Adjunctive Treatment For Schizophrenia Research Articles

Safety and Efficacy of Ondansetron and Simvastatin as Potential Adjunctive Treatment for Patients With Schizophrenia: A Systematic Review of Randomized Controlled Trials.

In a generation where advancements in research and understanding have led to remarkable achievements in medicine, it is still unfathomable that, after more thana century, the cause of schizophrenia is still a mystery. While antipsychotics, without a doubt, have brought on an exemplary revolution in the way psychiatric disorders are now treated, there are still imperative deficits that need to be addressed to ultimately enable individuals with schizophrenia to function normally in society. However, without a definite cause of schizophrenia, even though speculation has been made on its inflammatory and neurodegenerative nature, it has provided an unnecessary hindrance to finding further potential treatment modalities for these patients. Nevertheless, some trials are investigating potential adjunctive treatment regimens to antipsychotics, which can help achieve complete remission. Exploring these drugs will have significant implications for managing schizophrenia in future clinical practices. This systematic review was conducted between January 2012 to July 2022 according to Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines to evaluate the safety and efficacy of ondansetron and simvastatin as adjunctive treatment to antipsychotics in adult patients with schizophrenia. This review included nine randomized controlled trials. Overall, both simvastatin and ondansetron, when used as adjunctive treatment in schizophrenia, appear to be safe. Ondansetron showed promising results, with all studies on this drug showing positive overall results on schizophrenia symptoms. On the other hand, simvastatin demonstrated mixed results, which can be attributed to the limited participants in the studies and the shorter duration of the trials. However, more extensive trials with uniform assessment tools are needed to demonstrate concrete evidence of the effectiveness of these drugs, whether alone or in combination with each other or perhaps another drug such as aspirin in schizophrenia.

Selective 5HT3 antagonists and sensory processing: a systematic review

Ondansetron is a selective serotonin (5HT3) receptor antagonist that is under evaluation as an adjunctive treatment for schizophrenia, and a novel treatment for hallucinations in Parkinson’s disease. Ondansetron reverses sensory gating deficits and improves visuoperceptual processing in animal models of psychosis, but it is unclear to what extent preclinical findings have been replicated in humans. We systematically reviewed human studies that evaluated the effects of ondansetron and other 5HT3 receptor antagonists on sensory gating deficits or sensory processing. Of 11 eligible studies, eight included patients with schizophrenia who were chronically stable on antipsychotic medication; five measured sensory gating using the P50 suppression response to a repeated auditory stimulus; others included tests of visuoperceptual function. Three studies in healthy participants included tests of visuoperceptual and sensorimotor function. A consistent and robust finding (five studies) was that ondansetron and tropisetron (5HT3 antagonist and α7-nicotinic receptor partial agonist) improved sensory gating in patients with schizophrenia. Tropisetron also improved sustained visual attention in non-smoking patients. There was inconsistent evidence of the effects of 5HT3 antagonists on other measures of sensory processing, but interpretation was limited by the small number of studies, methodological heterogeneity and the potential confounding effects of concomitant medication in patients. Despite these limitations, we found strong evidence that selective 5HT3 antagonists (with or without direct α7-nicotinic partial agonist effects) improved sensory gating. Future studies should investigate how this relates to potential improvement in neurocognitive symptoms in antipsychotic naive patients with prodromal or milder symptoms, in order to understand the clinical implications.

Adjunctive Garcinia mangostana Linn. (Mangosteen) Pericarp for Schizophrenia: A 24-Week Double-blind, Randomized, Placebo Controlled Efficacy Trial: Péricarpe d'appoint Garcinia mangostana Linn (mangoustan) pour la schizophrénie : un essai d'efficacité de 24 semaines, à double insu, randomisé et contrôlé par placebo.

