Antipsychotic Switching Research Articles

Risk factors for early-phase clozapine discontinuation: A nested case-control study.

Safe and efficient methods for introducing clozapine to patients with treatment-resistant schizophrenia (TRS) are needed. We investigated risk factors for clozapine discontinuation in the early phase of its introduction. We conducted a nested case-control study at 14 psychiatric hospitals in Chiba, Japan. Data from pre-registered TRS patients were collected at 7 time points within 12 weeks before and after the start of clozapine introduction. We examined the demographic data, prior and concomitant psychotropic drugs, strategies for switching from prior antipsychotics, and blood test and Global Assessment of Function results. The Clinical Global Impression-Severity Scale was retrospectively scored at 12 weeks before and after clozapine introduction. Of 228 patients, clozapine treatment was continued in 213 (93.4 %) and discontinued in 15 (6.6 %) patients within 12 weeks. Clinical symptoms were improved to mild symptoms with a response rate of 14.9 %. Prior antipsychotics and concomitant psychotropic drugs except for mood stabilizers were significantly decreased. Histories of smoking (OR = 3.32, 95 %CI: 1.11-9.93) and antipsychotic treatment at chlorpromazine-equivalent doses <1200 mg within the past 5 years (OR = 3.93, 95 %CI: 1.24-12.50), but not antipsychotic switching strategy, were associated with clozapine discontinuation. Eosinophilia was the most frequent reason for discontinuation (n = 3, 20 %) and was associated with concomitant valproate at 4 weeks after the introduction. Clozapine is an effective option for TRS patients (especially those treated with higher doses of prior antipsychotics) in Japan. Clinicians should be cautious about concomitant valproate in the early phase of clozapine introduction due to a high risk of eosinophilia.

Effect of Switching to Brexpiprazole on Plasma Homovanillic Acid Levels and Antipsychotic-Related Side Effects in Patients with Schizophrenia or Schizoaffective Disorder.

ObjectiveAlthough switching antipsychotics is a common strategy in the treatment of schizophrenia, caution is needed because of the risk of worsening of psychosis, particularly when switching to a dopamine D2 partial agonist. Homovanillic acid (HVA), a dopamine metabolite, is thought to be a possible indicator of the response to antipsychotics. We examined the effects of switching to brexpiprazole monotherapy from other antipsychotics on plasma HVA levels and side effects during maintenance treatment of schizophrenia.MethodsThe antipsychotics of 37 Japanese patients with schizophrenia or schizoaffective disorder were switched to brexpiprazole for the improvement of side effects. We evaluated clinical symptoms and extrapyramidal symptoms (EPS) and took fasting blood samples at baseline and endpoint (eight weeks after completing the switch) to measure plasma levels of HVA, prolactin, and metabolic parameters.ResultsSwitching to brexpiprazole significantly decreased the Drug-Induced Extrapyramidal Symptoms Scale total score (p=0.008), prolactin levels (p<0.001), body weight (p=0.046), and body-mass index (p=0.034), and increased HDL cholesterol (p=0.008). On the other hand, switching to brexpiprazole did not change plasma levels of HVA or Positive and Negative Syndrome Scale scores.ConclusionSwitching to brexpiprazole significantly improved EPS, high prolactin levels, and metabolic side effects without elevating plasma HVA levels. Brexpiprazole may stabilize dopaminergic neural transmission and could be a useful strategy to decrease the burden in patients with schizophrenia during the maintenance phase. Because of the small sample size, further studies with larger sample sizes are needed to confirm and extend our results.

Association between the glyco-metabolic adverse effects of antipsychotic drugs and their chemical and pharmacological profile: a network meta-analysis and regression.

