Preliminary results from a multicenter trial of clomipramine in obsessive-compulsive disorder

Two multicenter, double-blind, placebo-controlled clinical trials were conducted to evaluate the effectiveness of 10 weeks of treatment with up to 300 mg daily of clomipramine in nondepressed patients with OCD. There were 575 patients enrolled in these clinical trials, and preliminary analyses of data from 384 of these patients demonstrate a virtual absence of placebo response, a very low rate of premature discontinuation, and for patients receiving clomipramine, a statistically and clinically significant improvement in OCD symptoms (40%-45% mean improvement with clomipramine vs. 4%-5% mean improvement with placebo). In general, clomipramine was well tolerated in doses of up to 300 mg daily.     

A double-blind study of adjuvant buspirone hydrochloride in clomipramine-treated patients with obsessive-compulsive disorder.

In this study, 14 patients with obsessive-compulsive disorder (OCD) who had received at least 3 months of treatment with clomipramine were treated with the anxiolytic agent buspirone in a 10-week, double-blind study. Before the addition of buspirone, these patients as a group had shown a partial but incomplete reduction (averaging 28%) in OCD symptoms during clomipramine treatment alone. Because buspirone has been reported to be efficacious as a sole agent and as an adjunct agent in combination with fluoxetine in patients with OCD, we were interested in assessing whether buspirone added to clomipramine treatment would be associated with further significant reductions in OCD or depressive symptoms. Although adjuvant buspirone treatment was well tolerated in most subjects, mean OCD and depressive symptoms, as evaluated by standardized rating scales, did not significantly change from baseline scores achieved on clomipramine treatment alone, either after the addition of placebo for 2 weeks or buspirone (57 +/- 7 mg/day) for an additional 10 weeks. However on an individual basis, 4 (29%) of the 14 patients did have an additional 25% reduction in OCD symptoms after adjuvant buspirone treatment. This double-blind study suggests that adjunctive buspirone therapy is not generally associated with significant further clinical improvement in OCD or depressive symptoms compared with clomipramine monotherapy, but that there may be a subgroup of patients who do benefit from adjuvant buspirone therapy.     

Fluvoxamine in obsessive-compulsive disorder: similar efficacy but superior tolerability in comparison with clomipramine

Some meta-analyses have suggested that the selective serotonin reuptake inhibitors (SSRIs) are less effective than clomipramine in the treatment of obsessive-compulsive disorder (OCD). The aim of this double-blind, randomised, multicentre study was to directly compare the efficacy and safety of fluvoxamine and clomipramine in patients with OCD. A total of 227 patients were randomised to flexible doses of fluvoxamine or clomipramine (both 150-300 mg/day) for 10 weeks. Fluvoxamine and clomipramine were both clinically effective and there were no statistically significant differences between the two treatment groups, at any visit, on the National Institute of Mental Health Obsessive-Compulsive global rating scale, the Yale-Brown Obsessive-Compulsive scale (total score and obsession and compulsion subscores), the Clinical Global Impression severity of illness and global improvement subscales, the Clinical Anxiety Scale and the 17-item Hamilton Depression Rating Scale. However, there were differences in safety between the two treatments. Compared with fluvoxamine-treated patients, those treated with clomipramine had more anticholinergic side effects (dry mouth, constipation and tremor) and premature withdrawals due to adverse events (18 versus 9). The results from this controlled study indicate that fluvoxamine is as effective as clomipramine in the treatment of OCD but has a better tolerability profile. Copyright 2001 John Wiley & Sons, Ltd.     