Garcinia mangostana Linn. ("mangosteen") pericarp contains bioactive compounds that may target biological pathways implicated in schizophrenia. We conducted a double-blind randomized placebo-controlled trial evaluating the efficacy of adjunctive mangosteen pericarp, compared to placebo, in the treatment of schizophrenia. People diagnosed with schizophrenia or schizoaffective disorder (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), recruited across 2 sites (Brisbane and Victoria, Australia), were randomized to receive 24 weeks of adjunctive mangosteen pericarp (1,000 mg/day) or matched placebo. The primary outcome measure was the Positive and Negative Symptom Scale total score. Secondary outcomes included positive and negative symptoms, general psychopathology, clinical global severity and improvement, participant reported overall improvement, depressive symptoms, functioning, quality of life, and safety data at 24 and 28 weeks (4 weeks postdiscontinuation). Data were collected from July 2016 to February 2019. Baseline assessments were conducted on 148 people (mangosteen = 74, placebo = 74); data analyses were conducted on 136 (92%) participants with postbaseline data. The treatment group had significantly higher symptom severity compared to placebo, and both groups significantly improved on all symptom, functioning, and quality of life measures over time. No between-group differences were found for the rate of change between baseline and 24 or 28 weeks. Despite promising preclinical and clinical work, our results do not support mangosteen pericarp extract as an adjunctive treatment for schizophrenia or schizoaffective disorder.

Raloxifene augmentation in men and women with a schizophrenia spectrum disorder: A study protocol

Although acute psychotic symptoms are often reduced by antipsychotic treatment, many patients with schizophrenia are impaired in daily functioning due to the persistence of negative and cognitive symptoms. Raloxifene, a Selective Estrogen Receptor Modulator (SERM) has been shown to be an effective adjunctive treatment in schizophrenia. Yet, there is a paucity in evidence for raloxifene efficacy in men and premenopausal women. We report the design of a study that aims to replicate earlier findings concerning the efficacy of raloxifene augmentation in reducing persisting symptoms and cognitive impairment in postmenopausal women, and to extend these findings to a male and peri/premenopausal population of patients with schizophrenia. The study is a multisite, placebo-controlled, double-blind, randomised clinical trial in approximately 110 adult men and women with schizophrenia. Participants are randomised 1:1 to adjunctive raloxifene 120 mg or placebo daily during 12 weeks. The treatment phase includes measurements at three time points (week 0, 6 and 12), followed by a follow-up period of two years. The primary outcome measure is change in symptom severity, as measured with the Positive and Negative Syndrome Scale (PANSS), and cognition, as measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Secondary outcome measures include social functioning and quality of life. Genetic, hormonal and inflammatory biomarkers are measured to assess potential associations with treatment effects. If it becomes apparent that raloxifene reduces psychotic symptoms and/or improves cognition, social functioning and/or quality of life as compared to placebo, implementation of raloxifene in clinical psychiatric practice can be considered.

Memantine effects on auditory discrimination and training in schizophrenia patients.

The uncompetitive low-affinity NMDA receptor antagonist, memantine, acutely increases electrophysiological measures of auditory information processing in both healthy subjects (HS) and patients with schizophrenia. Memantine effects on functional measures of auditory discrimination performance and learning are not known; conceivably, beneficial effects on these measures might suggest a role for memantine in augmenting the cognitive and functional impact of auditory targeted cognitive training (TCT). Here, carefully characterized HS (n = 20) and schizophrenia patients (n = 22) were tested in measures of auditory discrimination performance (words-in-noise (WIN), quick speech-in-noise (QuickSIN), gaps-in-noise) and auditory frequency modulation learning (a component of TCT) on 2 days about a week apart, after ingesting either placebo or 20 mg memantine po, in a double-blind, within-subject cross-over random order design. Memantine modestly enhanced functional measures of auditory discrimination in both schizophrenia patients (WIN) and HS (WIN and QuickSIN), as well as auditory frequency modulation learning in schizophrenia patients. These findings converge with a growing literature showing that memantine can enhance a range of metrics of auditory function. These properties could contribute to the apparent benefits of memantine as an adjunctive treatment in schizophrenia, and suggest that memantine might augment learning and potentially clinical gains from auditory-based TCT.

Effects of Doxycycline in Swiss Mice Predictive Models of Schizophrenia.