Glyco-metabolic deteriorations are the most limiting adverse reactions to antipsychotics in the long term. They have been incompletely investigated and the properties of antipsychotics that determine their magnitude are not clarified.To rank antipsychotics by the magnitude of glyco-metabolic alterations and to associate it to their pharmacological and chemical properties, we conducted a network meta-analysis. We searched PubMed, Embase, and Psycinfo on 10 September 2020. We selected studies containing the endpoint-baseline difference or the distinct values of at least one outcome among glucose, HbA1c, insulin, HOMA-IR, triglycerides, total/HDL/LDL cholesterols. Of 2094 articles, 46 were included in network meta-analysis. Study quality was assessed by the RoB 2 and ROBINS-I tools. Mean differences (MD) were obtained by random-effects network meta-analysis; relations between MD and antipsychotic properties were analyzed by linear regressions. Antipsychotic properties investigated were acidic and basic pKa, polar surface area, polarizability, and occupancies of D2, H1, M1, M3, α1A, α2A, 5-HT1A, 5-HT2A, 5-HT2C receptors. We meta-analyzed 46 studies (11 464 patients); on average, studies lasted 15.47 weeks, patients had between 17.68 and 61.06 years of mean age and 61.64% were males. Olanzapine and clozapine associated with greater deteriorations, aripiprazole and ziprasidone with smaller deteriorations. Higher polarizability and 5-HT1A receptor occupancy were associated with smaller deteriorations, H1, M1, and M3 receptor occupancies with larger deteriorations. Drug rankings may guide antipsychotic switching toward metabolically safer drugs. Mechanistic insights may suggest improvements for combination therapies and drug development. More data are required regarding newer antipsychotics.

Antipsychotics result in more weight gain in antipsychotic naive patients than in patients after antipsychotic switch and weight gain is irrespective of psychiatric diagnosis: A meta-analysis

Antipsychotics are associated with bodyweight gain and metabolic disturbance. Previous meta-analyses were limited to mainly antipsychotic switch studies in patients with a diagnosis of schizophrenia or psychosis with short follow-up periods. The present meta-analysis aimed to analyse the impact of weight change in antipsychotic-naive and antipsychotics switch patients and whether body weight change depended on diagnosis. We performed a meta-analysis of clinical trials of antipsychotics that reported weight change, irrespective of psychiatric diagnosis. Outcome measure was body weight change. Studies were classified into antipsychotic-naive and antipsychotic-switch. Forest plots stratified by antipsychotic and the duration of antipsychotic use were generated and results were summarised in figures. In total, 404 articles were included for the quantitative synthesis. 58 articles were on antipsychotic naive patients. In the antipsychotic naive group, all antipsychotics resulted in body weight gain. In the antipsychotic switch group, most antipsychotics likewise resulted in bodyweight gain, with exception of amisulpride, aripiprazole and ziprasidone that showed no body weight gain or even some weight loss after switching antipsychotics. Diagnosis was not a discriminating factor of antipsychotic induced weight change. Antipsychotic use resulted in substantial increase in body weight in antipsychotic-naive patients. In antipsychotic-switch patients the weight gain was mild and not present in amisulpride, aripiprazole and ziprasidone. In both groups, weight gain was irrespective of the psychiatric diagnosis.

Does Switching Antipsychotics Ameliorate Weight Gain in Patients With Severe Mental Illness? A Systematic Review and Meta-analysis.