Clomipramine: an antiobsessional tricyclic antidepressant

The chemistry, pharmacology, pharmacokinetics, adverse effects, and dosage of clomipramine hydrochloride are described, and clinical studies of the use of clomipramine in treating obsessive-compulsive disorder (OCD), other psychiatric conditions, and chronic pain are reviewed. Clomipramine hydrochloride, a tricyclic antidepressant, is a potent inhibitor of serotonin reuptake and may affect dopaminergic neurotransmission, suppress rapid eye movement sleep, produce changes in electrocardiograms, and elevate plasma prolactin. The drug is well absorbed from the gastrointestinal tract and undergoes extensive first-pass metabolism. Peak plasma concentrations occur three to four hours after a 150-mg oral dose. The mean elimination half-life is 39 hours. Some 66% of a dose is excreted in the urine, the remainder being eliminated in the feces. In clinical trials, clomipramine was significantly more effective than placebo, clorgiline, amitriptyline, imipramine, and doxepin in ameliorating the symptoms of OCD. Initial effects are seen at four weeks; improvement may continue for up to 18 weeks. Clomipramine may also be effective in treating panic attacks, phobias, depression, and chronic pain. The most common adverse effects of clomipramine are anticholinergic; others include nausea, seizures, and sexual difficulties. Interactions between clomipramine and barbiturates, haloperidol, monoamine oxidase inhibitors, and cigarette smoking have been documented. The usual initial adult dosage is 25-50 mg/day, titrated gradually to 250 mg/day if necessary. Clomipramine hydrochloride is a welcome new agent for the treatment of obsessive-compulsive disorder. Although its adverse-effect profile is like that of other tricyclic antidepressants, sexual dysfunction and seizures may be more frequent with this agent and limit its use.     

An update on the pharmacological treatment of obsessive-compulsive disorder

The purpose of this article is to introduce the reader to an updated evidence-based drug treatment algorithm to be employed in patients with obsessive-compulsive disorder (OCD). Relevant studies were identified through a comprehensive review and classified according to the type of patients enrolled, the quality of the study design and the invasiveness, availability and complexity of the therapeutic approach. When ineffective, therapeutic trials with first-line strategies (such as the selective serotonin re-uptake inhibitors [SSRIs] and venlafaxine) should be followed by treatment approaches such as clomipramine, augmentation with antipsychotics or pindolol, SSRI megadoses or cognitive behavioral therapy. These therapeutic strategies are expected to help most patients with OCD. Additional approaches include intravenous clomipramine, oral morphine, 'heroic drug strategies', deep brain stimulation and functional neurosurgery. Independent studies are urgently needed to help identify the most promising drug treatment sequences for OCD.     

舍曲林与氯米帕明治疗难治性强迫症对照研究

目的探讨舍曲林与氯米帕明治疗难治性强迫症的疗效和不良反应。方法对难治性强迫症60例,随机分为两组,分别用舍曲林与氯米帕明治疗8周。采用强迫症量表（Y-BOCS）和副反应量表（TESS）评价疗效及不良反应。结果两药的总体疗效相仿。舍曲林不良反应小,尤其是心血管系统及抗胆碱能不良反应少。结论舍曲林尤适用于难治性强迫症。     

Fluvoxamine. An updated review of its use in the management of adults with anxiety disorders

