Efficacy and safety of antidepressant augmentation of continued antipsychotic treatment in patients with schizophrenia.

OBJECTIVE: To evaluate the efficacy and safety of antidepressant augmentation of antipsychotics in schizophrenia. METHODS: Systematic literature search (PubMed/MEDLINE/PsycINFO/Cochrane Library) from database inception until 10/10/2017 for randomized, double-blind, efficacy-focused trials comparing adjunctive antidepressants vs. placebo in schizophrenia. RESULTS: In a random-effects meta-analysis (studies = 42, n = 1934, duration = 10.1 ± 8.1 weeks), antidepressant augmentation outperformed placebo regarding total symptom reduction [standardized mean difference (SMD) = -0.37, 95% confidence interval (CI) = -0.57 to -0.17, P < 0.001], driven by negative (SMD = -0.25, 95% CI = -0.44-0.06, P = 0.010), but not positive (P = 0.190) or general (P = 0.089) symptom reduction. Superiority regarding negative symptoms was confirmed in studies augmenting first-generation antipsychotics (FGAs) (SMD = -0.42, 95% CI = -0.77, -0.07, P = 0.019), but not second-generation antipsychotics (P = 0.144). Uniquely, superiority in total symptom reduction by NaSSAs (SMD = -0.71, 95% CI = -1.21, -0.20, P = 0.006) was not driven by negative (P = 0.438), but by positive symptom reduction (SMD = -0.43, 95% CI = -0.77, -0.09, P = 0.012). Antidepressants did not improve depressive symptoms more than placebo (P = 0.185). Except for more dry mouth [risk ratio (RR) = 1.57, 95% CI = 1.04-2.36, P = 0.03], antidepressant augmentation was not associated with more adverse events or all-cause/specific-cause discontinuation. CONCLUSIONS: For schizophrenia patients on stable antipsychotic treatment, adjunctive antidepressants are effective for total and particularly negative symptom reduction. However, effects are small-to-medium, differ across antidepressants, and negative symptom improvement seems restricted to the augmentation of FGAs.

Working memory dysfunction in schizophrenia patients with obsessive-compulsive symptoms: an fMRI study.

BACKGROUND: A substantial proportion of schizophrenia patients also meets DSM-IV criteria for obsessive-compulsive disorder (OCD). Schizophrenia with OCD ("schizo-obsessive") patients are characterized by distinct clinical characteristics, treatment response and prognosis. Whether schizo-obsessive patients exhibit a distinct pattern of brain activation is yet unknown. To address this question, the present functional magnetic resonance imaging (fMRI) study explicitly compared alterations in brain activation and functional connectivity (FC) underlying a working memory deficit in schizophrenia patients with and without OCD. METHODS: fMRI was applied during the N-back working memory (WM) task in three groups: schizo-obsessive (n=16), schizophrenia (n=17) and matched healthy volunteers (n=20). WM-related activation in the right dorsolateral prefrontal cortex (DLPFC) and the right caudate nucleus, brain areas relevant to schizophrenia and OCD, and FC analysis were used for the evaluation. RESULTS: The two schizophrenia groups with and without OCD exhibited a similar reduction in activation in the right DLPFC and right caudate, as well as decreased FC compared to the healthy controls. Notably, reduced regional brain activation was not related to severity of schizophrenic or OCD symptoms. CONCLUSIONS: Schizo-obsessive patients do not differ from their non-OCD schizophrenia counterparts in brain activation patterns during the N-back WM task. Cognitive paradigms taping alternative neural networks (e.g., orbitofrontal cortex) particularly relevant to OCD, are warranted in the search for potential distinctive brain activation patterns of the schizo-obsessive subgroup.

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 (>or=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.

Obsessive-compulsive disorder (OCD) with schizotypy vs. schizophrenia with OCD: diagnostic dilemmas and therapeutic implications.

Although schizophrenia and obsessive-compulsive disorder (OCD) are distinct diagnostic entities, there are substantial areas of overlap between the two disorders in clinical characteristics, affected brain areas and pharmacotherapy. Though OCD patients apparently do not have increased risk for developing schizophrenia, schizotypal personality disorder has consistently been found in OCD patients. Compelling evidence also points to an increased rate of OCD in schizophrenia patients. Accurate diagnosis of both disorders in their "pure" and overlapping forms is necessary in order to evaluate etiological mechanisms underlying schizophrenia and OCD, and to provide adequate treatment and prognosis. In this review, we address some aspects of the current status of research pertinent to the OCD-schizophrenia interface and suggest further steps towards the clinical and etiological identification of homogeneous subgroups on the putative OCD-schizophrenia axis.

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.

Fluvoxamine augmentation of antipsychotics improves negative symptoms in psychotic chronic schizophrenic patients: a placebo-controlled study.