Schizophrenia patients show very complex symptoms in several psychopathological domains. Some of these symptoms remain poorly treated. Therefore, continued effort is needed to find novel pharmacological strategies for improving schizophrenia symptoms. Recently, minocycline, a second-generation tetracycline, has been suggested as an adjunctive treatment for schizophrenia. The antipsychotic-like effect of doxycycline, a minocycline analog, was investigated here. We found that both minocycline and doxycycline prevented amphetamine-induced prepulse inhibition (PPI) disruption. However, neither of them blocked MK801-induced effects, albeit doxycycline had a modest impact against ketamine-induced effects. Neither c-Fos nor nNOS expression, which was evaluated in limbic regions, were modified after acute or sub-chronic treatment with doxycycline. Therefore, apomorphine inducing either PPI disruption and climbing behavior was not prevented by doxycycline. This result discards a direct blockade of D2-like receptors, also suggested by the lack of doxycyclinecataleptic-induced effect. Contrasting, doxycycline prevented SKF 38393-induced effects, suggesting a preferential doxycycline action at D1-like rather than D2-like receptors. However, doxycycline did not bind to the orthosteric sites of D1, D2, D3, D4, 5-HT2A, 5-HT1A, and A2A receptors suggesting no direct modulation of these receptors. Our data corroborate the antipsychotic-like effect of doxycycline. However, these effects are probably not mediated by doxycycline direct interaction with classical receptors enrolled in the antipsychotic effect.

Use of antidepressants and mood stabilizers in persons with first-episode schizophrenia

PurposeAntipsychotics are first-line treatment of schizophrenia. They are often accompanied by adjunctive treatments, such as antidepressant (AD) or mood stabilizer (MS), although there is only limited information of their use in first-episode schizophrenia. This study aimed to investigate AD and MS initiation and factors associated with initiation in persons with first-episode schizophrenia.MethodsRegister-based data was utilized to identify persons who received inpatient care due to schizophrenia during 1996–2014 in Finland and who did not use AD or MS at the time of first inpatient care diagnosis of schizophrenia (N = 7667, mean age 40.2, SD 18.2). Drug purchase data (1995–2017) was obtained from the National Prescription register and modelled with PRE2DUP method. Initiations of AD and MS use were followed up 3 years from first schizophrenia diagnoses. Cox proportional hazard models were used to investigate factors associated with AD or MS initiation.ResultsAmong persons with first-episode schizophrenia, 35.4% initiated AD and 14.1% initiated MS use within three years from diagnoses. Female gender, younger age, and benzodiazepine use were associated with higher risk of AD and MS initiation. The number of previous psychoses was associated with decreased risk of AD and increased risk of MS initiation.ConclusionClinical guidelines rarely recommend the use of AD or MS as adjunctive treatment in persons with schizophrenia. However, this population is often treated with AD or MS. More studies are needed to evaluate benefits and risks of these medications as adjunctive treatment of schizophrenia.

L-Tetrahydropalmatine, a Novel Dopamine Antagonist, Fails to Improve Psychiatric Symptoms as Adjunctive Treatment for Schizophrenia

Abstract Schizophrenia is a complex mental illness characterized by positive and negative symptoms. Antipsychotic medications are the main treatment for this condition; however, many patients have only a partial response. All currently available antipsychotics involve modulation of the dopamine system, although the underlying pathophysiology of this illness remains poorly understood. Increasing evidence suggests that inflammation plays a significant role in the development of schizophrenia. Thus, a medication that modulates both dopamine signaling and inflammation may be a promising treatment for schizophrenia. L-tetrahydropalmatine (l-THP) has modest affinity for dopamine receptors, acting as an antagonist at D1, D2, and D3 receptors. L-THP also has anti-inflammatory effects, decreasing levels of tumor necrosis factor-α and interleukin 6. We performed a 4-week, randomized, double-blind, placebo-controlled trial of oral l-THP (30 mg twice daily) as an adjunctive treatment in 63 adults with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) on stable antipsychotic medication. The primary psychiatric outcome measures were the presence of positive and negative symptoms. Plasma concentrations of 11 cytokines and C-reactive protein (CRP) were also measured. L-THP had no significant effect on any psychiatric measure but was well tolerated and associated with a significant decrease in extrapyramidal symptoms. L-THP significantly increased plasma concentrations, compared with placebo, of two inflammatory markers: soluble intracellular adhesion molecule 1 and CRP. These findings do not support the efficacy of L-THP as an add-on treatment for schizophrenia but suggest that L-THP may have previously unrecognized proinflammatory effects in people with this disease.

