerland in March 2002 for the treatment of depression. The U.Spain. launch followed in September 2002, with an additional approval for maintenance treatment of major depressive disorder. Escitalopram has also been approved for depression in France, Germany, Italy, Spain, and the United Kingdom. Phase III studies are under way to investigate its use in treating social anxiety disorder, panic disorder, and generalized anxiety disorder.

Escitalopram is approximately twice as potent as racemic citalopram: at 10 mg, it has an antidepressant effect equivalent to 20 mg racemic citalopram and is the most selective selective serotonin reuptake inhibitor antidepressant, including racemic citalopram. Theoretically, the advantage of the single s-enantiomer version is that any side effects associated with the renantiomer in racemic citalopram will be avoided. However, a fixed-dose outpatient trial found that 10 mg per day of escitalopram was similar in tolerability to 40 mg per day of citalopram with similar incidence of discontinuation due to adverse events. Overall, escitalopram may offer a slight advantage to a subset of depressed patients who respond better to one selective serotonin reuptake inhibitor than to another.

Escitalopram has not been studied in minor depression, but trials in major depression have been conducted. Escitalopram 10 or 20mg/day and citalopram 40mg/day were compared with placebo in a double-blind trial with outpatients (n = 491) diagnosed with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) criteria for major depression. Response to treatment was evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS); secondary measures used were the 24-item Hamilton Rating Scale for Depression (HAM-D), the Clinical Global Impressions scales, the Hamilton Rating Scale for Anxiety (HAM-A), and patient-rated quality-of-life scales.

At the eight-week study end point, patients taking escitalopram at either dose or citalopram experienced significant improvement relative to placebo on all measures of depression: 51.2% of patients taking either dose of escitalopram and 45.6% of patients taking citalopram satisfied the defined criteria for response to treatment by experiencing a 50% improvement on MADRS from baseline. Side effects experienced in all patient groups were consistent with the side-effect profile of selective serotonin reuptake inhibitors (e.g., nausea, diarrhea, dry mouth, ejaculatory disorder); differences in efficacy and side effects between patients taking escitalopram and citalopram were not significant.

The side effects of escitalopram are similar to those of other selective serotonin reuptake inhibitors. Escitalopram’s overall tolerability profile is favorable; the drug’s major drawbacks are the side effects of sexual dysfunction and delayed onset of action. Other adverse events that can occur during escitalopram therapy include gastrointestinal side effects (e.g., nausea, vomiting, diarrhea) and central nervous system  effects (e.g., tremor, agitation, headache, confusion). These effects usually occur during initial treatment and diminish over several days or weeks.

TABLE . Common Trial End Points for Depression Studies

Scale	Abbreviation	Description	Key End Points
Beck Depression Inventory	BDI	A 21-item scale that measures presence and degree of depression in adolescents and adults	Full remission is a score of 10 or less
Brief Psychiatric Rating Scale	BPRS	An 18-item scale assessing positive symptoms, general psychopathology, and affective symptoms	Often used as a secondary end point in clinical trials. Preferred key end point is not well established.
Clinical Global Impression Scale	CGIS	A three-item scale assessing treatment response in psychiatric patients	Response is typically defined as a score of 1 or 2
Global Assessment Scale	GAS	A one-item scale assessing a patientpsychopathology and social function on a scale of 0-100	Often used as a secondary end point. Preferred end point is not well-established.
Hamilton Rating Scale for Anxiety	HAM-A	A 14-item scale assessing treatment response in patients receiving therapy for anxiety disorders	Response is typically defined as a reduction from baseline of at least 50%
Hamilton Rating Scale for Depression	HAM-D	A 17-, 21 -, or 24-item scale assessing treatment response in patients receiving therapy for depressive disorders	Response is typically defined as a reduction from baseline of at least 50%. Remission is typically defined as a score less than 8 on the first 17-items of the HAM-D.
Hopkins Symptom Checklist Depression Scale	HSCL-D	A 25-item scale that measures the signs and symptoms of depression and anxiety	Often used as a secondry end point in clinical trials. Preferred end point results are not yet established.
Medical Outcomes Study Short Form	MOS-SF36	Multi-item scale measuring eight health concepts and used to compare self-reported health status across groups	Equivalency in measurements, across subgroups, is necessary in order to provide a meaningful interpretation of the data across groups
Montgomery-Asberg Depression Rating Scale	MADRS	A 10-item scale evaluating the efficacy of antidepressant treatment	A 50% reduction in depressive symptoms indicates response
Sheehan Disability Scale	SDS	A three-item instrument for assessingmental-health-related functional impairment. Can be used to assess the effect of a drug on disability.	Often used in clinical trials as a secondary end point. Preferred end points are not well-established.

