Perospirone augmentation of paroxetine in treatment of refractory obsessive-compulsive disorder with depression

Obsessive-compulsive disorder (OCD) is often complicated by depression. We report on a patient with treatment-refractory OCD and treatment-refractory major depression who demonstrated a robust response to augmentation of paroxetine with perospirone. Perospirone is a second-generation antipsychotic agent with antagonist effects on both serotonin 5-HT(2A) and dopamine D(2) receptors, as well as a unique agonist effects on serotonin 5-HT(1A) receptors. Future studies would be valuable to elucidate the utility of augmentation therapy of selective serotonin reuptake inhibitors with perospirone in the treatment of refractory OCD with depression.     

Olanzapine addition in obsessive-compulsive disorder refractory to selective serotonin reuptake inhibitors: an open-label case series.

BACKGROUND: Despite the efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of obsessive-compulsive disorder, a significant number of patients show no or only partial remission of symptoms. Some evidence exists to suggest that risperidone augmentation can be helpful in treating this refractory group. The efficacy of other atypical antipsychotic agents, such as olanzapine, in augmenting SSRIs in refractory obsessive-compulsive patients has yet to be systematically investigated. METHOD: A series of 10 patients with DSM-IV obsessive-compulsive disorder showing significant residual symptoms following an adequate SSRI trial (12 weeks) were given open-label olanzapine augmentation for a minimum of an additional 8 weeks. Treatment response was assessed using the Yale-Brown Obsessive Compulsive Scale and the Clinical Global Impressions scale. RESULTS: Nine of the 10 patients in this series treated with olanzapine and an SSRI completed the 8-week augmentation trial. Of these, 4 demonstrated a complete remission or major improvement in obsessive-compulsive symptoms, 3 had partial remission, and 2 experienced no benefit. Nine patients experienced minimal adverse effects, primarily sedation, which did not interfere with continuing treatment. One patient discontinued olanzapine owing to excessive sedation. CONCLUSION: The results of this preliminary, open-label trial suggest that olanzapine may be effective in augmenting ongoing SSRI treatment for a portion of patients with obsessive-compulsive disorder refractory to SSRI treatment. Larger, placebo-controlled trials appear warranted to investigate the clinical efficacy and tolerability of olanzapine augmentation of SSRI treatment in SSRI-refractory obsessive-compulsive disorder.     

Clinical features of patients with obsessive-compulsive disorder showing different pharmacological responses]

BACKGROUND: Although selective serotonin reuptake inhibitors (SSRIs) are the mainstay of pharmacological treatment for obsessive-compulsive disorder (OCD), some OCD patients do not show improvement. Sometimes, the addition of a low-dose atypical antipsychotic, such as risperidone, or olanzapine, to ongoing SSRI treatment has been shown to be effective. However, there are patients who still show no response after trials with this augmentation therapy. In the present study, we examined the clinical features of OCD patients who showed different responses to pharmacological treatment. SUBJECTS AND METHOD: Fifty OCD patients were divided into three groups according to their pharmacological responses: responders to SSRI (group A: n= 25), responders to SSRI with an atypical antipsychotic (group B: n= 15), and non-responders to both SSRI and SSRI with an atypical antipsychotic (group C: n= 10). We examined the clinical features such as age, sex, age of onset, duration of illness, types of obsessive-compulsive symptoms, severity, improvement after treatment, insight into disease, depression, comorbidity, involving family members in compulsive or ritualistic behavior, and the level of social adaptation of each OCD group. RESULTS: Twenty five patients showed a good response to SSRI monotherapy, 15 showed a response to antipsychotic augmentation, and 10 were non-responders to both SSRI and SSRI with an atypical antipsychotic. Significantly lower insight levels were observed only in group B and higher depressive levels in group C. OCD patients who were refractory to SSRI monotherapy showed comorbidity at a significantly higher frequency. OCD patients in group A showed significantly greater improvement, and group B showed inferior social adaptation after treatment. There were no significant differences in age, sex, age of onset, duration of illness, severity, involving family members in compulsive or ritualistic behavior, and social adaptation before treatment in the three OCD groups. CONCLUSION: There were differences in the clinical features of OCD patients who showed different responses to pharmacological treatment. Our results suggest that OCD is clinically and biologically heterogeneous. It may be important to divide OCD patients into subgroups for future studies.     