Lessons learned by giving amphetamine to antipsychotic-medicated schizophrenia patients.

Experimental Medicine studies in psychiatric populations test specific, mechanistic hypotheses related to the biology of mental illness, by combining well-characterized neurobiological probes and laboratory-based measures of behavioral performance and neurobiology. However, scientific inquiry through the acute administration of psychoactive drugs to patients with serious mental illness raises important ethical issues. These issues arise in studies in which the psychostimulant, amphetamine, is used as an Experimental Medicine probe in patients with schizophrenia. In this study, we summarize relevant aspects of our experience with acute, laboratory-based challenges of amphetamine in schizophrenia patients. Schizophrenia patients participated in one or more Experimental Medicine studies involving limited doses of amphetamine with clinical monitoring, over a 4-year period. Acute (within hours of ingestion; collective n = 53), subacute (three active doses over 4 weeks; n = 28), and long-term (mean = 17 months after ingestion; n = 19) effects of amphetamine ingestion were assessed. In antipsychotic (AP)-medicated schizophrenia patients, amphetamine was associated with no detrimental subjective, autonomic, or functional changes. Symptoms assessed acutely, subacutely, or long term were either unchanged or diminished. No adverse acute, subacute, or long-term consequences from the Experimental Medicine use of amphetamine in antipsychotic-medicated schizophrenia patients were detected. These findings do not address the safety or effectiveness of the use of amphetamine in unmedicated patients, or as an adjunctive treatment for schizophrenia. Indeed, it is important to distinguish evidence-based risks of symptom exacerbation in an Experimental Medicine setting vs. risks associated with long-term, daily clinical use or even misuse of amphetamine.

Protocol and Rationale: A 24-week Double-blind, Randomized, Placebo Controlled Trial of the Efficacy of Adjunctive Garcinia mangostanaLinn. (Mangosteen) Pericarp for Schizophrenia.

ObjectiveGarcinia mangostana Linn., commonly known as mangosteen, is a tropical fruit with a thick pericarp rind containing bioactive compounds that may be beneficial as an adjunctive treatment for schizophrenia. The biological underpinnings of schizophrenia are believed to involve altered neurotransmission, inflammation, redox systems, mitochondrial dysfunction, and neurogenesis. Mangosteen pericarp contains xanthones which may target these biological pathways and improve symptoms; this is supported by preclinical evidence. Here we outline the protocol for a double-blind randomized placebo-controlled trial evaluating the efficacy of adjunctive mangosteen pericarp (1,000 mg/day), compared to placebo, in the treatment of schizophrenia.MethodsWe aim to recruit 150 participants across two sites (Geelong and Brisbane). Participants diagnosed with schizophrenia or schizoaffective disorder will be randomized to receive 24 weeks of either adjunctive 1,000 mg/day of mangosteen pericarp or matched placebo, in addition to their usual treatment. The primary outcome measure is mean change in the Positive and Negative Symptom Scale (total score) over the 24 weeks. Secondary outcomes include positive and negative symptoms, general psychopathology, clinical global severity and improvement, depressive symptoms, life satisfaction, functioning, participants reported overall improvement, substance use, cognition, safety and biological data. A 4-week post treatment interview at week 28 will explore post-discontinuations effects.ResultsEthical and governance approvals were gained and the trial commenced.ConclusionA positive finding in this study has the potential to provide a new adjunctive treatment option for people with schizophrenia and schizoaffective disorder. It may also lead to a greater understanding of the pathophysiology of the disorder.