Obesity and adverse metabolic outcomes in patients with severe mental illness are clinically significant but potentially preventable. Importantly, the evidence for switching to antipsychotics to reduce cardiometabolic burden is unclear. PubMED, Embase, PsycINFO, and Cochrane were searched from inception to March 8, 2020. Articles reporting weight and metabolic changes after antipsychotic switching vs staying on the previous antipsychotic were meta-analyzed both across and within group. Of 61 identified studies, 59 were meta-analyzed (40% rated high quality). In the switch-vs-stay pairwise meta-analyses, only aripiprazole significantly reduced weight (-5.52 kg, 95% CI -10.63, -0.42, P = .03), while olanzapine significantly increased weight (2.46 kg, 95% CI 0.34, 4.57, P = .02). Switching to aripiprazole also significantly improved fasting glucose (-3.99 mg/dl, 95% CI -7.34, -0.64, P = .02) and triglycerides (-31.03 mg/dl, 95% CI -48.73, -13.34, P = .0001). Dropout and psychosis ratings did not differ between switch and stay groups for aripiprazole and olanzapine. In before-to-after switch meta-analyses, aripiprazole (-1.96 kg, 95% CI -3.07, -0.85, P < .001) and ziprasidone (-2.22 kg, 95% CI -3.84, -0.60, P = .007) were associated with weight loss, whereas olanzapine (2.71 kg, 95% CI 1.87, 3.55, P < .001), and clozapine (2.80 kg, 95% CI 0.26, 5.34, P = .03) were associated with weight gain. No significant weight or other cardiometabolic changes were observed when switching to amisulpride, paliperidone/risperidone, quetiapine, or lurasidone. Switching antipsychotics to agents with lower weight gain potential, notably to aripiprazole and ziprasidone, can improve weight profile and other cardiometabolic outcomes. When choosing switch agents, both the weight gain potential of the pre- and post-switch antipsychotic must be considered. Antipsychotic switching in psychiatrically stable patients must be weighed against the risk of psychiatric worsening.

Switching antipsychotics to support the physical health of people with severe mental illness: a qualitative study of healthcare professionals’ perspectives

ObjectivesThe side effects of antipsychotic medications (APs) can increase the risk of developing physical health conditions. Some APs pose a higher risk than others. Evidence suggests switching to lower risk...

Manage antipsychotic-induced akathisia by making changes to the antipsychotic drug regimen and/or adding anti-akathisia agents

Antipsychotic-induced akathisia (AIA) is a common and distressing adverse effect associated with many first- and second-generation antipsychotics. The risk of developing AIA can be minimized by administering the minimal effective dosage of an antipsychotic, avoiding rapid dose escalation and avoiding antipsychotic polypharmacy. Once AIA is diagnosed, patients should first receive an adjustment in their antipsychotic drug regimen (i.e. stop antipsychotic polypharmacy if applicable, lower the dosage of the antipsychotic medication or switch to an antipsychotic with lower AIA potential). If further intervention is needed, propranolol is considered as the first-choice anti-akathisia agent. Alternatively, low-dose mirtazapine, anticholinergics and benzodiazepines can also be considered.

Biopsychosocial factors associated with disordered eating behaviors in schizophrenia

BackgroundRecent hypotheses have suggested that schizophrenic patients are more likely to consume unhealthy foods, causing increased rates of mortality and morbidity associated with metabolic syndrome. This raises the need for more in-depth research on disordered eating behaviors (DEBs) in schizophrenic patients. This study, therefore, aimed to investigate biopsychosocial factors associated with DEBs in schizophrenia.MethodsIn this cross-sectional study, a total of 308 participants (including 83 subjects in the active phase of schizophrenia, 71 subjects in the remission phase of schizophrenia, and 154 control subjects) were recruited through convenience sampling among patients who referred to the Baharan Psychiatric hospital in Zahedan, Iran. Patients were assessed through Eating Attitudes Test (EAT-26), Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI-II), and Positive and Negative Syndrome Scale (PANSS). Data were analyzed using SPSS v25 software. Further, the statistical significance level was set at p < 0.05.ResultsThe prevalence of DEBs was 41.5% in schizophrenic patients (vs. 10.3% in the control group, p = 0.012). No significant difference was observed in the EAT-26 scores based on gender and phases of schizophrenia. According to multiple linear regression analysis, lack of psychosocial rehabilitation, use of atypical antipsychotics, early stages of psychosis, high level of anxiety and depression, expression of more active psychotic symptoms, tobacco smoking, and suffering from type 2 diabetes were all associated with increased development of DEBs among schizophrenic patients.ConclusionsSince the occurrence of DEBs is independent of different phases of schizophrenia, the risk of DEBs is required to be evaluated during the entire course of schizophrenia especially at earlier stages of schizophrenia. Moreover, the use of psychosocial interventions, treatment of affective disorders (i.e., anxiety and depression), antipsychotic medication switching, treatment of tobacco smoking and type 2 diabetes may reduce the risk of DEBs among schizophrenic patients. However, further investigations are required to prove the actual roles of the above factors in developing DEBs among schizophrenic patients.