The efficacy and safety of adding fluvoxamine to antipsychotic treatment in schizophrenic patients with mixed positive and negative symptoms was examined. Fifty-three patients selected for persistent negative and positive symptoms who were receiving antipsychotic treatment were randomly allocated to additional fluvoxamine (50-100 mg/day) or placebo in a double-blind manner. Fluvoxamine was associated with significant improvement in negative symptoms (Scale for the Assessment of Negative Symptoms) compared to placebo. The combination was well tolerated. Fluvoxamine augmentation of antipsychotics is safe in chronic schizophrenic patients with mixed positive and negative symptoms and may ameliorate negative symptoms in such patients.

Beneficial effect of olanzapine in schizophrenic patients with obsessive-compulsive symptoms.

Some studies suggest that obsessive-compulsive symptoms may be common (7.8-46%) in schizophrenic patients and seem to be poorly responsive to drug therapy. Conventional neuroleptics are of limited value, but adjunctive anti-obsessive agents (clomipramine, fluvoxamine) may be an option. Although novel atypical antipsychotics (clozapine, risperidone) reportedly aggravate the obsessive-compulsive symptoms, a recent trial has shown that olanzapine did not induce new-onset obsessive-compulsive symptoms in schizophrenic patients. We report our experience with three schizophrenic patients with obsessive-compulsive symptoms who were unsuccessfully treated with various conventional neuroleptics in combination with anti-obsessive agents and subsequently showed resistance or intolerance to clozapine. All of them were switched to olanzapine (10-20 mg/ day). All patients demonstrated a significant improvement in both schizophrenic and obsessive-compulsive symptoms as measured by the Brief Psychiatric Rating Scale (BPRS) and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Within 5-8 weeks of initiation of olanzapine, the BPRS scores of the three patient decreased by 53%, 51% and 48%, and the Y-BOCS scores by 68%, 73% and 85%. Olanzapine was well tolerated. These preliminary results suggest that olanzapine may be a therapeutic option in schizophrenic patients with obsessive-compulsive symptoms.

Actigraphic monitoring (actigraphy) of circadian locomotor activity in schizophrenic patients with acute neuroleptic-induced akathisia.

BACKGROUND: Actigraphy is a quantitative method for measurement of motor activity. In the present study we used actigraphy to examine diurnal variations in locomotor activity of schizophrenic patients with neuroleptic-induced akathisia (NIA). METHOD: Thirty-two schizophrenic patients, 16 with NIA and 16 without (DSM-IV criteria) underwent 24-h actigraphic monitoring. Clinical assessments of NIA were conducted with Barnes Akathisia Scale (BAS) at 08:00, 12:00, 16:00 and 20:00. Sleep parameters (duration, latency, continuity and efficacy) were assessed by actigraphy. Sleep quality was evaluated by a self-rated sleep questionnaire. RESULTS: NIA patients demonstrated persistent higher daytime motor activity from 11:30 to 14:15 and from 18:00 to 21:00 than controls. There were no differences between the groups in nighttime motor activity, confirming clinical observations that NIA tends to disappear during sleep. Subject's sleep assessments were similar in the two groups. CONCLUSIONS: Actigraphy seems to be a reliable, non-invasive, method of measuring motor activity in patients with NIA. Its sensitivity and specificity as an objective quantitative diagnostic instrument in patients with NIA merits further investigation.

Association between obsessive-compulsive disorder and polymorphisms of genes encoding components of the serotonergic and dopaminergic pathways.

Obsessive-compulsive disorder (OCD) is a severe and disabling anxiety disorder with a marked genetic contribution. Pharmacological data indicated involvement of the serotonergic and dopaminergic systems. We studied the association between OCD and six candidate genes encoding important components of the serotonergic and dopaminergic pathways in 75 biologically unrelated patients and 172 ethnically matched controls (Ashkenazi and non-Ashkenazi Jews). Polymorphisms in the following genes were studied: tryptophan hydroxylase (TPH), serotonin 2A receptor (HTR2A), serotonin 2C receptor (HTR2C), serotonin transporter (5-HTT), dopamine receptor D4 (DRD4), and dopamine transporter (DAT1). The genotypic and allelic distribution of all polymorphisms tested did not show statistically significant differences between patients and controls. Our results suggest that these polymorphisms do not play a major role in the genetic predisposition to OCD, although a minor contribution cannot be ruled out.

Obsessive-compulsive disorder in patients with first-episode schizophrenia.