Once-daily high-dose pindolol for SSRI-refractory depression

Selective serotonin reuptake inhibitor (SSRI) augmentation with the 5-HT1A antagonist pindolol has met with mixed results. Recent studies using positron emission tomography (PET) suggest that pindolol doses used in these studies were too low to effect 5-HT1A autoreceptor blockade. To test the hypothesis that a single higher dose of pindolol would effectively augment antidepressant responses in SSRI-refractory patients, nine subjects with major depression unresponsive to paroxetine 40 mg/day given for 2 months or more were randomized to AM pindolol 7.5 mg (n=4) or placebo (n=5). Subjects were administered the Hamilton Depression Scale (HAM-D), the Hamilton Anxiety Scale (HAM-A), the Bech-Rafaelsen Melancholia Scale, and the Zung Depression Inventory at baseline and weeks 1, 2, 3, and 4. Subjects receiving pindolol exhibited significant improvements in all ratings beginning at week 2 which continued through week 4. Aside from transient dizziness and a five-point decrease in systolic/diastolic blood pressure associated with pindolol, no adverse effects were reported. Although results must be verified in a larger sample, these findings support previous studies indicating that pindolol can accelerate antidepressant responses during SSRI therapy. In addition, results reported here suggest that a single high dose of pindolol (7.5 mg) is a more effective augmentation strategy in SSRI-refractory patients compared with the same total dose given at 2.5 mg tid.     

Responsiveness of 5-HT(1A) and 5-HT2 receptors in the rat orbitofrontal cortex after long-term serotonin reuptake inhibition

BACKGROUND: The only antidepressant drugs that are effective in the treatment of obsessive-compulsive disorder (OCD) are those that effectively block the reuptake of serotonin (5-hydroxytryptamine; 5-HT). In humans, positron emission tomography studies have implicated the orbitofrontal cortex (OFC) in the mediation of OCD symptoms. In animals, administration of selective serotonin reuptake inhibitors (SSRIs) for 8 weeks (but not 3 weeks) led to increased release of 5-HT in the OFC, because of desensitization of the terminal 5-HT autoreceptors. However, the increase in synaptic levels of 5-HT in the OFC after long-term administration of SSRIs might be cancelled out by desensitization of postsynaptic 5-HT receptors. This study was undertaken to investigate if these OFC receptors adapt under such conditions. METHODS: In vivo electrophysiologic techniques were used in this animal study. Male Sprague-Dawley rats received the SSRI paroxetine or vehicle control, delivered by implanted osmotic minipumps, for 3 or 8 weeks. With the rats under anesthesia, neuronal responsiveness to the microiontophoretic application of various drugs was assessed by determining the number of spikes suppressed per nanoampere of ejection current. RESULTS: After administration of paroxetine for either 3 weeks or 8 weeks, there was no modification in the inhibitory effect of 5-HT, the preferential 5-HT(2A) receptor agonist (+)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI) or the preferential 5-HT(2C) receptor agonist 3-chlorophenyl piperazine dihydrochloride (mCPP). In contrast, the inhibitory effect of the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propilamino)-tetralin (8-OH-DPAT) was attenuated in the OFC after both 3 and 8 weeks of paroxetine administration. CONCLUSION: These results indicate a desensitization of postsynaptic 5-HT(1A) receptors in the OFC but a lack of compensatory adaptation of the 5-HT receptor(s) mediating the main effect of 5-HT in this brain region. These observations imply that the activation of normosensitive postsynaptic 5-HT2-like receptors may mediate the effect of enhanced 5-HT release in the OFC.     

Response acceleration with mirtazapine augmentation of citalopram in obsessive-compulsive disorder patients without comorbid depression: a pilot study