Fluvoxamine is a potent and selective serotonin reuptake inhibitor (SSRI) that has little or no effect on other monoamine reuptake mechanisms. Relative to other SSRIs, fluvoxamine is a weak inhibitor of cytochrome P450 (CYP) 2D6, a moderate inhibitor of CYP2C19 and CYP3A4 and a potent inhibitor of CYP1A2. In randomised, double-blind trials. fluvoxamine 100 to 300 mg/day for 6 to 10 weeks significantly reduced symptoms of obsessive-compulsive disorder (OCD) compared with placebo. Response rates of 38 to 52% have been reported with fluvoxamine, compared with response rates of 0 to 18% with placebo. In patients with OCD, fluvoxamine had similar efficacy to that of clomipramine and, in smaller trials, the SSRIs paroxetine and citalopram and was significantly more effective than desipramine. Maintenance therapy with fluvoxamine may reduce the likelihood of relapses in up to 67% of patients with OCD. Fluvoxamine < or = 300 mg/day for 6 to 8 weeks was as effective as imipramine in patients with panic disorder, and significantly more effective than placebo. In addition, treatment with fluvoxamine < or = 300 mg/day for > or = 8 weeks improved symptoms of social phobia (social anxiety disorder), post-traumatic stress disorder (PTSD), pathological gambling, compulsive buying, trichotillomania, kleptomania, body dysmorphic disorder, eating disorders and autistic disorder. Large trials comparing the efficacy of fluvoxamine and other SSRIs in patients with anxiety disorders are warranted. Fluvoxamine is generally well tolerated; in postmarketing studies, nausea was the only adverse event occurring in >10% of patients with less commonly reported events including somnolence, asthenia, headache, dry mouth and insomnia. Fluvoxamine is associated with a low risk of suicidal behaviour, sexual dysfunction and withdrawal syndrome. Fewer anticholinergic or cardiovascular events are associated with fluvoxamine than tricyclic antidepressants. Although comparative data are lacking, the tolerability profile of fluvoxamine appears to be broadly similar to those of other SSRIs. CONCLUSION: Fluvoxamine has demonstrated short term efficacy in the treatment of OCD, panic disorder, social phobia, PTSD and in a range of obsessive-compulsive spectrum disorders. The drug is as effective as clomipramine in patients with OCD but appears to have a better tolerability profile. On the basis of current treatment guidelines, fluvoxamine, like other SSRIs, is recommended as first-line treatment for a number of anxiety disorders. It appears to offer some pharmacokinetic advantages and a different drug interaction profile to the other SSRIs with a broadly similar spectrum of adverse events. However, direct comparisons are required to assess the relative efficacy and tolerability of the different agents of this drug class.     

Plasma clomipramine levels in adult patients with obsessive-compulsive disorder

The aim of this study was to explore the possible relationship between plasma clomipramine and its major metabolite (N-desmethylclomipramine) levels and related parameters, and clinical features in patients with obsessive-compulsive disorder (OCD). Twenty-six outpatients (13 men, 13 women), suffering from OCD were consecutively enrolled in this study. The severity of OCD was assessed by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). The measurements were taken after 4 weeks and 6 months from the beginning of the treatment. The drug levels were measured by a high-performance liquid chromatography method developed by us. The correlations between biological and clinical parameters were analyzed by means of Spearman's correlation coefficient. The Mann-Whitney test was used for comparing biological and clinical variables between men and women. The results showed that clomipramine levels were related to the doses at the two assessment times. A significant and positive correlation was detected at the beginning between the N-desmethylclomipramine ratio and the Y-BOCS total score; however, this was true only for men, where the similar correlations were measured also with the Y-BOCS subscale. After 6 months of clomipramine, men showed a significant improvement of the compulsions. These findings would highlight the potential impact of assessing clomipramine plasma levels and their relationships with specific symptoms, as well as the influence of the sex on the drug response.     