Management of Tardive Syndrome: Medications and Surgical Treatments.

Tardive syndrome (TS) is an iatrogenic, often persistent movement disorder caused by drugs that block dopamine receptors. It has a broad phenotype including movement (orobuccolingual stereotypy, dystonia, tics, and others) and nonmotor features (akathisia and pain). TS has garnered increased attention of late because of the Food and Drug Administration approval of the first therapeutic agents developed specifically for this purpose. This paper will begin with a discussion on pathogenesis, clinical features, and epidemiology. However, the main focus will be treatment options currently available for TS including a suggested algorithm based on current evidence. Recently, there have been significant advances in TS therapy, particularly with the development of 2 new vesicular monoamine transporter type 2 inhibitors for TS and with new data on the efficacy of deep brain stimulation. The discussion will start with switching antipsychotics and the use of clozapine monotherapy which, despite the lack of higher-level evidence, should be considered for the treatment of psychosis and TS. Anti-dyskinetic drugs are separated into 3 tiers: 1) vesicular monoamine transporter type 2 inhibitors, which have level A evidence, are approved for use in TS and are recommended first-choice agents; 2) drugs with lower level of evidence for efficacy including clonazepam, Ginkgo biloba, and amantadine; and 3) drugs that have the potential to be beneficial, but currently have insufficient evidence including levetiracetam, piracetam, vitamin B6, melatonin, baclofen, propranolol, zolpidem, and zonisamide. Finally, the roles of botulinum toxin and surgical therapy will be examined. Current therapies, though improved, are symptomatic. Next steps should focus on the prevention and reversal of the pathogenic process.

Immediate versus wait-and-gradual discontinuation in antipsychotic switching: A meta-analysis.

In two previous meta-analyses of randomized controlled trials (RCTs) examining antipsychotic switching strategies in patients with schizophrenia, we showed no significant differences in any clinical outcomes between immediate versus gradual and gradual versus wait-and-gradual discontinuation of the pre-switch antipsychotic. In this report, we compared immediate versus wait-and-gradual antipsychotic discontinuation. We identified five RCTs examining immediate versus wait-and-gradual discontinuation of the pre-switch antipsychotic in antipsychotic switching involving patients with schizophrenia. However, no data were available from one RCT. The following clinical outcome data were extracted and meta-analyzed: study discontinuation, psychopathology, extrapyramidal symptoms, and treatment-emergent adverse events that were reported in two or more of the studies. The meta-analysis included four RCTs involving 351 patients (n=175 for immediate and n=176 for wait-and-gradual antipsychotic discontinuation). A significant difference was found in study discontinuation due to all causes (n=4, n=351, risk ratio=1.58, 95% confidence interval 1.15-2.17, p=0.005, I2=0%) between the immediate and wait-and-gradual antipsychotic discontinuation groups, while there was no significant difference in any other clinical outcomes. The group difference in study discontinuation due to all causes remained significant for the studies adopting immediate antipsychotic initiation but not for the studies switching to ziprasidone. Findings suggest that wait-and-gradual antipsychotic discontinuation may be preferable when a more cautious antipsychotic switch is needed. However, further long-term, double-blind RCTs are needed to confirm the present findings.

Long-acting Injectable vs. Oral Antipsychotics: Adherence, Persistence and Switching over three Years of Real-life Analysis.