Effects of N-acetylcysteine on brain glutamate levels and resting perfusion in schizophrenia

RationaleN-Acetylcysteine (NAC) is currently under investigation as an adjunctive treatment for schizophrenia. The therapeutic potential of NAC may involve modulation of brain glutamate function, but its effects on brain glutamate levels in schizophrenia have not been evaluated.ObjectivesThe aim of this study was to examine whether a single dose of NAC can alter brain glutamate levels. A secondary aim was to characterise its effects on regional brain perfusion.MethodsIn a double-blind placebo-controlled crossover study, 19 patients with a diagnosis of schizophrenia underwent two MRI scans, following oral administration of 2400 mg NAC or matching placebo. Proton magnetic resonance spectroscopy was used to investigate the effect of NAC on glutamate and Glx (glutamate plus glutamine) levels scaled to creatine (Cr) in the anterior cingulate cortex (ACC) and in the right caudate nucleus. Pulsed continuous arterial spin labelling was used to assess the effects of NAC on resting cerebral blood flow (rCBF) in the same regions.ResultsRelative to the placebo condition, the NAC condition was associated with lower levels of Glx/Cr, in the ACC (P < 0.05), but not in the caudate nucleus. There were no significant differences in CBF in the NAC compared to placebo condition.ConclusionsThese data provide preliminary evidence that NAC can modulate ACC glutamate in patients with schizophrenia. In contrast, physiological effects of NAC on the brain were not detectable as between session changes in rCBF. Future studies assessing the effects of a course of treatment with NAC on glutamate metabolites in schizophrenia are indicated.

Herbal medicines in the treatment of psychiatric disorders: 10-year updated review.

This paper provides a 10-year update of the 2007 systematic review of herbal medicines studied in a broad range of psychiatric disorders, including depression, anxiety, obsessive-compulsive, seasonal affective, bipolar, psychotic, phobic, somatoform, and attention-deficit hyperactivity disorders. Ovid Medline, PubMed, and the Cochrane Library were searched for herbal medicines with both pharmacological and clinical evidence of psychotropic activity. This updated review now covers clinical trial evidence for 24 herbal medicines in 11 psychiatric disorders. High-quality evidence was found to exist for the use of Piper methysticum (Kava), Passiflora spp. (passionflower) and Galphimia glauca (galphimia) for anxiety disorders; and Hypericum perforatum (St John's wort) and Crocus sativus (saffron) for major depressive disorder. Other encouraging herbal medicines with preliminary evidence include Curcuma longa (turmeric) in depression, Withania somnifera (ashwagandha) in affective disorders, and Ginkgo biloba (ginkgo) as an adjunctive treatment in Schizophrenia. Although depression and anxiety are commonly researched, many other mental disorders still require further prospective investigation. Although the previous review suggested increasing the adjunctive study of select herbal medicines with pharmaceuticals, this was still only found to sparingly occur in research designs. Aside from this, future focus should involve the incorporation of more biomarker analysis, in particular pharmacogenomics, to determine genetic factors moderating response to herbal medicines.

Adjunctive azapirone for schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials

Azapirones, which are serotonin1A (5-HT1A) receptor partial agonists, have been used as an adjunctive treatment for schizophrenia with mixed results. This is a meta-analysis of the efficacy and tolerability of azapirones for schizophrenia based on randomized, double-blind, placebo-controlled trials (RCTs). English and Chinese databases were systematically and independently searched by two investigators. Data were extracted and analyzed using the RevMan software (version 5.3). Seven RCTs (n = 368) of azapirones (buspirone in 6 RCTs and tandospirone in 1 RCT) were identified and analyzed. Only adjunctive buspirone outperformed placebo regarding total psychopathology [standardized mean difference: −1.03 (95% confidence interval (CI): −1.91, −0.15), P = 0.02; I2 = 92%], but the significance disappeared in sensitivity analysis after removing two outlying studies, and in 10 of the 12 subgroup analyses. In 5 RCTs examining neurocognitive function of azapirones, only 2 RCTs found the superiority of buspirone in improving attention/speeded motor performance, verbal and performance intelligence. Adjunctive buspirone outperformed placebo regarding extrapyramidal symptoms [SMD:-0.51, (95%CI: −0.99, −0.02), P = 0.04; I2 = 0%]. Similar rates of discontinuation [risk ratio:1.06 (95%CI:0.54, 2.07), P = 0.86, I2 = 0%] and adverse drug reactions were found between both groups. Adjunctive buspirone and tandospirone failed to show efficacy for psychotic symptoms, but adjunctive buspirone may be associated with improvement in extrapyramidal symptoms and cognitive deficits in schizophrenia. Due to the preliminary nature of this meta-analysis, larger sample size and higher quality RCTs are needed to confirm these finding.