BACKGROUND: Therapeutic action of selective serotonin reuptake inhibitors (SSRIs) is delayed from 8 to 12 weeks in patients with obsessive-compulsive disorder (OCD). Several different agents have been tested to reduce the SSRI therapeutic latency time. Mirtazapine, an antagonist at alpha2-adrenoceptors, does not enhance serotonin (5-HT) neurotransmission directly but disinhibits the norepinephrine activation of 5-HT neurons and thereby increases 5-HT neurotransmission by a mechanism that may not require a time-dependent desensitization of receptors. The present study was undertaken to determine whether the mirtazapine-citalopram combination could induce an earlier and/or greater effect on the 5-HT system in OCD subjects than citalopram alone. METHOD: Forty-nine patients with OCD (DSM-IV) without comorbid depression were randomly assigned to a 2-tailed, single-blind, 12-week clinical trial with citalopram (20-80 mg/day) plus placebo or citalopram plus mirtazapine (15-30 mg/day). Assessments were performed weekly with the Yale-Brown Obsessive Compulsive Scale (YBOCS), the Hamilton Rating Scale for Depression, and the Clinical Global Impressions scale. Data were collected from November 2001 to July 2003. RESULTS: The citalopram plus mirtazapine group achieved a reduction of at least 35% in YBOCS score and a "much improved" or "very much improved" rating on the Clinical Global Impressions-Improvement scale from the fourth week, while the citalopram plus placebo group obtained these results only from the eighth week. The number of responders was higher in the citalopram plus mirtazapine group at the fourth week of treatment, while no difference between groups in the response rate was noted at the eighth and twelfth weeks of treatment. CONCLUSIONS: We found an earlier onset of response action in OCD symptoms and reduced undesired side effects when mirtazapine was added to citalopram. This augmentation strategy deserves clinical and research consideration through further double-blind, placebo-controlled studies.     

Lack of effects on core obsessive-compulsive symptoms of tryptophan depletion during symptom provocation in remitted obsessive-compulsive disorder patients.

BACKGROUND: Pharmacological evidence support that enhancement of serotonin (5-HT) neurotransmission is critical for treatment efficacy in obsessive-compulsive disorder (OCD). Surprisingly, acute tryptophan depletion (ATD), a procedure known to reduce 5-HT neurotransmission, carried out in remitted OCD patients on selective serotonin reuptake inhibitors (SSRIs) failed to worsen obsessive-compulsive (OC) symptoms. We hypothesized that the putative symptom exacerbation resulting from ATD would only be observed during symptom provocation but not at rest. METHODS: Double-blind placebo-controlled ATD study conducted in 16 OCD patients with stable improvement under either SSRI (n = 8) or specialized cognitive behavior therapy alone (n = 8), coupled with gradual symptom provocation, performed 5 hours after drink ingestion. RESULTS: Acute tryptophan depletion markedly reduced total and free plasma tryptophan levels but did not significantly increase obsessions or compulsions at rest or following symptom provocation. However, subjective distress in response to triggering situations was significantly higher during ATD; significant mood lowering was also present during ATD. CONCLUSIONS: These results are consistent with the view that relapses in OC core symptoms in remitted OCD patients may not depend solely on short-term changes in presynaptic 5-HT availability. In contrast to its apparent lack of effect on core OC symptoms, ATD affected the patient's mood and distress level resulting from provocation.     

Pindolol does not augment cortisol and prolactin responses to paroxetine in healthy subjects

OBJECTIVE: Animal studies have shown that pindolol augmentation of selective serotonin re-uptake inhibitors (SSRIs) may act through inhibition of 5-HT(1A) autoreceptors in the raphe. The combination of pindolol plus a SSRI produces increased synaptic 5-HT levels that are greater than those achieved with a SSRI alone. However, it is unclear whether this actually occurs in humans, and clinical studies of pindolol augmentation have produced inconsistent results. Since the release of cortisol and prolactin is under serotonergic control, we hypothesized that pindolol augmentation of synaptic 5-HT concentrations produced by an SSRI in humans should lead to enhanced SSRI-induced cortisol and prolactin responses. METHODS: Cortisol and prolactin responses were measured after challenge tests with paroxetine (20-40 mg) plus pindolol (5 mg) and after paroxetine plus placebo in six non-depressed, healthy control subjects. RESULTS: No differences were observed in the cortisol or prolactin responses between either neuroendocrine challenge test. CONCLUSIONS: These results suggest that SSRI augmentation with usual clinical doses of pindolol does not increase central synaptic 5-HT neurotransmission sufficient to induce an enhanced neuroendocrine response.     

Cerebral perfusion response to successful treatment of depression with different serotoninergic agents

In 19 patients with major depressive disorder, effective treatment with selective serotonin reuptake inhibitors (SSRIs) or amesergide (AMSG) was associated with increased cerebral perfusion in anterior cingulate cortex (SSRI and AMSG) and in medial prefrontal cortex (AMSG). Both selective serotonin reuptake inhibitors and AMSG exert antidepressant action through the serotonin (5-HT) system as reuptake inhibitors. Amesergide differs from SSRIs in that it is also a highly selective 5-HT antagonist, which may in part account for differences in cerebral blood flow response to treatment.     

Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder

BACKGROUND: Due to their favorable side-effect profile, atypical antipsychotic agents offer important therapeutic advantages in mood disorders. Ziprasidone, an atypical antipsychotic agent with strong 5-HT(1A) agonist activity, may be particularly useful when used in conjunction with standard antidepressants in treatment-resistant depression. The purpose of this study is to test this hypothesis in depressed outpatients who have not experienced significant clinical improvement following an adequate trial of a selective serotonin reuptake inhibitor (SSRI). METHOD: Twenty patients with major depressive disorder (MDD) who had failed to experience a clinical response to an adequate trial of an SSRI were treated with open-label ziprasidone in addition to their SSRI for 6 weeks between February 2002 and December 2002. MDD was diagnosed with the Structured Clinical Interview for DSM-IV Axis I disorders. Clinical response was defined as a 50% or greater decrease in depressive symptoms during the course of the trial (baseline to endpoint), as measured by the HAM-D-17 total score. RESULTS: Thirteen of 20 patients (65.0%) completed the trial. Using a completer analysis, 8 patients (61.5%) were classified as responders. An intent-to-treat (ITT) analysis resulted in 10 responders (50.0%). The overall proportion of remitters was 5 of 13 (38.5%) using a completer analysis and 5 of 20 (25.0%) using the ITT analysis. Ziprasidone administration appeared to be safe, with no clinically significant QTc prolongation or severe adverse events observed in any of the study participants. CONCLUSION: These results suggest a possible augmentation role for ziprasidone when used in conjunction with SSRIs in SSRI-resistant MDD.     

How to treat OCD in patients with Tourette syndrome

Obsessive-compulsive disorder (OCD) constitutes an etiologically heterogeneous set of conditions, including a subtype that seems etiologically related to Tourette syndrome (TS). In order to treat OCD patients optimally, the clinician needs to integrate educational, psychological and pharmacological approaches. The most effective psychological intervention is cognitive-behavior therapy (CBT). Drug treatment includes clomipramine and all selective serotonin reuptake inhibitors (SSRIs). A subgroup of OCD patients, however, shows no significant improvement. Few studies suggest that the presence of tics is associated to a worse treatment response to SSRIs and that such patients benefit from combined therapy of serotonin-reuptake inhibitors plus neuroleptics. Independently of the presence of tics, there are several different augmentation strategies for resistant cases with drugs that interfere in the dopamine, serotonin, opioid and gonadal hormone systems. In addition, new therapies are now being tested against presumed postinfectious autoimmune processes. Finally, new developments are promising in neural circuit-based therapies, including neurosurgery for refractory patients.     

Olanzapine augmentation of serotonin uptake inhibitors in obsessive-compulsive disorder: an open study.

OBJECTIVE: This study evaluates the clinical response to olanzapine used in association with selective serotonin reuptake inhibitors (SSRIs) or clomipramine in treatment-resistant obsessive-compulsive disorder (OCD). METHODS: We describe the cases of 9 patients with serotonin uptake inhibitor-resistant OCD who were given an open-label adjunctive treatment of olanzapine for a minimum of 6 weeks. The response was assessed by using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Clinical Global Impression Scale (CGI). RESULTS: Six patients showed improvement of symptoms after the augmentation with olanzapine. One patient (treated with clomipramine) discontinued olanzapine due to side effects, and another 2 did not respond. CONCLUSION: Olanzapine augmentation of SSRIs in treating OCD showed a good (two-thirds) response rate, and it could therefore be considered as a treatment option when conventional therapies have failed.     

