A review of the efficacy of selective serotonin reuptake inhibitors in obsessive-compulsive disorder

BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic illness associated with substantial morbidity; it often requires long-term medication. The best-studied therapeutic agent in the treatment of this disorder is the tricyclic antidepressant clomipramine. Since other tricyclic antidepressants appear to lack efficacy in OCD, that of clomipramine has been linked to its potent effects on serotonin. Consequently, agents that selectively inhibit serotonin reuptake have been the focus of several large-scale, placebo-controlled studies of OCD. Their efficacy in OCD is the focus of our review. DATA SOURCES: MEDLINE search (1966 to present) of OCD treatment with clomipramine or SSRI antidepressant medication using the key words obsessive-compulsive disorder, serotonin reuptake inhibitors, clomipramine, and pharmacology. STUDY FINDINGS: The selective serotonin reuptake inhibitors fluoxetine, sertraline, fluvoxamine, and paroxetine have, in separate multicenter trials, demonstrated efficacy and tolerability in the treatment of OCD. In contrast, clomipramine, though efficacious, is often associated with substantial adverse events, particularly anticholinergic side effects. While 2 recent meta-analyses support the superior efficacy of clomipramine over selective serotonin reuptake inhibitors in the treatment of OCD, 5 of 6 head-to-head comparisons of either fluoxetine or fluvoxamine versus clomipramine have found similar efficacy but a lower incidence of side effects with the selective serotonin reuptake inhibitor. A recently completed multicenter, 12-week, double-blind trial of paroxetine versus clomipramine versus placebo showed paroxetine to be as effective as clomipramine. With significantly fewer dropouts due to adverse effects than clomipramine, paroxetine was also associated with superior tolerability. CONCLUSION: The suggestion that selective serotonin reuptake inhibitors possess efficacy similar to that of clomipramine, but have a superior side effect profile, may have important implications for patients with OCD who require long-term treatment.     

A differential response to nortriptyline and fluoxetine in melancholic depression: the importance of age and gender

OBJECTIVE: To consider the impact of age and gender on the antidepressant response to nortriptyline and fluoxetine in melancholic depression. METHOD: Of 191 depressed patients, 113 met study criteria for melancholia. All patients were randomized to receive either fluoxetine or nortriptyline. Response rates, defined as an improvement of 60% or more on the Montgomery Asberg Depression Rating Scale over 6 weeks of antidepressant treatment on an intention to treat basis, were examined by age, and by age and gender. RESULTS: Melancholic depressed patients 40 years or older, especially men, had a markedly superior response to nortriptyline compared with fluoxetine. Conversely, melancholic depressed patients, age 18-24 years, especially women, had a markedly superior response to fluoxetine. CONCLUSION: Age and gender appear to be critical variables in understanding differential antidepressant responses to tricyclic antidepressants and selective serotonin reuptake inhibitors in melancholic depression.     

Patterns and predictors of remission,response and recovery in major depression treated with fluoxetine or nortriptyline

OBJECTIVE: The first objective of this paper was to describe the pattern of remission, response and recovery in patients with major depression who were randomised for treatment with fluoxetine ornortriptyline. The second objective was to report on the demographic and diagnostic predictors of the response and recovery in these depressed patients. METHOD: One hundred and ninety-five patients with major depression were recruited for this outpatient study. After a detailed clinical and neurobiological evaluation patients were randomized to receive either fluoxetine or nortiptyline as an initial antidepressant treatment. RESULTS: Of the 195 depressed patients randomised to treatment,154 completed an adequate 6-week trial of either fluoxetine or nortriptyline as their initial antidepressant. Of the 41 patients who did not complete an adequate trial the dropout rate was higher on those randomized to nortriptyline (p = 0.02). There was also an important interaction of drug and gender in determining dropouts in that women did not complete an adequate trial with nortriptyline and men did not complete an adequate trial with fluoxetine (p = 0.002).Of the 154 patients who completed an adequate 6-week antidepressant trial there were no significant differences in 6-week measures of depression severity or of percentage improvement. However, if we use an intention to treat analysis and dichotomise outcomes into response,remission or recovery; then recovery rates were significantly higher with fluoxetine than nortriptyline (p = 0.005).Using an intention to treat analysis fluoxetine was superior tonortriptyline in women, in those less than 25-years old, and in those with atypical depression. Independent of drug, those with chronic depressions had a poorer outcome. CONCLUSION: In this sample of depressed patients randomized tonortriptyline or fluoxetine the change in depressive symptoms over 6 weeks were comparable between fluoxetine and nortriptyline. However,when we look at the more clinically important variable of recovery then fluoxetine was superior to nortriptyline. Predictors of a poorer response to nortriptyline were gender, young age and atypical depression.The results challenge traditional beliefs that selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressant have comparable efficacy.     