Tai Chi for Schizophrenia: A Systematic Review.

BackgroundTai Chi as a form of moderate aerobic exercise originating in China, could promote balance and healing of the mind-body. Furthermore, Tai Chi has been used as an adjunctive treatment for patients with schizophrenia. However, no meta-analysis or systematic review on adjunctive Tai Chi for patients with schizophrenia has yet been reported.AimA systematic review and meta-analysis was conducted to examine the efficacy of Tai Chi as an adjunctive treatment for schizophrenia using randomized controlled trial (RCT) data.MethodTwo evaluators independently and systematically searched both English- and Chinese-language databases for RCTs of Tai Chi for schizophrenia patients, selected studies, extracted data, conducted quality assessment and data synthesis. Statistical analyses were performed using the Review Manager (version 5.3). The Cochrane Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) was used to assess the strength of the evidence.ResultsIn 6 RCTs conducted in mainland China and Hong Kong, there were 483 participants including 215 subjects in the intervention group and 268 subjects in the control group. The trials lasted 16.0 (6.2) weeks. Compared to control group, we found significant differences regarding improvement of negative symptoms assessed by the Positive and Negative Syndrome Scale (PANSS) negative symptom sub-score (2 trials) and Scale for the Assessment of Negative Symptoms (SANS) (3 trials) over the study period in the intervention group (5 trials with 6 treatment arms, n=451, SMD: -0.87 (95%CI: -1.51, -0.24), p=0.007; I2=90%). Furthermore, there is no significant difference regarding improvement of positive symptoms assessed by the PANSS positive symptom sub-score (2 trials) and Scale for the Assessment of Positive Symptoms (SAPS) (2 trials) over the study period (4 trials with 5 treatment arms, n=391, SMD: -0.09 (95%CI: -0.44, 0.26), p=0.60; I2=65%). All included RCTs did not report side effects. Based on the GRADE, the strength of the evidence for primary outcome was ‘very low’.ConclusionsThe data available on the effectiveness of adjunctive Tai Chi in patients with schizophrenia who are receiving antipsychotic is insufficient to arrive at a definitive conclusion about its efficacy. Furthermore, follow-up time in the available studies was relatively short, and all studies did not use blinded assessment of outcome measures. High-quality randomized trials are needed to inform clinical recommendations.

Alpha7 nicotinic acetylcholine receptor agonists and PAMs as adjunctive treatment in schizophrenia. An experimental study

Nicotine has been found to improve cognition and reduce negative symptoms in schizophrenia and a genetic and pathophysiological link between the α7 nicotinic acetylcholine receptors (nAChRs) and schizophrenia has been demonstrated. Therefore, there has been a large interest in developing drugs affecting the α7 nAChRs for schizophrenia. In the present study we investigated, in rats, the effects of a selective α7 agonist (PNU282987) and a α7 positive allosteric modulator (PAM; NS1738) alone and in combination with the atypical antipsychotic drug risperidone for their utility as adjunct treatment in schizophrenia. Moreover we also investigated their utility as adjunct treatment in depression in combination with the SSRI citalopram. We found that NS1738 and to some extent also PNU282987, potentiated a subeffective dose of risperidone in the conditioned avoidance response test. Both drugs also potentiated the effect of a sub-effective concentration of risperidone on NMDA-induced currents in pyramidal cells of the medial prefrontal cortex. Moreover, NS1738 and PNU282987 enhanced recognition memory in the novel object recognition test, when given separately. Both drugs also potentiated accumbal but not prefrontal risperidone-induced dopamine release. Finally, PNU282987 reduced immobility in the forced swim test, indicating an antidepressant-like effect. Taken together, our data support the utility of drugs targeting the α7 nAChRs, perhaps especially α7 PAMs, to potentiate the effect of atypical antipsychotic drugs. Moreover, our data suggest that α7 agonists and PAMs can be used to ameliorate cognitive symptoms in schizophrenia and depression.