Paroxetine

Paroxetine (GSK’s Paxil, Seroxat) was the first selective serotonin reuptake inhibitor approved for depression and is available in all the major pharmaceutical markets. A controlled-release version of paroxetine (using SkyePharma’s Geomatrix delivery technology) was approved in the United States in 1999 and launched by GSK in April 2002 for the treatment of depression and panic disorder. Paroxetine boasts a wider range of approved indications than any other selective serotonin reuptake inhibitor and was the first selective serotonin reuptake inhibitor approved for social anxiety disorder; in Japan, the drug is in Phase II development for the treatment of social anxiety disorder. In addition, paroxetine is approved for obsessive-compulsive disorder, generalized anxiety disorder, and post-traumatic stress disorder in the United States and Europe. Paroxetine has also shown efficacy in small studies of premenstrual dysphoric disorder.

Paroxetine‘s mechanism of action and side-effect profile are similar to those of other selective serotonin reuptake inhibitors on the market.

Paroxetine has been studied for the treatment of dysthymia and minor depression. In a randomized, placebo-controlled, multicenter trial (n = 415) evaluating 10-40 mg/day of paroxetine or psychotherapy in elderly patients diagnosed with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition proposed minor depression and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition dysthymia, paroxetine showed greater efficacy than placebo. The primary measures of efficacy in this study were depressive symptoms as measured by the 20-item Hopkins Symptom Checklist Depression Scale (HSCL-D), the HAM-D, and functional status by the Medical Outcomes Study Short Form.

Overall, at the end of 11 weeks of treatment, patients taking paroxetine showed greater symptom resolution than did patients taking placebo as measured by the HSCL-D. Patients being treated with psychotherapy did not show more improvement than placebo; however, their symptoms did improve more rapidly than did those of patients taking placebo during the latter treatment weeks. In particular for dysthymia, paroxetine improved mental health functioning versus placebo among patients whose baseline functioning was high or intermediate. Mental health functioning in dysthymic patients was not improved by psychotherapy versus placebo. For minor depression, both paroxetine and psychotherapy improved mental health functioning in patients in the lowest third of baseline functioning.

Paroxetine has also been studied in trials for the treatment of major depression. Two identical, double-blind trials with outpatients (n = 820) diagnosed with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition major depression compared immediate- and controlled-release paroxetine, 20-50 mg/day and 25-62.5 mg/day, respectively, with placebo. Responses to treatment and remission rates were evaluated using the 17-item HAM-D; secondary measures were the depressed mood (HAM-D item 1) and psychic anxiety (HAM-D item 10) scores.

At the six-week study end point, investigators pooled study results and found that both the immediate- and controlled-release formulations of paroxetine exhibited efficacy in major depressive disorder as assessed by the 17-item HAM-D and that depressed mood and psychic anxiety symptoms also improved. Response rates, defined as a 50% or greater reduction in the baseline HAM-D score, in patients who completed the study were 74% for controlled-release paroxetine, 73% for immediate-release paroxetine, and 61% for placebo. Rates of remission, defined as a HAM-D score of 7 or less, in patients who completed the study were 56% for controlled-release paroxetine, 50% for immediate-release paroxetine, and 44% for placebo. Side effects experienced by patients in this trial were similar to side effects of other selective serotonin reuptake inhibitors.

The efficacy of immediate-release paroxetine has also been compared with that of TCA therapy (amitriptyline, imipramine, lofepramine, and clomipramine), selective serotonin reuptake inhibitor therapy (fluoxetine, fluvoxamine, and sertraline), and serotonin/norepinephrine reuptake inhibitor therapy (venlafaxine) in several clinical trials. In both the TCA and selective serotonin reuptake inhibitor comparator trials, no significant differences in response rates were noted between the active treatment groups; however, results from a pooled data analysis of depressed patients (n = 1,108), presented at the 2001 American Psychiatric Association annual meeting, showed that venlafaxine-treated patients consistently showed greater response to treatment across time than did patients in the paroxetine groups.

Paroxetine‘s mechanism of action and side-effect profile are similar to those of other selective serotonin reuptake inhibitors on the market. However, paroxetine has a greater tendency to cause mild anticholinergic (e.g., dry mouth, impaired ability to focus at close range, constipation, urinary hesitation) side effects than the other selective serotonin reuptake inhibitors and has been associated more often than other selective serotonin reuptake inhibitors with discontinuation syndrome (i.e., severe dizziness, nausea, and electric shock sensations), following rapid withdrawal of treatment. Therefore, paroxetine‘s labeling recommends a gradual reduction of the dose rather than abrupt cessation when discontinuing treatment.

Like all other selective serotonin reuptake inhibitors and serotonin/norepinephrine reuptake inhibitors, paroxetine causes sexual dysfunction in up to 70% of patients. In a non-placebo-controlled clinical trial that assessed the incidence of sexual dysfunction associated with antidepressants (amineptine, citalopram, fluoxetine, fluvoxamine, mirtazapine, moclobemide, nefazodone, paroxetine, sertraline, and venlafaxine), more than 70% of patients taking paroxetine experienced sexual dysfunction.

In June 2003, the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) of the Department of Health banned the use of paroxetine in patients younger than 18. The agency based its decision on a meta-analysis of nine separate studies that measured the efficacy and safety of paroxetine in children with major depression, social anxiety disorder, and obsessive-compulsive disorder and found an increase in self-harm and suicidal behaviors in teenagers. Although current evidence is not sufficient to confirm an association between the use of paroxetine and suicidal behavior in adults, the committee that examined the pediatric paroxetine studies is now examining paroxetine‘s safety in adults (M2 communications, press release, June 10, 2003).