Spotlight on fluvoxamine in anxiety disorders in children and adolescents

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) which may be used for the management of anxiety disorders in children and adolescents. Absorption of fluvoxamine was similar in adolescents to that in adults, which suggests that the maximum dosage of the drug for patients aged between 12 and 17 years can be as high as 300 mg/day. However, steady-state plasma fluvoxamine concentrations were 2 to 3 times higher in children (aged between 6 and 11 years) than in adolescents; thus, the maximum fluvoxamine dosage recommended for children is 200 mg/day. Fluvoxamine (50 to 300 mg/day) for 8 to 16 weeks significantly reduced symptoms of obsessive-compulsive disorder (OCD) [measured across multiple assessment scales] compared with placebo in a well controlled trial in paediatric patients (n = 120) or from baseline in noncomparative trials in adolescent (n = 20) or paediatric (n = 16) patients. Improvements with fluvoxamine (up to 200 mg/day) were observed for up to 1 year in 98 patients with OCD in a noncomparative trial. The drug (up to 250 or 300 mg/day) also improved symptoms of anxiety compared with placebo in an 8-week well controlled trial in 128 paediatric patients with social phobia, separation anxiety disorder or generalised anxiety disorder (GAD). Fluvoxamine (50 to 300 mg/day) appears to be well tolerated in paediatric patients, with most adverse events with the drug (except abdominal discomfort, which occurred more often in patients receiving fluvoxamine) occurring with a similar incidence to those with placebo. The most common adverse events involved the CNS or gastrointestinal system. Most adverse events reported by paediatric patients with OCD were similar to those reported by adults. In conclusion, fluvoxamine is generally well tolerated and has demonstrated short-term efficacy compared with placebo in the treatment of OCD, and social phobia, separation anxiety disorder or GAD in well controlled trials in paediatric patients. Reductions in symptoms of anxiety with fluvoxamine have been observed for up to 1 year in children and adolescents with OCD. However, there are currently no comparative trials of fluvoxamine with other pharmacological agents. In the absence of such trials, current consensus opinion recommends that when pharmacotherapy is indicated, fluvoxamine, like other SSRIs, can be used as first-line treatment for anxiety disorders, particularly OCD, in paediatric patients. However, direct comparisons are required to assess the relative efficacy and tolerability of pharmacological agents in order to make firm recommendations for the treatment of anxiety disorders in this patient group.     

Multicentre, double-blind, comparison of fluvoxamine and clomipramine in the treatment of obsessive-compulsive disorder

The aim of this prospectively randomized, double-blind, parallel group, multicentre study was to compare the efficacy and tolerability of fluvoxamine and clomipramine in patients suffering from obsessive-compulsive disorder (OCD) (DSM-III-R). Fourteen centres participated in this trial. Sixty-eight patients were randomized to receive fluvoxamine and 65 to receive clomipramine. The duration of the study was 10 weeks. The two treatment groups showed a marked improvement of obsessive-compulsive symptomatology, as determined by the Yale-Brown Obsessive-Compulsive Scale, the National Institute of Mental Health Obsessive-Compulsive Global Scale and Clinical Global Impression. No statistically significant differences were found between fluvoxamine and clomipramine in terms of efficacy during the study. A similar number of patients in each group withdrew from the study prematurely, but there were more dropouts due to adverse events in the clomipramine group. Concerning tolerability, there were significantly more reports of constipation and dry mouth in the clomipramine group. The results show that fluvoxamine and clomipramine have similar efficacy in the treatment of patients suffering from OCD, but fluvoxamine is better tolerated. In view of the superior safety profile of fluvoxamine compared to clomipramine in terms of a risk-benefit assessment, the use of fluvoxamine would appear to be advantageous for this patient population.     

Potential effect of enalapril on clomipramine metabolism

In two patients treated for hypertension with enalapril for more than 12 months, clomipramine was introduced in small to moderate doses for the treatment of dysthymic disorders. Rapid improvement of depressive symptoms was noted, which was followed by signs of antidepressant overdosage. The blood levels of clomipramine and desmethylchlomipramine were high. After reducing the dose, the symptoms resolved and the blood level of antidepressant returned to the usual therapeutic range. Enalapril would appear to reduce the clearance of clomipramine; the association enalapril + clomipramine does not appear to modify blood pressure.     

A double-blind, placebo controlled study of trazodone in patients with obsessive-compulsive disorder.