Persistence and adherence to treatment are considered efficacy outcomes in psychiatric disorders. One of the best ways to improve these values in patients with psychiatric disorders is to prefer Long-Acting Injectable (LAI) drugs to oral AP. The objective of this study is to evaluate adherence, persistence and switching of antipsychotics and compare in real life long-acting with oral formulations. This pharmacological, observational, retrospective and non-interventional study involved all patients of the ASL of Pescara treated in the front-line with AP in the period between January 2011 and February 2019. Adherence was measured using the ratio between the received daily dose and prescribed daily dose. Persistence to treatment with antipsychotics was calculated as the daily difference between the beginning and end of treatment. We examined 840 patients treated with aripiprazole, 130 patients treated with paliperidone and 925 patients treated with risperidone. Adherence was significantly better in long-acting formulations with values of 0.89 (aripiprazole) and 0.82 (paliperidone and risperidone) than in oral formulations with values of 0.78, 0.70 and 0.58, respectively (p> 0.999, p= 0.0091, p=< 0.0001). Threeyear persistence curves relating to three study drugs did not show a statistically significant difference (p = 0.3314). Persistence curves based on formulation have not shown a statistically significant difference (p= 0, 4658, p=0, 4794, p=0, 2199 for ariprazolo, paliperidone and risperidone, respectively). 7% of patients were treated with aripiprazole, 12% of patients were treated with risperidone and 28% of patients were treated with paliperidone switched therapy. In all the drugs of present study, adherence values were better in LAI than in OA, whereas no statistically significant difference was found in persistence values.

Metformin add-on vs. antipsychotic switch vs. continued antipsychotic treatment plus healthy lifestyle education in overweight or obese youth with severe mental illness: results from the IMPACT trial.

Antipsychotics are used for many psychiatric conditions in youth. Although developmentally inappropriate weight gain and metabolic abnormalities, which are risk factors for premature cardiovascular mortality, are especially frequent in youth, optimal strategies to reduce pediatricantipsychotic-induced overweight/obesity are unclear. The Improving Metabolic Parameters in Antipsychotic Child Treatment (IMPACT) was a randomized, parallel group, 24-week clinical trial which enrolled overweight/obese, psychiatrically stable youth, aged 8-19 years, with a DSM-IV diagnosis of severe mental illness (schizophrenia spectrum disorder, bipolar spectrum disorder or psychotic depression), at four US universities. All of them had developed substantial weight gain following treatment with a second-generation antipsychotic. The centralized, computer-based randomization system assigned participants to unmasked treatment groups: metformin (MET); antipsychotic switch (aripiprazole or, if already exposed to that drug, perphenazine or molindone; SWITCH); or continued baseline antipsychotic (CONTROL). All participants received healthy lifestyle education. The primary outcome was body mass index (BMI) z-score change from baseline, analyzed using estimated least squares means. Altogether, 127 participants were randomized: 49 to MET, 31 to SWITCH, and 47 to CONTROL. BMI z-score decreased significantly with MET (week 24: -0.09±0.03, p=0.002) and SWITCH (week 24: -0.11±0.04, p=0.003), while it increased non-significantly with CONTROL (week 24: +0.04±0.03). On 3-way comparison, BMI z-score changes differed significantly (p=0.001). MET and SWITCH were each superior to CONTROL (p=0.002), with effect sizes of 0.68 and 0.81 respectively, while MET and SWITCH did not differ. More gastrointestinal problems occurred in MET than in SWITCH or CONTROL. The data safety monitoring board closed the perphenazine-SWITCH arm because 35.2% of subjects discontinued treatment due to psychiatric worsening. These data suggest that pediatric antipsychotic-related overweight/obesity can be reduced by adding metformin or switching to a lower risk antipsychotic. Healthy lifestyle education is not sufficient to prevent ongoing BMI z-score increase.

Association of antipsychotic treatment switching in patients with schizophrenia, bipolar, and major depressive disorders