Single-blind, randomized controlled trial of effectiveness of Naikan therapy as an adjunctive treatment for schizophrenia over a one-year follow-up period.

BackgroundCurrent treatments for schizophrenia are often only partially effective.AimsAssess the possible benefit of using adjunctive Naikan therapy, a cognitive approach based on self-reflection that originated in Japan for the treatment of schizophrenia.MethodsAfter resolution of acute psychotic symptoms, 235 psychiatric inpatients with schizophrenia who had a middle school education or higher were randomly assigned to a control group (n=112) that received routine medication and inpatient rehabilitative treatment or an intervention group (n=123) that also received adjunctive Naikan therapy for 2 hours daily, 5 days a week for 4 weeks. The patients were then discharged and followed up for 12 months. The Positive and Negative Syndrome Scale (PANSS), Personal and Social Performance scale (PSP), and Insight and Attitude Questionnaire (ITAQ) were used to assess patients at enrollment, after the 1-month intervention, and after the 12-month follow-up. Evaluators were blind to the group assignment of patients.Results Only 13 (10.6%) of the intervention group participants relapsed over the 12-month follow-up, but 23 (20.5%) control group participants relapsed (X2=4.50, p=0.034). Using a modified intention-to-treat analysis and a repeated measure analysis of variance, the PANSS, PSP, and ITAQ total scores all showed significantly greater improvement over the 12-month follow-up in the Naikan group than in the control group. The drop in mean chlorpromazine-equivalent dosage from enrollment to the end of follow-up was significantly different in the intervention group but not in the control group, though the change in dosage over time between groups was not statistically significant.ConclusionsThis study provides robust support for the effectiveness of Naikan therapy as an adjunctive treatment during the recovery period of schizophrenia. Compared to treatment as usually, adjunctive Naikan therapy can sustain the improvement in psychotic symptoms achieved during acute treatment, improve insight about the illness, enhance social functioning, and reduce relapse over a one-year follow-up period. Further research of this treatment with larger and more diverse samples of patients with schizophrenia is merited.

Minocycline as a potential treatment in the early stages of schizophrenia: a translational approach

Despite the wide variety of currently available antipsychotics, their efficacy is limited only to the improvement in positive symptoms. In addition, longitudinal cohort studies of patients with first episode psychosis show worsening in different psychopathological domains and progressive loss of brain gray matter volumes. Beyond changes in neurotransmitter systems, most notably in the dopaminergic and glutamatergic systems, there is growing evidence of an immune and inflammatory component in the pathophysiology of schizophrenia, indicating an increase of cytokines (e.g., interleukin 1β, interleukin 6 and TNF-α) and microglial activation in patients with this disorder. Growing evidence indicates that minocycline may enhance the antipsychotic treatment and may prevent some brain changes observed in the early stages of schizophrenia. Minocycline is a tetracycline with broad anti-inflammatory activity and with evidence of neuroprotective action. However, the precise effects of minocycline in the CNS are still elusive. In the other hand, several points can be addressed, providing rational hypotheses for understanding how minocycline can improve symptoms and modulate brain structure and function in schizophrenia. In this article, relevant data about minocycline action are reviewed, linking bench to bedside. The potent inhibition of brain microglia activation and the broad anti-inflammatory effects of minocycline, in addition to indirect modulation of dopaminergic and glutamatergic systems, may mediate the effects of minocycline in schizophrenia. Further longitudinal studies with larger samples and measurement of inflammatory markers are needed to evaluate the potential of minocycline as adjunctive treatment in schizophrenia.

Off-label use of memantine as adjunctive treatment in schizophrenia: a retrospective case series study.