Patients with obsessive-compulsive disorder (OCD) have been shown to be preferentially responsive to serotonin (5-HT) uptake-inhibiting antidepressants including clomipramine, fluoxetine, fluvoxamine, and sertraline. The nontricyclic antidepressant, trazodone, also possesses serotonin reuptake inhibiting properties and has been reported to be efficacious in OCD in several case reports and open trials. In order to investigate trazodone's potential antiobsessive efficacy in a controlled fashion, 21 patients with OCD were entered into a double-blind, parallel design comparison of trazodone and placebo. There were no significant differences in baseline rating scores of OCD or depressive symptoms between those who entered the trazodone phase (N = 13) versus those who entered the placebo phase (N = 8). As measured by standardized OCD and depression rating scales, there was no significant difference in OCD or depressive symptoms in the 17 patients who completed 10 weeks of trazodone (N = 11, mean daily dose, 235 +/- 10 mg) versus 10 weeks of placebo (N = 6) administration. In comparison to clomipramine and fluoxetine treatment which we have found to be associated with greater than 95% reduction in platelet 5-HT concentration, there was only a 26% mean reduction in platelet 5-HT concentration after 10 weeks of trazodone administration. These results indicate that trazodone lacks substantial antiobsessive effects and is associated with only modest reductions in platelet 5-HT concentrations.     

Clomipramine, clonazepam, and clonidine treatment of obsessive-compulsive disorder.

Serotonergic reuptake inhibitors have been the primary medications for treatment of obsessive-compulsive disorder (OCD); however, other serotonergic and alpha 2-adrenergic medications also have been reported to reduce obsessive-compulsive symptoms. In this study, we compare three medications with reported efficacy in OCD to a control medication, diphenhydramine, a medication without theoretical or demonstrated treatment benefit. The three active medications were clomipramine, a serotonergic reuptake inhibitor; clonazepam, a benezodiazepine with putative serotonergic properties; and clonidine, an alpha 2-adrenergic agonist. Twenty-eight subjects with DSM-III-R diagnosis of OCD rotated through 6-week trials of each of the four medications in a randomized, double-blind, multiple crossover protocol. Clomipramine and clonazepam were both effective relative to the control medication in reducing OCD symptoms. There was a significant cross-response between these two medications; however 40% of subjects failing clomipramine trials had a clinically significant response to clonazepam treatment. The control medication, diphenhydramine, itself produced a significant decrement in symptoms, whereas clonidine was ineffective in reducing OCD symptoms. Clonazepam improvement was unrelated to changes in anxiety and occurred early in treatment. Clonazepam was significantly more effective than the other medications during the first 3 weeks of treatment. The results confirm the efficacy of clomipramine in the treatment of OCD and suggest that clonazepam might be a useful alternative treatment for patients with this disorder.     

Nisoldipine. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of angina pectoris, hypertension and related cardiovascular disorders

Nisoldipine is an orally administered calcium entry blocking drug structurally related to nifedipine. In limited clinical trials it has been shown to be effective and relatively well tolerated in the treatment of patients with chronic stable angina pectoris and mild to moderate essential hypertension. As for all dihydropyridine-calcium antagonists, its major properties include potent peripheral and coronary vasodilation and improvement in myocardial oxygen supply relative to demand. These actions occur without depression of cardiac conduction or left ventricular function. Short term clinical trials have shown nisoldipine to produce both symptomatic and objective improvements in patients with chronic angina of effort and have suggested a benefit in vasospastic angina. A small number of comparative trials indicate that nisoldipine is equally as effective as nifedipine. In addition, in combination with beta-adrenoceptor blockade nisoldipine appears to offer additional benefit compared with beta-blockade alone and is well tolerated. In patients with mild to moderate essential hypertension nisoldipine monotherapy, in 1 or 2 daily doses, has maintained blood pressure control and has also been a useful addition to diuretics and beta-adrenoceptor blocking drugs in patients with poorly controlled disease. Side effects appear to be dose related, generally mild and transient, and are primarily those resulting from potent peripheral vasodilation - headache, flushing and pretibial or ankle oedema. Although studies to date are promising, there are no published long term studies (greater than 1 year) of nisoldipine in comparison with other calcium entry blockers and other drugs currently in clinical use for the treatment of angina pectoris or hypertension. Until such studies are completed the exact place of nisoldipine in the treatment of these diseases remains to be established.     