Aims: To evaluate the association of relapse and healthcare resource utilization in patients with schizophrenia (SZ), bipolar disorder (BD), or major depressive disorder (MDD) who switched antipsychotic medication versus those who did not.Materials and methods: Medicaid claims from six US states spanning six years were retrospectively analyzed for antipsychotic switching versus non-switching. For all patients with SZ, BD, or MDD, and for the subset of patients who also had ≥1 extrapyramidal symptoms (EPS) diagnosis at baseline, times to the following outcomes were analyzed: underlying disease relapse, other psychiatric relapse, all-cause emergency room (ER) visit, all-cause inpatient (IP) admission, and EPS diagnosis.Results: Switchers (N = 10,548) had a shorter time to disease relapse, other psychiatric relapse, IP admissions, ER visits, and EPS diagnosis (all, log-rank p < .001) than non-switchers (N = 31,644). Switchers reached the median for IP admission (21.50 months) vs non-switchers (not reached) and for ER visits (switchers, 9.07 months; non-switchers, 13.35 months). For disease relapse, other psychiatric relapse, and EPS diagnosis, <50% of patients had an event during the two-year study period. Subgroup analysis of those with ≥1 EPS diagnosis revealed similar associations.Limitations: Only association, not causation, may be inferred, and there may be differences between the patient groups in parameters not evaluated.Conclusions: These results show that disease and other psychiatric relapse, all-cause ER visits, IP admissions, and EPS diagnosis occurred earlier for patients who switched antipsychotics than for those who did not, suggesting that switching is associated with an increased risk of relapse in patients with SZ, BD, and MDD. This may be attributed to more-severely ill patients being less responsive than those with less-severe illness, which, in turn, may require more episodes of switching.

Patient characteristics, burden and pharmacotherapy of treatment-resistant schizophrenia: results from a survey of 204 US psychiatrists

BackgroundMinimal/non-response to antipsychotic treatment, and persistent positive symptoms despite treatment, are common among patients with schizophrenia. The aim of this study was to characterize a US treatment-resistant schizophrenia (TRS) population in terms of patient demographics, burden of symptoms, treatment history, and factors influencing therapeutic choice.MethodsIn an online survey, 204 psychiatrists self-selected and completed three patient records: two TRS and one schizophrenia (‘non-TRS’).ResultsRespondents reported that 29.5% of their schizophrenia caseload had TRS. Selected TRS (n = 408) vs non-TRS (n = 204) patients were more likely to be unemployed (74.5% vs 45.1%, p < 0.001), hospitalized at least once (93.4% vs 74.0%, p < 0.001), and to have physical/psychiatric comorbidities including obesity (40.2% vs 23.5%, p < 0.001) and depression (38.7% vs 25.0%, p = 0.001). Psychiatric symptoms were more frequent and severe in TRS, and interfered more with social and functioning domains. Of positive symptoms, eliminating delusions and hallucinations was considered most important to improve a patient’s long-term prognosis. In TRS, clozapine monotherapy was the most common treatment (15.9%), though ranked fifth of ten options to treat TRS. Psychiatrists typically increased the antipsychotic dose or added a second antipsychotic before initiating clozapine or switching antipsychotics. Antipsychotic switches were most commonly due to lack of efficacy (TRS = 71.4% vs non-TRS = 54.3%, p < 0.001) and intolerability (34.4% vs 38.4%, p = 0.22) with the prior antipsychotic. Persistent hallucinatory behavior was the top symptom leading to treatment switches in TRS (63.9% vs 37.1%, p < 0.001).ConclusionsAccording to psychiatrists, symptoms have a greater clinical burden on patients with TRS than non-TRS. TRS is commonly managed by antipsychotic dose increases/combinations, with clozapine the fifth preference despite being the only approved TRS medication. New treatments are needed for patients who do not respond to available antipsychotics.

Long-Term Response to Clozapine and Its Clinical Correlates in the Treatment of Tardive Movement Syndromes: A Naturalistic Observational Study in Patients With Psychotic Disorders.