Role of serotonin and noradrenaline in social dysfunction: a review of data on reboxetine and the Social Adaptation Self-evaluation Scale (SASS)

Social impairment is a common feature of depressive illness, often causing substantial and clinically meaningful dysfunction. Although the depressive symptoms and social impairment are linked, the naturalistic course and response to treatment of these two aspects of depression do not necessarily correlate. A variety of self-report and clinician-administered assessment scales which are specific for the measurement of social functioning and have good psychometric properties have been developed in the past 40 years. The most recent of these instruments is the Social Adaptation Self-evaluation Scale (SASS), a 21-item scale designed in 1989 to assess patient response to antidepressant treatment. SASS was used in two clinical trials comparing reboxetine, the new selective noradrenaline reuptake inhibitor (selective NRI), with fluoxetine. While no difference in efficacy was detectable by traditional assessments of symptoms, reboxetine proved to be significantly more effective than fluoxetine in improving social functioning in patients with depression. Reboxetine was also more effective than fluoxetine in rectifying social functioning in the subset of patients who remitted from an episode of major depression. Specifically, reboxetine improved patient motivation, energy and self-perception. These results indicate that antidepressant therapy can achieve more than symptom relief in depression. It is speculated that there may be a difference in the roles played by serotonin and noradrenaline in social functioning.     

Pharmacotherapy in depressed children and adolescents

In children and adolescents, antidepressants are used in the treatment of depressive symptoms and several other psychiatric conditions. In the treatment of mild and moderate depressive symptoms, non-pharmacological approaches such as psychotherapy play a major role, a severe symptomatology may demand a combination with antidepressants. As first-choice medication for the treatment of juvenile depression, the selective serotonin reuptake inhibitor (SSRI) fluoxetine is recommended, due to its efficacy and approval. As second-choice antidepressants the SSRIs sertraline, escitalopram and citalopram might be used. Other antidepressants - such as tricyclic antidepressants, α(2)-adrenoceptor antagonists, selective noradrenalin reuptake inhibitors (SNRI) - may be alternatively used, but not as first- or second-choice medications. In the case of "off-label" use, patients and parents have to be carefully informed prior to the start of medication, after a thorough risk-benefit analysis. In the following overview we address a general framework, therapeutic strategies and the issues of antidepressant pharmacotherapy for the treatment of unipolar depression in childhood and adolescence.     

Treatment options for refractory depression

A significant proportion of patients with depressive disorders do not experience a full response with antidepressant treatment. Fortunately, most eventually remit, even though the time to response may be significantly delayed in many patients. A variety of options exist to deal with these difficult clinical situations. Established strategies include switching to an antidepressant of an alternative class (e.g., tricyclic to a monoamine oxidase inhibitor [MAOI] or selective serotonin reuptake inhibitor [SSRI]), electroconvulsive therapy (ECT), and augmentation with lithium or thyroid hormone. Promising alternatives include combined serotonin and norepinephrine enhancement strategies (e.g., SSRI plus serotonin norepinephrine reuptake inhibitor [NSRI] or higher doses of venlafaxine or fluoxetine), steroid suppression therapy, augmentation with atypical antipsychotics, and psychotherapy.     

Fluoxetine versus trimipramine in the treatment of depression in geriatric patients

INTRODUCTION: Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), and trimipramine, a tricyclic antidepressant (TCA), were compared in terms of efficacy and tolerability in a six-week, parallel group, double-blind pilot study in 41 geriatric patients with major depression (61 - 85 years old). METHOD: The Hamilton Rating Scale for Depression (HAMD-17), the Montgomery-Asberg Rating Scale (MADRS), the Adjective Mood Scale (Bf-S), the Clinical Global Impression (CGI), and the Patients Global Impression (PGI) were used to measure changes in depressive symptoms. RESULTS: Improvement with treatment was found on all scales. Efficacy and tolerability were similar in both groups. No statistically significant differences were found. CONCLUSION: These findings suggest that fluoxetine and trimipramine are comparable in terms of efficacy and tolerability in the treatment of major depression in geriatric patients.     

