Michael Poyurovsky

Obsessive-compulsive disorder in hospitalized patients with chronic schizophrenia.

Obsessive-compulsive (OC) symptoms have been observed in a substantial proportion of schizophrenic patients. In this study, we assessed the rate of occurrence of OC symptoms and the interrelationship between OC and schizophrenic symptoms in 68 hospitalized chronic schizophrenic patients. The patients were interviewed with the Structured Clinical Interview for Axis-I DSM-IV Disorders - Patient Edition (SCID-P) and the appropriate rating scales including the Scale for the Assessment of Positive Symptoms, the Scale for the Assessment of Negative Symptoms, the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Barnes Akathisia Scale, the Abnormal Involuntary Movement Scale, and the Social Behaviour Schedule (SBS). Sixteen patients (23.5%) met the DSM-IV criteria for OCD. A comparison of schizophrenic patients with and without OCD showed that the schizo-obsessive patients were significantly (1.7-fold) more impaired in basic social functioning, as reflected by the SBS score. No significant between-group differences for any of the other clinical variables were found. There was no significant correlation between OC and schizophrenic symptoms within the schizo-obsessive subgroup. The mean Y-BOCS score for the patients with both schizophrenia and OCD was within the typical range (22.8+/-1.7) observed in OCD without psychosis. The findings provide further evidence for the importance of the OC dimension in schizophrenia and may have important implications for the application of effective treatment approaches in this difficult-to-treat subgroup of schizophrenic patients.

Obsessive-Compulsive Disorder in Schizophrenia

There is a considerable overlap of schizophrenia and obsessive-compulsive disorder (OCD) in the structural and functional brain abnormalities involved, role of the dopamine/serotonin neurotransmitter systems, and some demographic and clinical characteristics. Although OCD co-occurs in a substantial proportion of schizophrenia patients, a systematic evaluation of the clinical features and treatment of this population is lacking. This review critically evaluates findings of recent studies pertaining to the rate of occurrence of OCD or obsessive-compulsive symptoms (OCS) in schizophrenia and the clinical characterisation of the schizo-obsessive subtype. Specifically, interrelationships between obsessive-compulsive and schizophrenic symptoms in terms of temporal relationships and their association with specific schizophrenia subtypes and the effect of OCS on the severity of schizophrenia symptoms are addressed. In the absence of evidence-based data, tentative therapeutic approaches in this difficult-to-treat patient subgroup are suggested. These include monotherapy with atypical antipsychotic agents or a combination of either typical or atypical antipsychotic s with SSRIs or clomipramine. The clinical characteristics of antipsychotic-induced OCS/OCD are also presented to facilitate identification and management of this rare but clinically significant adverse effect. Finally, future directions of research in schizophrenia-OCD comorbidity relevant to clinical practice are discussed.

Lamotrigine augmentation in schizophrenia and schizoaffective patients with obsessive-compulsive symptoms.

Obsessive-compulsive symptoms (OCS) are clinically important phenomena in schizophrenia patients. Lamotrigine has a modulating effect on glutamatergic neurotransmission relevant to pathophysiology of both schizophrenia and OCD. Efficacy and tolerability of lamotrigine in schizophrenia and schizoaffective patients with comorbid OCS were evaluated. In an 8-week, open-label trial, lamotrigine (25 mg/day for 1 week, 50 mg for 2 weeks, 100 mg for 2 weeks, 200 mg for 3 weeks) was added to ongoing psychotropic drug regimens in schizophrenia (N = 5) and schizoaffective disorder (N = 6) patients with clinically significant OCS [Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score > 16]. The Y-BOCS score for nine completers decreased significantly from baseline to week 8 (22.9 ± 6.1 vs 17.4 ± 3.6; t = 2.33, df = 1, P = 0.033). Five patients, all with schizoaffective disorder, were responders (≥35% decrease in Y-BOCS score). No significant changes were detected in schizophrenia symptom severity. Depressive symptoms, assessed with the Calgary Depression Rating Scale, improved significantly (6.4 ± 1.5 vs 4.0 ± 2.5; t = 3.19, df = 1, P = 0.013); this change positively correlated with OCS improvement (r = 0.69, P = 0.04). Lamotrigine was safe and well tolerated. Explicit evaluation of therapeutic efficacy of adjunctive lamotrigine in schizoaffective disorder patients with comorbid OCS merits further investigation.

The effect of betahistine, a histamine H1 receptor agonist/h3 antagonist, on olanzapine-induced weight gain in first-episode schizophrenia patients

Histamine antagonism has been implicated in antipsychotic drug-induced weight gain. Betahistine, a histamine enhancer with H1 agonistic/H3 antagonistic properties (48 mg t.i.d.), was coadministered with olanzapine (10 mg/day) in three first-episode schizophrenia patients for 6 weeks. Body weight was measured at baseline and weekly thereafter. Clinical rating scales were completed at baseline and at week 6. All participants gained weight (mean weight gain 3.1±0.9 kg) and a similar pattern of weight gain was observed: an increase during the first 2 weeks and no additional weight gain (two patients) or minor weight loss (one patient) from weeks 3 to 6. None gained 7% of baseline weight, which is the cut-off for clinically significant weight gain. Betahistine was safe and well tolerated and did not interfere with the antipsychotic effect of olanzapine. Our findings justify a placebo-controlled evaluation of the putative weight-attenuating effect of betahistine in olanzapine-induced weight gain.