Given that switching to clozapine is an important treatment option for tardive movement syndrome (TMS), its effect and clinical correlates have not been fully explored yet. This study investigated the improvement of TMS after switching to clozapine and factors associated with the response in a naturalistic outpatient setting. Subjects were 35 patients with schizophrenia or bipolar disorder receiving only clozapine as an antipsychotic drug for more than 12 months. Their prior antipsychotics were switched to clozapine after the onset of tardive dyskinesia and/or tardive dystonia. Tardive movement syndrome and clinical characteristics were assessed through direct examination and review of hospital records. Offending antipsychotics administered at the time of TMS onset were second-generation antipsychotics in 88.6% of patients. Tardive movement syndrome symptoms were remitted in 65.7% of patients after switching to clozapine. Younger age, younger age at onset of TMS, and lower baseline Abnormal Involuntary Movement Scale score were significantly associated with remission of TMS. Female sex and good antipsychotic effects of clozapine showed a trend of association with better response. Clozapine seems to be an excellent treatment option for TMS in the era of second-generation antipsychotics, especially for younger patients with mild tardive dyskinesia. Clinical trials comparing the effect of switching antipsychotics to clozapine with add-on therapy of new drugs targeting TMS are difficult to design in ordinary clinical settings. Therefore, more naturalistic observational studies are warranted to identify predictors of TMS response to clozapine.

Rates and predictors of one-year antipsychotic treatment discontinuation in first-episode schizophrenia: Results from an open-label, randomized, “real world” clinical trial

Antipsychotic treatment discontinuation is a major challenge in the treatment of first-episode schizophrenia (FES) patients. However, the rate and predictors remain unclear. Five hundred and sixty-nine FES patients were randomized to risperidone (n = 190), olanzapine (n = 185) or aripiprazole (n = 194) in a six-site study in China with 1-year follow-up. Patients failing the initially assigned antipsychotic were switched to one of the other 2 antipsychotics. By 52 weeks, 47.1% of FES patients discontinued all antipsychotics. In the 8-week acute phase, an antipsychotic switch was protective against antipsychotic discontinuation, whereas higher positive symptoms at the endpoint predicted discontinuation. In the maintenance phase, discontinuation was predicted by male gender and higher CGI-S score at the endpoint. The findings indicate that in China nearly half of patients with FES discontinued antipsychotic treatment during one year treatment. Clinicians should employ strategies other than medication choice to keep them from discontinuing.

Switch-associated adverse events: focus on olanzapine.

Switching between different antipsychotic therapies is a frequent occurrence in the management of patients with schizophrenia and other psychotic disorders. This paper provides a review of the principles of antipsychotic switching and discusses pharmacological principles underlying adverse events that occur while switching olanzapine to another antipsychotic medication. It offers suggestions for management of switch-associated adverse events in clinical settings. Few publications explore olanzapine switch-related adverse events, the underlying pharmacological principles and appropriate switching strategies to minimise the risk of adverse events. There is still a need for further studies to verify existing knowledge and assist in the development of 'gold standard' guidelines that outline appropriate switching strategies and duration of the switching process to reduce and avoid adverse events.

Amisulpride and olanzapine followed by open-label treatment with clozapine in first-episode schizophrenia and schizophreniform disorder (OPTiMiSE): a three-phase switching study