抗抑郁药物治疗的依从性观察

目的　探讨抗抑郁药物临床治疗的依从性。方法　对 10 2例抑郁症患者所服用阿米替林、氯丙咪嗪、氟西汀、盐酸帕罗西汀、文拉法辛 5种抗抑郁药的开放性治疗情况进行了 6个月的随访观察。结果　 5种药物治疗后患者获得痊愈的比例和脱落情况无显著差异 (P >0 0 5 ) ,但在起效时间、不良反应、处方依从、治疗态度等方面存在着差异 (P <0 0 5 )。结论　SSRI和SNRI抗抑郁药的临床依从性显著高于传统的三环类抗抑郁药     

Emergence of depressive symptoms during treatment for panic disorder with specific 5-hydroxytryptophan reuptake inhibitors

Selective serotonin reuptake inhibitors (SSRI) have been established as effective drugs in the treatment of depressive and anxiety disorders. However, there are also reports that they can induce depressive symptoms and suicidal thoughts in patients. Eighty of 230 patients who met the DSM-III-R criteria for panic disorder received, during the course of treatment, fluvoxamine (a selective serotonin reuptake inhibitor) at a dose level between 50–200 mg/day. The patients were clinically evaluated for a history of affective disorder and for the presence of affective symptoms before the treatment and for emergence of depressive symptoms during the treatment. Seven of the 80 patients (9%) developed symptoms of depression despite a good antianxiety response. Five of the 7 patients received fluvoxamine as second choice after tricyclic antidepressants (TCA). These patients had no history of affective disorder, and no symptoms of depression were present before the treatment with fluvoxamine. The depressive symptoms abated after the fluvoxamine was discontinued and TCA or clonazepam was prescribed. The depressive symptoms reappeared when fluoxetine was administered. None of these 7 patients developed depressive symptoms while treated with TCA or clonazepam. Among the 150 patients treated with TCA and benzodiazepines, not a single case of depression was seen in patients without a previous history of depression. These results suggest a vulnerability among some of panic disorder patients to noradrenergic-serotonergic imbalance caused by SSRI, which has to be taken into clinical consideration.     

Antidepressant effectiveness in severe depression and melancholia

While outcome has improved in patients with depressive disorders since the introduction of the newer antidepressants, some physicians still treat severely depressed patients with the older tricyclic antidepressants because of conflicting reports about the efficacy of the newer agents, particularly the selective serotonin reuptake inhibitors, in severe depression. However, a standardized operational definition of severe depression is lacking, and treatment studies are difficult to evaluate due to variation in methodology. Remission rates are relatively low in many of the short-term clinical trials of the newer antidepressants in severe depression, but may improve if the research design were to include a longer trial and aggressive dosing. There is some evidence that venlafaxine, a serotonin-norepinephrine antidepressant, may offer some advantage for severely depressed patients.     

Pharmacological treatment of adolescent major depression

Antidepressant agents are widely prescribed for adolescents, although specific data regarding their efficacy in this age range are limited. The aims of the present article are to review research findings regarding the use of antidepressant drugs for adolescent depression and to discuss the main results in light of our clinical experience. Only 13 controlled trials on the use of antidepressant drugs for adolescent major depression are available in the literature. Six studies evaluated the efficacy of tricyclic antidepressants, yet they only included 196 adolescents altogether. Seven studies, including a total of 1,403 patients, evaluated the efficacy of three specific serotonin reuptake inhibitors: fluoxetine, paroxetine, and sertraline. Based on published data, serotonin reuptake inhibitors appear to be the first-line psychopharmacologic treatment for adolescent depression, as three compounds (fluoxetine, paroxetine, and sertraline) appeared to be effective in this indication. Conversely, all published studies failed to demonstrate that the tricyclic antidepressants were superior to placebo. Several questions remain open and are discussed: How should we use available scientific data in clinical practice? Are there nonspecific factors implicated in treatment response? Is there a serotonin hypothesis for juvenile depression? What are the priorities for future research?     