5-HT(2B) receptors are required for serotonin-selective antidepressant actions

The therapeutic effects induced by serotonin-selective reuptake inhibitor (SSRI) antidepressants are initially triggered by blocking the serotonin transporter and rely on long-term adaptations of pre- and post-synaptic receptors. We show here that long-term behavioral and neurogenic SSRI effects are abolished after either genetic or pharmacological inactivation of 5-HT(2B) receptors. Conversely, direct agonist stimulation of 5-HT(2B) receptors induces an SSRI-like response in behavioral and neurogenic assays. Moreover, the observation that (i) this receptor is expressed by raphe serotonergic neurons, (ii) the SSRI-induced increase in hippocampal extracellular serotonin concentration is strongly reduced in the absence of functional 5-HT(2B) receptors and (iii) a selective 5-HT(2B) agonist mimics SSRI responses, supports a positive regulation of serotonergic neurons by 5-HT(2B) receptors. The 5-HT(2B) receptor appears, therefore, to positively modulate serotonergic activity and to be required for the therapeutic actions of SSRIs. Consequently, the 5-HT(2B) receptor should be considered as a new tractable target in the combat against depression.     

Risperidone augmentation of selective serotonin reuptake inhibitors in major depression

BACKGROUND: At low doses, risperidone acts as a 5-HT2 antagonist. Preclinical data suggest 5-HT2 antagonists may enhance the action of serotonin. This report examines the clinical use of risperidone to augment selective serotonin reuptake inhibitor (SSRI) anti-depressants in patients who have not responded to SSRI therapy. METHOD: In 8 patients with major depressive disorder without psychotic features (DSM-IV) who had not responded to an SSRI, risperidone was added to the ongoing SSRI treatment. Hamilton Rating Scale for Depression scores were obtained before and after the addition of risperidone. RESULTS: These 8 patients remitted within 1 week of the addition of risperidone. Risperidone also appeared to have beneficial effects on sleep disturbance and sexual dysfunction. CONCLUSION: Risperidone may be a useful adjunct to SSRIs in the treatment of depression.     

Imaging the serotonergic system in depression

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) allow for the in vivo visualisation and measurement of, e.g. the serotonergic system in the brain of depressed patients. Currently, the available ligands permit the investigation of 5-HT2A and 5-HT1A receptors, the serotonin transporter and serotonin synthesis. 5-HT2A receptors have most extensively been investigated and increases, decreases or no differences in ligand binding have been found. Previous treatment and suicidality could be major confounding variables. Tricyclics seem to decrease ligand binding, while SSRIs in most studies increase ligand binding. A few studies have looked at the 5-HT1A receptor and demonstrated decreases in binding. The one study which looked at the effect of an SSRI treatment did not find any effect. The serotonin transporter availability seems to be reduced in depression. Tryptophane depletion studies have demonstrated effects on brain metabolism in serotonin related regions and on 5-HT2A receptors. Finally, serotonin synthesis studies have shown interesting differences between males and females.     

A Double-Blind,Placebo-Controlled Trial of Clonazepam in Obsessive-Compulsive Disorder

Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line pharmacological agents in treating obsessive-compulsive disorder (OCD). Appropriate treatment for OCD also involves cognitive behavioural therapy (CBT), including exposure and response prevention. As there is a time delay in seeing full therapeutic response, and not all patients tolerate SSRIs, there remains an unmet need for additional treatment approaches in OCD. In addition, most responders report only a partial reduction in symptoms. Clonazepam has demonstrated effectiveness in several preliminary reports in treating OCD. Twenty-seven patients with OCD were entered into a 10-week, double-blind, parallel design trial of clonazepam vs. placebo. Overall, only 3 out of 25 patients who had ≥ 1 rating on clonazepam/placebo were judged to be treatment responders, by scoring a 1 (very much improved) or 2 (much improved) on the CGI improvement scale. Responders included 2 of 9 in the placebo group and 1 of 16 in the clonazepam group. No significant difference was found between clonazepam and placebo groups on responder/non responder status (X² = 1.39, df = 1,24, p=0.238), nor on change in YBOCS, HAM-A, HAM-D or NIMH scales from beginning to last evaluation carried forward. These findings suggest that clonazepam is not effective as monotherapy in treating OCD. Its effectiveness in specific subgroups of OCD patients with co-morbid anxiety disorders or as an augmentation strategy added to SSRIs remains to be determined.     

A double-blind, placebo-controlled trial of clonazepam in obsessive-compulsive disorder.

Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line pharmacological agents in treating obsessive-compulsive disorder (OCD). Appropriate treatment for OCD also involves cognitive behavioural therapy (CBT), including exposure and response prevention. As there is a time delay in seeing full therapeutic response, and not all patients tolerate SSRIs, there remains an unmet need for additional treatment approaches in OCD. In addition, most responders report only a partial reduction in symptoms. Clonazepam has demonstrated effectiveness in several preliminary reports in treating OCD. Twenty-seven patients with OCD were entered into a 10 week, double-blind, parallel design trial of clonazepam vs. placebo. Overall, only 3 out of 25 patients who had >/= 1 rating on clonazepam/placebo were judged to be treatment responders, by scoring a 1 (very much improved) or 2 (much improved) on the CGI improvement scale. Responders included 2 of 9 in the placebo group and 1 of 16 in the clonazepam group. No significant difference was found between clonazepam and placebo groups on responder/non responder status (Chi(2 )=1.39, df =1,24, p=0.238), nor on change in YBOCS, Ham-A, Ham-D or NIMH scales from beginning to last evaluation carried forward. These findings suggest that clonazepam is not effective as monotherapy in treating OCD. Its effectiveness in specific subgroups of OCD patients with co-morbid anxiety disorders or as an augmentation strategy added to SSRIs remains to be determined.     

5-Hydroxytryptamine in premature ejaculation: opportunities for therapeutic intervention

Ejaculation, although mediated by a spinal ejaculation generator, is subject to descending supraspinal modulation from several brain regions. 5-Hydroxytryptamine (5-HT or serotonin) is involved in ejaculatory control, with its ejaculation-retarding effects likely to be attributable to activation of 5-HT1B and 5-HT2C receptors, both spinally and supraspinally. By contrast, stimulation of 5-HT1A receptors precipitates ejaculation. Selective serotonin reuptake inhibitors (SSRIs), which are used for treatment of psychiatric disorders, can delay ejaculation in humans and are widely used 'off-label' for treatment of premature ejaculation. SSRIs require 1-2 weeks' chronic dosing to be effective, similar to their use for treatment of depression. However, a new short-acting SSRI is effective 'on demand' and might represent the first of a new generation of therapies targeted to premature ejaculation.     

Peripheral and central neurochemical effects of the selective serotonin reuptake inhibitors (SSRIs) in humans and nonhuman primates: assessing bioeffect and mechanisms of action

It is clear that selective serotonin reuptake inhibitors (SSRIs) act powerfully to inhibit serotonin (5-hydroxytryptamine, 5-HT) uptake centrally and peripherally. However, there are a number of critical unanswered questions concerning the effects of the drugs in adults and children. The influence of age and duration of treatment on the extent of uptake inhibition and on the enhancement of central serotonergic functioning are unclear. In addition, the relationship of these factors and effects to the therapeutic and adverse effects of the SSRIs remain to be clarified. The general clinical utility of platelet 5-HT measurement is reviewed and studies assessing central and peripheral uptake blockade in infants and children and non-human primates are discussed. Recent investigations of central neurochemical effects of the SSRIs in primates assessed through measurement of 5-HT and related compounds in cisternal cerebrospinal fluid (CSF) of the rhesus monkey are presented. In summary, the studies described have found that: human fetal exposure to SSRIs has substantial effects on 5-HT transport in utero; exposure to SSRIs through breastmilk of mothers treated for postpartum depression usually has negligible effects on 5-HT uptake; prescribed SSRIs appear to exert similar effects on 5-HT transporter blockade in children and adults; and rapid and sustained increases are seen in monkey cisternal CSF levels of 5-HT upon initiation of SSRI administration. The implications of the observations in terms of behavioral effects, clinical practice, and underlying mechanisms of action of the SSRIs are discussed.     

On the pharmacotherapy of obsessive-compulsive disorder: is a consensus possible?

OBJECTIVE: To examine the efficacy and tolerability of clomipramine compared with the selective serotonin reuptake inhibitors (SSRIs) in the treatment of obsessive-compulsive disorder (OCD), bearing in mind the recent Expert Consensus Guidelines recommendation to use clomipramine after 2 to 3 failed SSRI trials. METHOD: The literature on the pharmacotherapy of OCD was critically examined. RESULTS: The available research evidence is not conclusive but suggests that clomipramine possesses greater anti-obsessional efficacy than do the SSRIs. In addition, when clomipramine is presented to patients in a positive way, and properly used in small initial doses with gradual increases, it seems to be tolerated as well as the SSRIs. CONCLUSION: Recently expressed opinions that clomipramine should be used to treat OCD after 2 to 3 failed SSRI trials are not supported by research evidence. Both clomipramine and the SSRIs may be used as first-line treatments for OCD.