***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Based on the evidence that lamotrigine added to clozapine in refractory schizophrenic patients has reported promising results , the present 24-week double-blind , r and omized , placebo-controlled trial had the aim to explore the efficacy of lamotrigine add-on pharmacotherapy on clinical symptomatology and cognitive functioning in a sample of treatment-resistant schizophrenic patients receiving clozapine .  After clinical and neurocognitive assessment s patients were r and omly allocated to receive , in a double-blind design , either up to 200 mg/day of lamotrigine or a placebo .  A final sample of fifty-one patients completed the study . The results obtained indicate that lamotrigine added to stable clozapine treatment showed a beneficial effect on the negative , positive and general psychopathological symptomatology in a sample of treatment-resistant schizophrenic patients . Regarding cognitive functions , improvement was observed in some explored areas , such as attentional resistance to interference , verbal fluency and executive functioning . The findings provide evidence that lamotrigine augmentation of clozapine treatment is well tolerated and may be proposed as an effective therapeutic strategy to improve outcome in treatment-resistant schizophrenia Background Dysfunction of neuroplasticity due to N-methyl-d-aspartate ( NMDA ) receptor hypofunction may be a causal factor for memory and executive dysfunctioning in schizophrenia . Deregulation of NMDA transmission in the prefrontal cortex may also explain negative and positive symptoms . Clozapine augmentation with memantine targets altered NMDA receptor-mediated neurotransmission in schizophrenia and showed substantial beneficial effects on several symptom domains in a small proof-of-concept study . We evaluate effects of memantine add-on treatment to clozapine for memory and executive function , and negative and positive symptoms in schizophrenia . Method  Clozapine-treated patients with refractory schizophrenia were r and omly assigned to 12 weeks of double-blind adjunctive treatment with memantine  ( n = 26 ) or placebo  ( n = 26 ) . Crossover occurred after a 2-week placebo wash-out period . Primary endpoints were change from baseline to 12 weeks treatment and 14 weeks to 26 weeks treatment on memory and executive function using the Cambridge Neuropsychological Test Automated Battery ( CANTAB ) , Positive and Negative Syndrome Scale ( PANSS ) , and Clinical Global Impression Severity Scale ( CGI-S ) . Side effects were assessed using the Liverpool University Neuroleptic Side-Effect Rating Scale . Results When compared with placebo , memantine improved a composite memory score comprising verbal recognition memory and paired associates learning task scores on the CANTAB ( effect size = 0.30 ) and PANSS negative subscale score ( effect size = 0.29 ) . Side effects were mild and transient . Conclusions In patients with clozapine-treated refractory schizophrenia , memantine addition significantly improved verbal and visual memory and negative symptoms without serious adverse effects . These results justify further investigations on long-term memantine augmentation to clozapine in treatment-resistant schizophrenia Schizophrenia is a devastating psychiatric disorder . Clozapine has long been the gold st and ard for treatment of patients with treatment-resistant schizophrenia ;  however , some patients are only partially responsive to clozapine treatment . Augmentation of clozapine treatment might enhance its effectiveness in partial responders , but only a few studies have investigated possible augmentation strategies . This study compared the effectiveness and tolerability of the combination of amisulpride and clozapine with the combination of quetiapine and clozapine in patients who were only partially responsive to clozapine monotherapy . Fifty-six treatment-resistant patients who were partially responsive to clozapine  were r and omly assigned to receive amisulpride or quetiapine along with an ongoing stable dose of clozapine .  