No established treatment algorithm exists for patients with schizophrenia. Whether switching antipsychotics or early use of clozapine improves outcome in (first-episode) schizophrenia is unknown. This three-phase study was done in 27 centres, consisting of general hospitals and psychiatric specialty clinics, in 14 European countries and Israel. Patients aged 18-40 years who met criteria of the DSM-IV for schizophrenia, schizophreniform disorder, or schizoaffective disorder were treated for 4 weeks with up to 800 mg/day amisulpride orally in an open-label design (phase 1). Patients who did not meet symptomatic remission criteria at 4 weeks were randomly assigned to continue amisulpride or switch to olanzapine (≤20 mg/day) during a 6-week double-blind phase, with patients and staff masked to treatment allocation (phase 2). Randomisation was done online by a randomisation website; the application implemented stratification by site and sex, and applied the minimisation method for randomisation. Patients who were not in remission at 10 weeks were given clozapine (≤900 mg/day) for an additional 12 weeks in an open-label design (phase 3). The primary outcome was the number of patients who achieved symptomatic remission at the final visits of phases 1, 2, and 3, measured by intention-to-treat analysis. Data were analysed with a generalised linear mixed model, with a logistic link and binomial error distribution. This trial is registered with ClinicalTrials.gov, number NCT01248195, and closed to accrual. Between May 26, 2011, and May 15, 2016, we recruited 481 participants who signed informed consent. Of the 446 patients in the intention-to-treat sample, 371 (83%) completed open-label amisulpride treatment, and 250 (56%) achieved remission after phase 1. 93 patients who were not in remission continued to the 6-week double-blind switching trial, with 72 (77%) patients completing the trial (39 on olanzapine and 33 on amisulpride); 15 (45%) patients on amisulpride versus 17 (44%) on olanzapine achieved remission (p=0·87). Of the 40 patients who were not in remission after 10 weeks of treatment, 28 (70%) started on clozapine; 18 (64%) patients completed the 12-week treatment, and five (28%) achieved remission. The number of serious adverse events did not differ between the treatment arms in phase 2: one patient on olanzapine was admitted to hospital because of an epileptic seizure, and one patient on amisulpride was admitted to hospital twice because of exacerbations of psychotic symptoms. Over the course of the trial, two serious suicide attempts were reported. For most patients in the early stages of schizophrenia, symptomatic remission can be achieved using a simple treatment algorithm comprising the sequential administration of amisulpride and clozapine. Since switching to olanzapine did not improve outcome, clozapine should be used after patients fail a single antipsychotic trial-not until two antipsychotics have been tried, as is the current recommendation. European Commission Seventh Framework Program.

Switching and augmentation strategies for antipsychotic medications in acute-phase schizophrenia: latest evidence and place in therapy.

In terms of effectiveness of antipsychotics in schizophrenia, discrepancy often exists between results from double-blind randomized controlled trials and observations in emergency or acute-phase clinical practice. For instance, the antipsychotic switching strategy is not always applicable in emergency or acute-phase situations, and augmentation of another antipsychotic is occasionally done instead. In this review, we discuss strategies for early nonresponse to an antipsychotic drug such as switching and augmentation from the perspective of emergency and acute-phase treatment. We searched PubMed for the latest evidence on switching and augmentation strategies of antipsychotics for an emergency or acute-phase period. For risperidone and olanzapine, there is some evidence on switching and augmentation strategies in the management of acute-phase schizophrenia. There may be responders to olanzapine alone among early nonresponders to risperidone, whereas there may be few responders to risperidone alone among early nonresponders to olanzapine. However, there is still insufficient evidence at this time for application of these findings to routine clinical practice. For other antipsychotics, there is little evidence for their augmentation in acute-phase practice. We should be wary of polypharmacy, as multiple agents are too often prescribed by clinicians when not warranted. Considering current evidence, we propose how to switch antipsychotics in the acute phase of schizophrenia in routine practice.

Treating depressive episodes or symptoms in patients with schizophrenia.

Depressive episodes or symptoms occur frequently in patients with schizophrenia and may have far-reaching consequences. Despite the high prevalence rate and clinical relevance of this comorbidity, knowledge about treatment options is still limited. The aim of this review is to provide an overview of the literature concerning treatment options for depressive episodes or symptoms in schizophrenia. Based on the current evidence, we present a stepwise treatment approach. The first step is to evaluate the current antipsychotic treatment of psychotic symptoms and consider lowering the dosage, since increased blockade of the dopamine D2 receptors may be associated with a worse subjective sense of well-being and dysphoria. A second step is to consider switching antipsychotics, since there are indications that some antipsychotics (including sulpiride, clozapine, olanzapine, aripiprazole, quetiapine, lurasidone, or amisulpride) are slightly more effective in reducing depressive symptoms compared to other antipsychotics or placebo. In the case of a persistent depressive episode, additional therapeutic interventions are indicated. However, the evidence is indecisive regarding the treatment of choice: either starting cognitive-behavioral therapy or adding an antidepressant. A limited number of studies examined the use of antidepressants in depressed patients with schizophrenia showing modest effectiveness. Overall, additional research is needed to determine the most effective treatment approach for patients with schizophrenia and depressive episodes.