OBJECTIVE: The aim of the present study was to determine the rate of obsessive-compulsive disorder (OCD) in patients with first-episode schizophrenia. METHOD: Fifty patients consecutively hospitalized with first-episode psychosis who met DSM-IV criteria for schizophrenia spectrum disorders were assessed for OCD. The instruments used were the Structured Clinical Interview for DSM-IV, Schedule for the Assessment of Positive Symptoms (SAPS), Schedule for the Assessment of Negative Symptoms (SANS), and Yale-Brown Obsessive Compulsive Scale. RESULTS: Seven (14%) of the 50 schizophrenic patients met DSM-IV criteria for OCD and scored significantly lower than schizophrenic patients without OCD on the formal thought disorder subscale of the SAPS and the flattened affect subscale of the SANS. CONCLUSIONS: OCD is relatively frequent in patients with first-episode schizophrenia and may have a "protective" effect on some schizophrenic symptoms, at least in the early stages of the disease.

Lack of efficacy of the 5-HT3 receptor antagonist granisetron in the treatment of acute neuroleptic-induced akathisia.

The specific mechanism underlying the apparent involvement of the serotonergic (5-HT) system in the pathophysiology of extrapyramidal side-effects, particularly neuroleptic-induced akathisia (NIA), remains unknown. We hypothesized that the 5-HT3 receptor subtype may play a role in the light of the moderate-to-high affinity to this receptor of some of the atypical antipsychotic agents which have a low propensity to cause akathisia, as well as our earlier findings with the 5-HT2/5-HT3 antagonist mianserin. In an open-label pilot study, we administered the selective 5-HT3 antagonist granisetron (fixed dose, 2 mg/day) for 4 days to 10 neuroleptic-treated patients with acute NIA. Three patients discontinued granisetron because of a lack of response. The remainder showed no significant change in score on the Barnes Akathisia Scale during the trial. NIA symptoms remained unchanged or worsened in five patients (71.4%) and improved to a certain degree in only two. It seems that the 5-HT3 subtype of serotonergic receptor is not involved in the development of NIA, and 5-HT3 antagonists are ineffective in the serotonin-related pharmacotherapy of NIA.

Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways.

Major depressive disorder (MDD) is a severe psychiatric disorder with a lifetime prevalence of about 15%.1 The importance of the genetic component is well accepted,2 but the mode of inheritance is complex and non-Mendelian. A line of evidence suggests the involvement of serotonin and dopamine neurotransmitters in the pathophysiology of depression. In the present study, 102 unipolar MDD patients and 172 healthy controls were genotyped for polymorphisms in four serotonergic and three dopaminergic candidate genes [tryptophan hydroxylase (TPH), serotonin receptor 2A (HTR2A), serotonin receptor 2C (HTR2C), serotonin transporter promoter region (5-HTTLPR), dopamine receptor D4 (DRD4), dopamine transporter (DAT1) and catechol-O-methyl transferase (COMT)]. There were no statistical differences between MDD patients and healthy controls in the genotypic and allelic distribution of all polymorphisms investigated. Thus, our study does not support a major role for these polymorphisms in contributing to susceptibility to MDD, although it does not preclude minor effects.

Treatment of neuroleptic-induced akathisia with the 5-HT2 antagonist mianserin. Double-blind, placebo-controlled study.

BACKGROUND: Serotonin (5-HT):dopamine imbalance may underlie neuroleptic-induced akathisia. AIM: To evaluate the efficacy of the 5-HT2 antagonist, mianserin in neuroleptic-induced akathisia. METHODS: Thirty neuroleptic-treated patients with schizophrenia were randomly allocated in a double-blind design to receive either mianserin (15 mg/day) or placebo for five days. Patients were assessed at baseline and on Days 3 and 5 by the Barnes Akathisia Scale (BARS), as well as by other relevant clinical rating scales. RESULTS: Compared with the placebo group, the mianserin-treated patients showed a significant reduction in all four BARS subscales by Day 5, with mean reductions in the BARS global score of 9.9% and 52.2%, respectively (P = 0.006). Response to treatment (a reduction of at least two points on the BARS global subscale), was noted in six patients (40%) in the mianserin group and only one patient (9.1%) in the placebo group (P = 0.04, log odds ratio 2.23). CONCLUSIONS: Mianserin at a low dose may be a promising therapeutic option for patients with acute neuroleptic-induced akathisia.

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.

Emergence of obsessive--compulsive symptoms and tics during clozapine withdrawal.

Treatment with clozapine may be associated with the appearance of obsessive-compulsive (OC) symptoms in up to 10% of schizophrenic patients. We present the first report of the emergence of de novo OC symptoms during clozapine withdrawal in two schizophrenic patients, associated in one with Tourette's syndrome-like tics. Resumption of clozapine led to the complete disappearance of the OC symptoms and a substantial alleviation of the tics. It is suggested that an imbalance between the dopamine and serotonin systems may account for this complication.