Sertraline

Sertraline (Pfizer’s Zoloft) was first launched in the United Kingdom in 1990 and is now available for depression in most other European markets and the United States. It has been approved for depression, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, and acute and long-term treatment of social anxiety disorder. In Japan, Pfizer Seiyaku has filed for approval of sertraline for depression, panic disorder, and obsessive-compulsive disorder.

Sertraline acts like other selective serotonin reuptake inhibitors; that is, it exerts its anxiolytic effect by inhibiting 5-HT activity. It differs slightly from other selective serotonin reuptake inhibitors in its selectivity for serotonin receptors; sertraline is highly selective for serotonin over norepinephrine and second only to citalopram in its serotonin selectivity.

No trials evaluating the efficacy of sertraline in treating minor depression have been published. There are, however, trials in major depression. A randomized, double-blind trial with patients (n = 369) diagnosed according to DSM-III criteria for major depression compared sertraline — 50, 100, and 200mg/day — with placebo. Response to treatment was evaluated using the HAM-D, HAM-D Beck Depression Cluster, Clinical Global Impressions Severity, Clinical Global Impressions Improvement, and Profile of Mood States Depression/Dejection Factor. At the six-week end point, all doses of sertraline showed efficacy as measured on all scales. Side effects in this study were consistent with the selective serotonin reuptake inhibitor side-effect profile and increased with the higher doses.

Sertraline has also proved to be comparable in efficacy to the TCA imipramine (Novartis’s Tofranil, generics) for the treatment of depression and to selective serotonin reuptake inhibitors such as fluoxetine and citalopram for the treatment of depression.

Sertraline’s side-effect profile is similar to that of other selective serotonin reuptake inhibitors on the market; however, given its relatively shorter half-life, dose tapering is suggested during the final weeks of treatment. Despite its shorter half-life, sertraline has exhibited better tolerability than paroxetine during dose-tapering in clinical trials. One study that investigated panic disorder found that tapering off paroxetine is associated with significant clinical worsening compared with tapering off sertraline: the percentage of patients who were panic-free during sertraline taper increased from 54% to 58% but declined during paroxetine taper from 53% to 42%. Moreover, the study found that paroxetine is less well tolerated than sertraline and has higher attrition rates due to adverse events (18% versus 12%).

Fluoxetine

Fluoxetine (Eli Lilly’s Prozac, generics), the most widely recognized selective serotonin reuptake inhibitor, has been available for depression in the United States and Europe since 1988. Chugai and Eli Lilly were codeveloping fluoxetine in Japan, but the two companies terminated the codevelopment agreement when fluoxetine was in Phase III development. Fluoxetine is also approved in the United States and Europe for the treatment of obsessive-compulsive disorder, bulimia, and panic disorder. Fluoxetine has been evaluated, in a large clinical trial funded by the National Institute of Mental Health (NIMH), for its effectiveness in treating minor depression as defined by the National Institute of Mental Health Diagnostic Interview Schedule (DIS).

Fluoxetine is the least selective selective serotonin reuptake inhibitor and has the longest half-life (seven to ten days for its active metabolite, norfluoxetine). The drug’s extended half-life allows for missed doses without the loss of effect associated with some other selective serotonin reuptake inhibitors. However, the drug’s comparatively longer time to elimination necessitates an extended washout period (two to five weeks) after discontinuation of therapy — a drawback when a patient needs to be switched to another agent. Eli Lilly took advantage of fluoxetine’s extended half-life and developed a once-weekly version of fluoxetine; this enteric-coated, delayed-release fluoxetine (Prozac Weekly) is available for patients stabilized on immediate-release fluoxetine who want weekly instead of daily administration. This formulation has not flourished commercially.

Fluoxetine has been evaluated for the acute treatment of minor depression. A randomized, double-blind trial with patients (n = 162) diagnosed with minor depression compared 12 weeks of treatment with 10-20 mg of fluoxetine with 12 weeks of treatment with placebo; the primary diagnostic tool for defining minor depression was the National Institute of Mental Health Diagnostic Interview Schedule (which is in accord with the proposed Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for minor depression). The primary end point was the 30-item Inventory of Depressive Symptomatology (clinician-rated version); secondary measures included several HAM-D scales and the Beck Depression Inventory.

After 12 weeks of treatment, the fluoxetine group improved significantly more than the placebo group on four of five measures of depressive symptom severity (Inventory of Depressive Symptomatology, self-rated Beck Depression Inventory, HAM-D 17-item scale, HAM-D 21-item scale). Overall, 40.5% of fluoxetine-treated patients were rated on the Clinical Global Impression (Clinical Global Impressions) measures as “normal, not at all depressed” after 12 weeks; in contrast, only 24.1% of patients in the placebo group achieved this level of remission. No difference was observed between the two groups on measures of psychosocial function, a finding the investigators speculated might be the result of an insufficient treatment period or insufficient baseline impairment levels to detect a between-group difference.