Fifty patients completed the study . Patients were evaluated at baseline and at the first , third , sixth , and eighth weeks . Efficacy measures consisted of the Brief Psychiatric Rating Scale ( BPRS ) , the Scale for the Assessment of Negative Symptoms ( SANS ) , the Scale for the Assessment of Positive Symptoms ( SAPS ) , and the Clinical Global Impression ( CGI ) scale . Tolerability and adverse effects were assessed with the Udvalg for Kliniske Undersogelser ( UKU ) Side Effect Rating Scale and the Simpson Angus Scale ( SAS ) . A substantial improvement occurred in both groups by the end of the eighth week ; however , the improvement associated with amisulpride was significantly greater than that seen with quetiapine . This difference was noted as early as the third week of follow-up in terms of CGI scores , and by the sixth week with regard to BPRS , SANS , and SAPS scores . Both drugs were well tolerated , as measured by UKU and SAS . Improvement favoring clozapine+amisulpride could be attributed to the selective D2/D3 binding property of amisulpride , which had an additional effect in improving symptoms of schizophrenia . The authors concluded that amisulpride seems to be effective and well tolerated for augmentation purpose s in clozapine-resistant patients Schizophrenia is a complex and heterogeneous psychiatric disorder . Auditory verbal hallucinations occur in 50 - 70 % of patients with schizophrenia and are associated with significant distress , decreased quality of life and impaired social functioning . This study aim ed to investigate the effects of active compared with sham 1-Hz repetitive transcranial magnetic stimulation ( rTMS ) applied to the left temporal-parietal cortex in patients with schizophrenia treated with clozapine . Symptom dimensions that were evaluated included general psychopathology , severity of auditory hallucinations , quality of life and functionality . Seventeen right-h and ed patients with refractory schizophrenia experiencing auditory verbal hallucinations and treated with clozapine were r and omly allocated to receive either active rTMS or sham stimulation . A total of 384 min of rTMS was administered over 20 days using a double-masked , sham-controlled , parallel design . There was a significant reduction in Brief Psychiatric Rating Scale ( BPRS ) scores in the active group compared with the sham group . There was no significant difference between active and sham rTMS on Quality of Life Scale ( QLS ) , Auditory Hallucinations Rating Scale ( AHRS ) , Clinical Global Impressions ( CGI ) and functional assessment staging ( FAST ) scores . Compared with sham stimulation , active rTMS of the left temporoparietal cortex in clozapine-treated patients showed a positive effect on general psychopathology . However , there was no effect on refractory auditory hallucinations . Further studies with larger sample sizes are needed to confirm these findings Objective Clozapine is the most effective antipsychotic for treatment refractory people with schizophrenia , yet many patients only partially respond . Accumulating pre clinical and clinical data suggest benefits with minocycline . We tested adjunct minocycline to clozapine in a 10-week , double-blind , placebo-controlled trial . Primary outcomes tested were positive , and cognitive symptoms , while avolition , anxiety/depression , and negative symptoms were secondary outcomes . Methods Schizophrenia and schizoaffective participants ( n = 52 ) with persistent positive symptoms were r and omized to receive adjunct minocycline ( 100 mg oral capsule twice daily ; n = 29 ) or placebo ( n = 23 ) . Results Brief Psychiatric Rating Scale ( BPRS ) psychosis factor ( P = 0.098 ; effect size [ ES ] , 0.39 ) and BPRS total score ( P = 0.075 ; ES , 0.55 ) were not significant . A change in total BPRS symptoms of more than or equal to 30 % was observed in 7 ( 25 % ) of 28 among minocycline and 1 ( 4 % ) of 23 among placebo participants , respectively ( P = 0.044 ) . Global cognitive function ( MATRICS Consensus Cognitive Battery ) did not differ , although there was a significant variation in size of treatment effects among cognitive domains ( P = 0.03 ) , with significant improvement in working memory favoring minocycline ( P = 0.023 ; ES , 0.41 ) . The Scale for the Assessment of Negative Symptoms total score did not differ , but significant improvement in avolition with minocycline was noted ( P = 0.012 ; ES , 0.34 ) . Significant improvement in the BPRS anxiety/depression factor was observed with minocycline ( P = 0.028 ; ES , 0.49 ) . Minocycline was well tolerated with significantly fewer headaches and constipation compared with placebo . Conclusions Minocycline 's effect on the MATRICS Consensus Cognitive Battery composite score and positive symptoms were not statistically significant . Significant improvements with minocycline were seen in working memory , avolition , and anxiety/depressive symptoms in a chronic population with persistent symptoms . Larger studies are needed to vali date these findings Despite its superior efficacy , clozapine is helpful in only a subset of patients with schizophrenia unresponsive to other antipsychotics . This lack of complete success has prompted the frequent use of various clozapine combination strategies despite a