Low-Dose Mirtazapine: A New Option in the Treatment of Antipsychotic-Induced Akathisia. A Randomized, Double-Blind, Placebo- and Propranolol-Controlled Trial

BACKGROUND Preliminary evidence indicates a beneficial effect of serotonin 2A (5-HT(2A)) receptor antagonists in antipsychotic-induced akathisia (AIA). We investigated the antiakathisia effect, safety, and tolerability of low-dose mirtazapine, an agent with marked 5-HT(2A) antagonism. METHODS In a 7-day double-blind trial, 90 antipsychotic-treated patients meeting DSM-IV criteria for AIA were randomly assigned to mirtazapine (n = 30; 15 mg), propranolol (n = 30; 80 mg), or placebo (n = 30). Primary outcome measures were between-group differences in Barnes Akathisia Scale (BAS) global scores and in the proportion of responders (reduction of > or = 2 points on BAS). Analysis was by intention to treat. RESULTS Twenty-four patients (26.6%) who were assigned treatment did not complete the study (7 mirtazapine, 8 propranolol, 9 placebo), due to lack of response (n = 19) and adverse events (n = 5). Both mirtazapine and propranolol significantly reduced AIA severity (BAS: -34% mirtazapine and -29% propranolol vs. placebo -11%; p = .012 and p = .023, respectively). Thirteen (43.3%) mirtazapine and 9 (30.0%) propranolol-treated patients versus 2 (6.7%) placebo-treated patients responded (the corresponding odds ratios 10.7 [95% confidence interval (CI), 2.1-53.3] and 6.0 [95% CI, 1.1-30.7]). Five (16.7%) of 30 propranolol-treated patients and none in the mirtazapine and placebo groups (p = .0195 for both) prematurely discontinued the study due to clinically significant hypotension or bradycardia. CONCLUSIONS The comparable efficacy and better tolerability of low-dose mirtazapine versus propranolol, the current first-line treatment for AIA, position mirtazapine as a favorable candidate for the treatment of acute AIA and may improve current therapeutic practices.

Fluvoxamine Treatment in Clozapine-Induced Obsessive-Compulsive Symptoms in Schizophrenic Patients

Interest in the association of obsessive-compulsive (OC) symptoms and schizophrenia has been reawakened since the introduction of clozapine for treatment of schizophrenia. We describe the appearance of this disorder and examine the efficacy of adding fluvoxamine to ongoing clozapine treatment of the OC and schizophrenic symptoms. Four patients with DSM-III-R schizophrenic disorder, in whom OC symptoms appeared during the course of clozapine treatment, are reported. In two patients, fluvoxamine, a serotonin-selective reuptake inhibitor (SSRI), was added to clozapine under open-trial conditions. The patients were serially assessed by using the Brief Psychiatric Rating Scale, Yale-Brown Obsessive-Compulsive Scale, and Scale for the Assessment of Negative Symptoms. The de novo occurrence and eventual spontaneous reduction of OC symptoms were noted in two schizophrenic patients treated with clozapine. In the other two patients, one with previous and the other with a family history of OC disorder, the addition of fluvoxamine to clozapine was effective in eliminating the OC symptoms. A concomitant improvement in the schizophrenic symptomatology was seen as well. It appears that disabling OC symptoms may occur as in response to clozapine treatment in chronic drug-resistant schizophrenic patients. Some of the latter may benefit from the addition of an SSRI to the ongoing clozapine regimen.

The effect of famotidine addition on olanzapine-induced weight gain in first-episode schizophrenia patients: a double-blind placebo-controlled pilot study

Olanzapine treatment is associated with substantial weight gain. In this double-blind placebo-controlled study we evaluated whether the H2 antagonist famotidine may prevent/attenuate olanzapine-induced weight gain. Fourteen first-episode DSM-IV schizophrenia patients were randomly allocated to receive either famotidine (40 mg/day, n=7) or placebo (n=7) in addition to olanzapine (10 mg/day) for 6 weeks. All patients completed the trial. Patients in both groups showed a similar increase in body weight (olanzapine/famotidine: 4.8 (3.2) kg and olanzapine/placebo: 4.9 (1.6) kg, respectively; a between-group difference of 0.14 (1.3) kg). Four of seven (57.1%) patients in the olanzapine/famotidine group and three of seven (42.9%) in the olanzapine/placebo group gained at least 7% of their initial body weight, a cut-off for clinically significant weight gain. Famotidine addition was safe and well tolerated and did not interfere with olanzapines therapeutic effect. In conclusion, famotidine (40 mg/day for 6 weeks) is not effective in preventing/attenuating weight gain in olanzapine-treated first-episode schizophrenia patients.