Current concepts in the pharmacological treatment of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a chronic and often disabling disease. OCD is characterised by intrusive, unwanted and persistently recurring mental events (obsessions) that usually evoke discomfort or anxiety, and/or repetitive ritualistic behaviours (compulsions) that are aimed at reducing discomfort and anxiety. However, the compulsions succeed only in achieving transient relief, followed by a growing sense of pressure. 10 years ago, OCD was considered a rare and treatment-refractory disorder. Recent well designed studies document a lifetime prevalence rate for OCD of more than 2% in the general population. The outlook for patients with OCD has changed in the last decade, with many well controlled studies showing that OCD patients respond to specific behavioural and pharmacological treatments. The specific form of behavioural therapy is in vivo exposure coupled with response prevention. Only serotonin reuptake inhibitors, such as clomipramine, fluoxetine and fluvoxamine, are effective in the treatment of both depressed and not depressed OCD patients. Fluoxetine and fluvoxamine lack the anticholinergic side effects of clomipramine and, thus, provide an alternative treatment for patients who cannot tolerate clomipramine. Other nonserotonergic antidepressants (tricyclics and monoamine oxidase inhibitors) and anxiolytic agents have not been found to be consistently effective in this disorder. Insufficient data on the efficacy of neuroleptics and their potentially irreversible side effects limit their use in OCD patients. Behavioural and the pharmacological treatment are complementary, and a combination of the 2 therapies is apparently more effective than either modality alone.     

Clomipramine, a better reference drug for panic/agoraphobia. I. Effectiveness comparison with imipramine

An 8-week, double-blind, flexible-dose trial comparing low doses of clomipramine (mean=50 mg) with moderate doses of imipramine (mean=113.8 mg and propanteline (active placebo), was carried out in 60 out-patients with panic disorder with or without agoraphobia. Efficacy evaluation included global, anxiety and depression rating scales, and the determination of rates of relapse over up to 10 weeks of single-blind placebo follow-up. Both tricyclics were significantly more effective than propanteline, but clomipramine tended to act faster and more consistently than imipramine on most measures. Given the degree of blindness achieved and the significantly lower doses of clomipramine, this seems a better reference drug than imipramine for clinical trials in panic/agoraphobia.     

Escitalopram : a review of its use in the management of major depressive and anxiety disorders

Escitalopram is the therapeutically active S-enantiomer of RS-citalopram, a commonly prescribed SSRI. The R-enantiomer is essentially pharmacologically inactive. Escitalopram 10 or 20 mg/day produced significantly greater improvements in standard measurements of antidepressant effect (Montgomery-Asberg Depression Rating Scale [MADRS], Clinical Global Impressions Improvement and Severity scales [CGI-I and CGI-S] and Hamilton Rating Scale for Depression [HAM-D]) in patients with major depressive disorder (MDD) than placebo in several 8-week, placebo-controlled, randomised, double-blind, multicentre studies. Symptom improvement was rapid, with some parameters improving within 1-2 weeks of starting escitalopram treatment. In addition, escitalopram showed earlier and clearer separation from placebo than RS-citalopram, at one-quarter to half the dosage, in 8-week, placebo-controlled trials; had significantly better efficacy than RS-citalopram in a subgroup of patients with moderate MDD in a 24-week trial; and produced sustained response and remission significantly faster than venlafaxine extended release in patients with MDD. Escitalopram reduced relapse rate compared with placebo and increased the percentage of patients in remission in long-term trials (up to 52 weeks). Consistently significant improvements for all efficacy parameters were also observed in patients with generalised anxiety disorder, social anxiety disorder and panic disorder treated with escitalopram for 8-12 weeks in individual, randomised, placebo-controlled, double-blind investigations. The good tolerability profile of escitalopram is predictable and similar to that of RS-citalopram. Such adverse events as nausea, ejaculatory problems, diarrhoea and insomnia are expected but, with the exception of ejaculatory problems and nausea, which is mild and transient, these were generally no more frequent than with placebo in fully published clinical trials. No adverse events not previously seen in acute trials were reported with long-term use.CONCLUSIONS: Escitalopram, the S-enantiomer of RS-citalopram, is a highly selective inhibitor for the serotonin transporter, ameliorates depressive symptoms in patients with MDD at half the RS-citalopram dosage, has a rapid onset of symptom improvement and has a predictable tolerability profile of generally mild adverse events. Like RS-citalopram, escitalopram is expected to have a low propensity for drug interactions, a potential benefit in the management of patients with comorbidities. In combination, these properties place escitalopram, like other SSRIs, as first-line therapy in patients with MDD. Escitalopram is indicated for use in patients with panic disorder in Europe and, should further evidence confirm early findings that escitalopram reduces anxiety, the drug may well find an additional role in the management of anxiety disorders.     