paucity of evidence from r and omized controlled trials supporting their efficacy . Pimozide , a diphenylbutylpiperidine , possesses pharmacological and clinical properties distinct from other typical antipsychotics . An open-label trial of pimozide adjunctive treatment to clozapine provided promising pilot data in support of a larger controlled trial . Therefore , we conducted a double-blind , placebo-controlled , parallel- design ed 12-week trial of pimozide adjunctive treatment added to ongoing optimal clozapine treatment in 53 patients with schizophrenia and schizoaffective disorder partially or completely unresponsive to clozapine monotherapy . An average dose of 6.48 mg/day of pimozide was found to be no better than placebo in combination with clozapine at reducing Positive and Negative Syndrome Scale total , positive , negative , and general psychopathology scores . There is no suggestion from this rigorously conducted trial to suggest that pimozide is an effective augmenting agent if an optimal clozapine trial is ineffective . However , given the lack of evidence to guide clinicians and patients when clozapine does not work well , more controlled trials of innovative strategies are warranted BACKGROUND The treatment of schizophrenia with multiple antipsychotic drugs is common , but the benefits and risks are not known . METHODS In a r and omized , double-blind study , we evaluated patients with schizophrenia and a poor response to treatment with clozapine .  The patients continued to take clozapine and were r and omly assigned to receive eight weeks of daily augmentation with 3 mg of risperidone or with placebo . This course of treatment was followed by an optional 18 weeks of augmentation with risperidone . The primary outcome was reduction in the total score for severity of symptoms on the Positive and Negative Syndrome Scale ( PANSS ) . The secondary outcomes included cognitive functioning . RESULTS A total of 68 patients were r and omly assigned to treatment . In the double-blind phase , the mean total score for the severity of symptoms decreased from baseline to eight weeks in both the risperidone and the placebo groups . There was no statistically significant difference in symptomatic benefit between augmentation with risperidone and placebo : 9 of 34 patients receiving placebo and 6 of 34 receiving risperidone responded to treatment ( P=0.38 ) . The mean difference in the change in PANSS scores from baseline to eight weeks between those receiving risperidone and those receiving placebo was 0.1 ( 95 percent confidence interval , -7.3 to 7.0 ) . The verbal working-memory index showed a small decline in the risperidone group and a small improvement in the placebo group ( P=0.02 for the comparison between the two groups in the change from baseline ) . The increase in fasting blood glucose levels was mildly greater in the risperidone group than in the placebo group ( 16.2 vs. 1.8 mg per deciliter [ 0.90 vs. 0.10 mmol per liter ] , P=0.04 ) . The incidence and severity of other side effects did not differ between the two groups . CONCLUSIONS In this short-term study , the addition of risperidone to clozapine did not improve symptoms in patients with severe schizophrenia . ( Clinical Trials.gov number , NCT00272584 ) BACKGROUND We hypothesised that a combined regimen of clozapine , a relatively weak D2-dopaminergic antagonist , and sulpiride , a selective D2 blocker , would demonstrate a greater antipsychotic efficacy by enhancing the D2 blockade of clozapine . METHOD Twenty-eight people with schizophrenia , previously unresponsive to typical antipsychotics and only partially responsive to current treatment with clozapine  , received , double-blind , 600 mg/day sulpiride or placebo , in addition to an ongoing clozapine treatment . The clinical status was evaluated before , during , and at the end of 10 weeks of sulpiride addition using the Brief Psychiatric Rating Scale ( BPRS ) , Scale for the Assessment of Positive Symptoms ( SAPS ) , Scale for the Assessment of Negative Symptoms , and Hamilton Rating Scale for Depression . RESULTS The clozapine-sul 
    Output:
    
Single studies of certain antipsychotics ( penfluridol ) , antidepressants ( paroxetine , duloxetine ) , lithium and Ginkgo biloba showed potential , while electroconvulsive therapy was highly promising .
Mixed treatment comparisons were only possible for antipsychotics , and these gave similar results to the pairwise meta-analyses .
Conclusions : On the basis of the limited data available , the best evidence is for the use of aripiprazole , fluoxetine and sodium valproate as augmentation agents for total psychosis symptoms  and memantine  for negative symptoms .