Fluvoxamine treatment of obsessive-compulsive symptoms in schizophrenic patients: an add-on open study.

Obsessive-Compulsive (OC) symptoms are observed in a substantial proportion of schizophrenic patients and pose a significant therapeutic challenge. Based on findings of the benefit of the anti-obsessive agent clomipramine, we designed an open-label study to examine the effect of adding the serotonin-selective reuptake inhibitor (SSRI) fluvoxamine to the ongoing antipsychotic regimen of schizo-obsessive patients. The study population consisted of ten neuroleptic-stabilized chronic schizophrenic patients with OC symptoms. Fluvoxamine (up to 150 mg/day) was added to the ongoing antipsychotic treatment, which remained unchanged for the entire 12-week trial period. The patients were evaluated before the trial and at weeks 1, 2, 4, 6, 8 and 12 (end point) with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Schedule for Assessment of Positive Symptoms and the Schedule for Assessment of Negative Symptoms. The results showed a significant improvement in obsessions (P < 0.02) (but not compulsions) and both positive (P < 0.01) and negative (P < 0.05) schizophrenic symptoms. By the end of the trial, three patients showed a more than 50% reduction in the Y-BOCS score, with complete amelioration of the OC symptoms in one of them. Three patients were dropped from the study during the first 4 weeks, two because of aggressiveness and one because of psychotic exacerbation. No exacerbation or new onset of extrapyramidal side-effects (EPS), as measured by the Barnes Akathisia Scale (BARS) and the Simpson-Angus Scale (SAS), was noted during the course of the trial and there were no other significant clinical side-effects of fluvoxamine addition. We conclude that fluvoxamine may be an effective adjunctive agent in some schizo-obsessive patients.

Global Functional Connectivity Deficits in Schizophrenia Depend on Behavioral State

Schizophrenia is a devastating psychiatric illness characterized by deterioration of cognitive and emotional processing. It has been hypothesized that aberrant cortical connectivity is implicated in the disease (Friston, 1998), yet previous studies of functional connectivity (FC) in schizophrenia have shown mixed results (Garrity et al., 2007; Jafri et al., 2008; Lynall et al., 2010). We measured FC using fMRI in human schizophrenia patients and healthy controls during two different tasks and a rest condition, and constructed a voxel-based global FC index. We found a striking FC decrease in patients compared with controls. In the task conditions, relatively weaker FC was specific to regions of cortex not active during the task. In the rest condition, the FC difference between patients and controls was larger and allowed a case-by-case separation between individuals of the two groups. The results suggest that the relative reduction of FC in schizophrenia is dependent on the state of cortical activity, with voxels not activated by the task showing higher levels of FC deficiency. This novel finding may shed light on previous reports of FC in schizophrenia. Whether this neural characteristic is related to the development of the disorder remains to be established.

Efficacy of low-dose mirtazapine in neuroleptic-induced akathisia: A double-blind randomized placebo-controlled pilot study

The nonselective serotonin (5-HT)-2A antagonists ritanserin, mianserin, and cyproheptadine were found efficacious in neuroleptic-induced akathisia (NIA). Mirtazapine is structurally and pharmacologically similar to mianserin, and the authors sought to determine its anti-NIA activity. Twenty-six neuroleptic-treated schizophrenic patients with DSM-IV diagnosis of NIA received add-on mirtazapine (15 mg/day) or placebo for 5 days in a double-blind design. Patients were assessed at baseline and days 3 and 5 with the Barnes Akathisia Scale (BAS), Positive and Negative Symptom Scale, Hamilton Rating Scale for Depression, and Simpson-Angus Scale for parkinsonism. Analysis of covariance with repeated measurements revealed significant group × time effects in favor of the mirtazapine group in both completers (n = 10 in each group) and intent-to-treat analysis (n = 13 in each group) for the BAS global subscale (F [1, 17] = 14.87, p = 0.001, and F [1, 23] = 13.24, p = 0.01, respectively) and objective subscale (F [1, 17] = 8.25, p = 0.011, and F [1, 23] = 7.35, p = 0.012, respectively) and borderline significant superiority for the BAS subjective subscale (F [1, 17] = 4.39, p = 0.051, and F [1, 23] = 4.12, p = 0.054, respectively) and distress subscale (F [1, 17] = 4.21, p = 0.056, and F [1, 23] = 3.80, p = 0.064, respectively). Significantly more mirtazapine-than placebo-treated patients (53.8% [7/13] vs. 7.7% [1/13], respectively; χ2 = 8.3, p = 0.004) met operational response criterion, a reduction of at least two points on the BAS global subscale. Mirtazapine treatment was associated with modest improvement of psychotic and parkinsonian symptoms. Mild sedation was the only side effect. Our study demonstrated that mirtazapine (15 mg/day) is an efficacious and well-tolerated therapeutic option in NIA. Marked 5HT2A/2C antagonistic activity of mirtazapine apparently accounts for its anti-NIA activity. The role of mirtazapine in the treatment of akathisia induced by atypical antipsychotic agents merits further investigation.