Possible therapeutic effect of clonazepam upon elderly depressive patients

The patient, a 77‐year‐old man, was diagnosed with senile depression. He was also diagnosed with depression at other hospitals, and pharmacotherapy by antidepressants was carried out. He was given sulpiride, selective serotonin reuptake inhibitors, a serotonin‐norepinephrine reuptake inhibitor, an atypical antidepressant, and tricyclic and tetracyclic antidepressants, but conventional pharmacotherapies using these antidepressant drugs did not alleviate his symptoms. The patient was then administered 0.5 mg/day of clonazepam at bed time. Following 2 weeks of administration, his symptoms were alleviated. The dosage of clonazepam was increased to 0.75 mg/day and remission was facilitated. Four weeks later, the patient displayed further alleviation of his depressive symptoms, so he has been continued on 0.75 mg/day of clonazepam. Essential drug selections for senile depression includes selective serotonin reuptake inhibitors, serotonin‐norepinephrine reuptake inhibitors, and atypical antidepressants, but when these are ineffective, tricyclic antidepressants or tetracyclic antidepressants are alternatively selected. When a patient’s symptoms are not alleviated by essential drug selection, as occurred in the current case, clonazepam is considered to be another therapeutic candidate. If they fail to alleviate symptoms, however, then early referral to a specialist is crucial. Enhancing primary‐care physicians’ understanding of senile depression and coordination with specialists is essential in the medical care of elderly patients with depression.     

Prolactin response to d-fenfluramine in major depression before and after treatment with serotonin reuptake inhibitors.

BACKGROUND: Central serotonin dysfunction is thought to be involved in the etiology of major depression. Serotonergic challenge studies before and after treatment of depressed patients have yielded conflicting results; however, these studies have not focused on the effect of antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs) on serotonergic challenge studies. METHODS: The authors studied 19 outpatients with major depressive disorder using prolactin response to d-fenfluramine as a measure of central serotonergic functioning. Testing of patients was conducted just before and right after 8 weeks of treatment with either fluoxetine (n = 10) or fluvoxamine (n = 9) as part of a randomized, double-blind treatment trial. Blood samples for prolactin were collected prior to administration of d-fenfluramine (0.5 mg/kg) and then over the next 5 hours. RESULTS: Unlike previous studies in which antidepressant treatment produced an enhanced prolactin response to fenfluramine, in this study there was no increase in prolactin response to d-fenfluramine following SSRI treatment. In fact, prolactin response to d-fenfluramine was significantly diminished after treatment with fluvoxamine but not fluoxetine. CONCLUSIONS: The implications of these findings are discussed with regard to possible mechanisms of action of SSRI treatment.     

Symptomatic and syndromal anxiety and depression.

The diagnosis of anxiety disorders and major depression can be reliably made based on signs and symptoms. However there are significant limitations to the current system of classification including overlapping criteria, high comorbidity, and the issue of subthreshold syndromes. The literature on treatment response documents that selective serotonin reuptake inhibitors are effective in the treatment of the various anxiety disorders, including when comorbid major depression is present. The literature also suggests that tricyclic antidepressant medications have superior benefits over selective serotonin reuptake inhibitors in major depression. Examination of the functional anatomy of the fear and reward systems may shed light on the underlying processes in the anxiety and depressive disorders. Such an approach points out the importance of addressing avoidance behaviors, which may be more responsive to cognitive behavioral treatments than pharmacological agents.     

The effectiveness of atypical antipsychotic medications in depressive disorders

Clinical evidence supporting the use of atypical antipsychotic medication (broad-spectrum psychotropic agents) in the treatment of depressive disorders is increasing rapidly. Animal models suggest that when atypical antipsychotic medications are used in combination with a selective serotonin reuptake inhibitor there is additional activation of frontal dopaminergic and noradrenergic neurotransmitter systems. This stimulated the initiation of several clinical trials that showed the efficacy of atypical antipsychotic medication augmentation of selective serotonin reuptake inhibitors for patients with treatment-resistant depression. There also are few case reports of successful treatment of depression with atypical antipsychotic medication alone. When a clinician is treating a depressed patient who did not achieve relief after trials with two different antidepressant regimens, one option to consider is augmentation with an atypical antipsychotic medication to ameliorate depressive symptoms.     

Paroxetine augmentation to tianeptine treatment causes exacerbation of depressive symptoms: presentation of two cases

We present two cases whose depressive symptoms partially remitted with tianeptine treatment but exacerbated after paroxetine augmentation to tianeptine. Although tianeptine has structural similarities with tricyclic antidepressants, unlike tricyclic agents or selective serotonin- reuptake inhibitors(SSRIs), it enhances 5-HT reuptake in brain, leading to decreased availability of the transmitter in the synaptic cleft. Thus, efficacy of tianeptine as an antidepressant agent caused a challenge to the concept of serotonergic deficit theory in depression. Both paroxetine and tianeptine are found equivalently effective in treatment of major depression, but no data are available for combined use of these two agents.     