A double-blind, randomized, controlled trial of fluoxetine plus quetiapine or clomipramine versus fluoxetine plus placebo for obsessive-compulsive disorder

Obsessive-compulsive disorder patients who do not improve sufficiently after treatment with a selective serotonin reuptake inhibitor might improve further if other drugs were added to the treatment regimen. The authors present a double-blind, placebo-controlled trial comparing the efficacy of adding quetiapine or clomipramine to a treatment regimen consisting of fluoxetine. Between May 2007 and March 2010, a total of 54 patients with a primary diagnosis of obsessive-compulsive disorder, as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, and a current Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score of at least 16, the score having dropped by less than 35% after fluoxetine monotherapy, were allocated to 1 of 3 arms (n = 18 per arm): quetiapine + fluoxetine (≤200 and ≤40 mg/d, respectively), clomipramine + fluoxetine (≤75 and ≤40 mg/d, respectively), or placebo + fluoxetine (≤80 mg/d of fluoxetine). Follow-up was 12 weeks. The Y-BOCS scores were the main outcome measure. No severe adverse events occurred during the trial, and 40 patients (74%) completed the 12-week protocol. The Y-BOCS scores (mean [SD]) were significantly better in the placebo + fluoxetine and clomipramine + fluoxetine groups than in the quetiapine + fluoxetine group (final: 18 [7] and 18 [7], respectively, vs 25 [6], P < 0.001) (reduction from baseline: -6.7 [confidence interval {CI}, -9.6 to -3.8; and -6.5 [CI, -9.0 to -3.9], respectively, vs -0.1 [CI, -2.9 to 2.7], P < 0.001; number needed to treat = 2.4). The clomipramine-fluoxetine combination is a safe and effective treatment for fluoxetine nonresponders, especially those who cannot tolerate high doses of fluoxetine. However, the period of monotherapy with the maximum dose of fluoxetine should be extended before a combination treatment strategy is applied.     

Aripiprazole augmentation strategy in clomipramine-resistant depressive patients: An open preliminary study

Recent evidence supports the use of second generation antipsychotics in drug resistant depression. The aim of the present open-label study was to evaluate the effect of aripiprazole as an add-on medication in drug-resistant depressed patients who had not responded to clomipramine. Thirty-five patients with major depressive disorder (MDD) were included in the study. All patients had not responded to a previous adequate treatment with an SSRI and had been receiving clomipramine (daily doses ranging from 100 to 300 mg) for 113.9 ± 18.9 days without getting significant clinical improvement. Aripiprazole was added at the fixed dose of 5 mg/day and clinical status as well as clomipramine plasma levels were monitored before and after 4, 8, and 24 weeks of combined treatment. Hamilton depression rating scale scores significantly decreased over the follow-up period with 91.4% and 34.3% of patients getting a response or a remission, respectively, after 24 weeks of combined treatment. No worsening of clomipramine-related side effects nor new side effects were observed. The clinical improvement was accompanied by a progressive and significant increase in clomipramine plasma levels. With the limitation of an open-label design, these data suggest for the first time the putative efficacy and safety of aripiprazole in combination with a tricyclic medication in drug resistant depressed patients. The role of the observed pharmacokinetic interaction in the mechanism of aripiprazole antidepressant activity remains to be proved.     