Memantine, an uncompetitive N-methyl D-aspartate receptor (NMDAR) open-channel blocker holds great promise for its potential clinical effectiveness as add-on therapy to on-going treatment with antipsychotics. We report here the results of a chart review-based retrospective case series study that examined the effectiveness of off-label use of memantine in patients with schizophrenia when used as adjunctive therapy to standard neuroleptic therapy. 17 of the 26 patients, whose case files were reviewed using a study-specific proforma showed clinical improvement in positive and/or negative psychopathology as well as in cognitive and/or functional domains. The doses of on-going antipsychotic medications could be reduced in a sizeable number of responders. None of the subjects reported serious adverse events. Memantine holds great promise as adjunctive therapy for treatment of schizophrenia. Randomized controlled trials, wherein memantine is administered at adequate doses for an adequate period of time to ongoing antipsychotic treatment are required to confirm its efficacy in alleviating symptoms of schizophrenia.

Moderating factors for the effectiveness of group art therapy for schizophrenia: secondary analysis of data from the MATISSE randomised controlled trial.

PurposeAlthough some studies suggest that art therapy may be useful in the treatment of negative symptoms of schizophrenia, a recent large trial of group art therapy found no clinical advantage over standard care, but the study population was heterogeneous and uptake of the intervention was poor. This study aimed to investigate whether art therapy was more effective for specific subgroups of patients.MethodsSecondary analysis of data from a randomised controlled trial of group art therapy as an adjunctive treatment for schizophrenia (n = 140) versus standard care alone (n = 137). Positive and Negative Syndrome Scale scores at 12 months were compared between trial arms. Interaction between intervention effect and different subgroups, including those with more severe negative symptoms of schizophrenia, and those who expressed a preference for art therapy prior to randomisation, was tested using a linear mixed model.ResultsThe clinical effectiveness of group art therapy did not significantly differ between participants with more or less severe negative symptoms [interaction for difference in PANSS = 1.7, 95 % CI (−8.6 to 12.1), P = 0.741], or between those who did and did not express a preference for art therapy [interaction = 3.9, 95 % CI (−6.7 to 14.5), P = 0.473]. None of the other exploratory subgroups suggested differences in intervention effect.ConclusionsThere was no evidence of greater improvement in clinical symptoms of schizophrenia for those with more severe negative symptoms or those with a preference for art therapy. Identification of patients with schizophrenia who may benefit most from group art therapy remains elusive.

N-acetyl cysteine reverses social isolation rearing induced changes in cortico-striatal monoamines in rats

Schizophrenia is causally associated with early-life environmental stress, implicating oxidative stress in its pathophysiology. N-acetyl cysteine (NAC), a glutathione precursor and antioxidant, is emerging as a useful agent in the adjunctive treatment of schizophrenia and other psychiatric illnesses. However, its actions on brain monoamine metabolism are unknown. Social isolation rearing (SIR) in rats presents with face, predictive and construct validity for schizophrenia. This study evaluated the dose-dependent effects of NAC (50, 150 and 250mg/kg/day × 14days) on SIR- vs. socially reared induced changes in cortico-striatal levels of dopamine (DA), serotonin (5-HT) noradrenaline (NA) and their associated metabolites. SIR induced significant deficits in frontal cortical DA and its metabolites, 3,4-dihydroxyphenylacetic acid (Dopac) and homovanillic acid (HVA), reduced 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and reduced levels of the NA metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG). In addition, significant elevations in frontal cortical NA and striatal DA, Dopac, HVA, 5-HT, 5-HIAA, NA and MHPG were also observed in SIR rats. NAC at 150 and 250mg/kg reversed all cortico-striatal DA, Dopac, HVA, 5-HT, 5-HIAA and striatal NA alterations in SIR animals, with 250mg/kg of NAC also reversing alterations in cortico-striatal MHPG. In conclusion, SIR profoundly alters cortico-striatal DA, 5-HT and NA pathways that parallel observations in schizophrenia, while these changes are dose-dependently reversed or abrogated by sub-chronic NAC treatment. A modulatory action on cortico-striatal monoamines may explain NACs' therapeutic use in schizophrenia and possibly other psychiatric disorders, where redox dysfunction or oxidative stress is a causal factor.