Course of psychomotor agitation during pharmacotherapy of depression: Analysis from double-blind controlled trials with fluoxetine

Psychomotor agitation, a common clinical feature of major depression, may first emerge or intensify during pharmacotherapy. Whether agitation is part of the underlying course of depression or iatrogenic complicates treatment planning. We analyzed data from blinded clinical trials involving 4,737 patients with major depression assigned to a selective serotonin reuptake inhibitor (fluoxetine), a comparator antidepressant (usually a tricyclic antidepressant [TCA]), or placebo. Item 9 of the Hamilton Depression Rating Scale was used to assess the degree of psychomotor agitation. The vast majority of depressed patients exhibited baseline psychomotor agitation. The rate of increased agitation from baseline during acute pharmacotherapy was comparable between fluoxetine and either placebo or TCAs. Substantial emergence of psychomotor agitation also occurred at a similar incidence across the three treatment groups and typically appeared within the first 3 wk. Improvement in agitation was significantly more prominent (P < 0.001) among fluoxetine-treated than among placebo-treated patients. Fluoxetine-treated patients demonstrated numerically superior improvement rates compared with TCA-treated patients; however, this difference was not significant. Data derived from this large series of clinical trials suggested no evidence that either fluoxetine or TCAs induced psychomotor agitation at rates exceeding the natural course of the disorder over time (placebo cohort). On the contrary, pharmacotherapy with either fluoxetine or TCAs was typically associated with diminished agitation, probably as part of the response pattern of depression. Depression and Anxiety 4:294–311, 1996/1997.© 1997 Wiley-Liss, Inc.     

Suicidality in pediatric patients treated with antidepressant drugs

CONTEXT: There has been concern that widely used antidepressant agents might be associated with an increased risk of suicidal ideation and behavior (suicidality) in pediatric patients. OBJECTIVE: To investigate the relationship between antidepressant drugs and suicidality in pediatric patients participating in randomized, placebo-controlled trials. DATA SOURCES: Data were derived from 23 trials conducted in 9 drug company-supported programs evaluating the effectiveness of antidepressants in pediatric patients and 1 multicenter trial (the Treatment for Adolescents With Depression Study) that evaluated fluoxetine hydrochloride. STUDY SELECTION: All placebo-controlled trials submitted to the Food and Drug Administration were eligible for inclusion. Evaluable data were derived from 4582 patients in 24 trials. Sixteen trials studied patients with major depressive disorder, and the remaining 8 studied obsessive-compulsive disorder (n = 4), generalized anxiety disorder (n = 2), attention-deficit/hyperactivity disorder (n = 1), and social anxiety disorder (n = 1). Only 20 trials were included in the risk ratio analysis of suicidality because 4 trials had no events in the drug or placebo groups. DATA EXTRACTION: Individual patient data were available for all the trials. DATA SYNTHESIS: A meta-analysis was conducted to obtain overall suicidality risk estimates for each drug individually, for selective serotonin reuptake inhibitors in depression trials as a group, and for all evaluable trials combined. There were no completed suicides in any of these trials. The multicenter trial was the only individual trial to show a statistically significant risk ratio (4.62; 95% confidence interval [CI], 1.02-20.92). The overall risk ratio for selective serotonin reuptake inhibitors in depression trials was 1.66 (95% CI, 1.02-2.68) and for all drugs across all indications was 1.95 (95% CI, 1.28-2.98). The overall risk difference for all drugs across all indications was 0.02 (95% CI, 0.01-0.03). CONCLUSION: Use of antidepressant drugs in pediatric patients is associated with a modestly increased risk of suicidality.     

Effects of imipramine on depression and obsessive-compulsive symptoms

Most of the controlled studies on the efficacy of medical treatments of obsessive-compulsive disorder (OCD) have involved clomipramine, a tricyclic antidepressant reputed to have anti-obsessional properties. To test the possibility that the drug's antidepressant action mediates the reduction of obsessive-compulsive symptoms, we treated 37 OCD patients with imipramine (mean dose = 233 mg/day) or placebo for 6 weeks and assessed improvement on both obsessive-compulsive and depressive symptoms. Imipramine reduced depression in highly depressed OCD patients, but did not affect obsessive-compulsive symptoms in these or in less depressed patients.