Moclobemide: therapeutic use and clinical studies

Moclobemide is a reversible inhibitor of monoamine-oxidase-A (RIMA) and has been extensively evaluated in the treatment of a wide spectrum of depressive disorders and less extensively studied in anxiety disorders. Nearly all meta-analyses and most comparative studies indicated that in the acute management of depression this drug is more efficacious than placebo and as efficacious as tricyclic (or some heterocyclic) antidepressants or selective serotonin reuptake inhibitors (SSRIs). There is a growing evidence that moclobemide is not inferior to other antidepressants in the treatment of subtypes of depression, such as dysthymia, endogenous (unipolar and bipolar), reactive, atypical, agitated, and retarded depression as with other antidepressants limited evidence suggests that moclobemide has consistent long-term efficacy. However, more controlled studies addressing this issue are needed. For patients with bipolar depression the risk of developing mania seems to be not higher with moclobemide than with other antidepressants. The effective therapeutic dose range for moclobemide in most acute phase trials was 300 to 600 mg, divided in 2 to 3 doses. While one controlled trial and one long-term open-label study found moclobemide to be efficacious in social phobia, three controlled trials subsequently revealed either no effect or less robust effects with the tendency of higher doses (600 - 900 mg/d) to be more efficacious. Two comparative trials demonstrated moclobemide to be as efficacious as fluoxetine or clomipramine in patients suffering from panic disorder. Placebo-controlled trials in this indication are, however, still lacking. A relationship between the plasma concentration of moclobemide and its therapeutic efficacy is not apparent but a positive correlation with adverse events has been found. Dizziness, nausea and insomnia occurred more frequently on moclobemide than on placebo. Due to negligible anticholinergic and antihistaminic actions, moclobemide has been better tolerated than tri- or heterocyclic antidepressants. Gastrointestinal side effects and, especially, sexual dysfunction were much less frequent with moclobemide than with SSRIs. Unlike irreversible MAO-inhibitors, moclobemide has a negligible propensity to induce hypertensive crisis after ingestion of tyramine-rich food ("cheese-reaction"). Therefore, dietary restrictions are not as strict. However, with moclobemide doses above 900 mg/d the risk of interaction with ingested tyramine might become clinically relevant. After multiple dosing the oral bioavailability of moclobemide reaches almost 100%. At therapeutic doses, moclobemide lacks significant negative effects on psychomotor performance, cognitive function or cardiovascular system. Due to the relative freedom from these side effects, moclobemide is particularly attractive in the treatment of elderly patients. Moclobemide is a substrate of CYP2C19. Although it acts as an inhibitor of CYP1A2, CYP2C19, and CYP2D6, relatively few clinically important drug interactions involving moclobemide have been reported. It is relatively safe even in overdose. The drug has a short plasma elimination half-life that allows switching to an alternative agent within 24 h. Since it is well tolerated, therapeutic doses can often be reached rapidly upon onset of treatment. Steady-state plasma levels are reached approximately at one week following dose adjustment. Patients with renal dysfunction require no dose reduction in contrast to patients with severe hepatic impairment. Cases of refractory depression might improve with a combination of moclobemide with other antidepressants, such as clomipramine or a SSRI. Since this combination has rarely been associated with a potentially lethal serotonin syndrome, it requires lower entry doses, a slower dose titration and a more careful monitoring of patients. Combination therapy with moclobemide and other serotonergic agents, or opioids, should be undertaken with caution, although no serious adverse events have been published with therapeutic doses of moclobemide to date. On the basis of animal data the combined use of moclobemide with pethidine or dextropropoxyphene should be avoided. There is no evidence that moclobemide would increase body weight or produce seizures. Some preclinical data suggest that moclobemide may have anticonvulsant property.