Journal of Psychopharmacology

Quetiapine has varied dose ranges and immediate-(QTP-IR) and extended-release (QTP-ER) formulations.

We hypothesized that QTP-IR is inferior to QTP-ER at any dose in efficacy for the acute treatment in schizophrenia and tested using a dose–response model-based network meta-analysis (NMA).

We searched PubMed, the Cochrane Library, CINHAL, and ClinicalTrials.gov for randomized placebo-controlled trials comparing QTP-IR and/or QTP-ER for acute psychosis in patients with schizophrenia up to September 21, 2022. A random effect Bayesian dose–response model-based NMA was performed to compare the dose–response relationships between QTP-IR and QTP-ER.

The relationship between doses and antipsychotic effects was partially bell-shaped for QTP-IR but not for QTP-ER. The respective peak effect dose was 279.7 mg for QTP-IR and 557.2 mg for QTP-ER, with no significant difference in peak effect. QTP-IR ranging from 100 to 300 mg were significantly superior to QTP-ER at the same doses. In addition, QTP-IR ranging from 100 to 400 mg were significantly better than placebo, whereas QTP-ER ranging from 500 to 800 mg were significantly more effective than placebo. Moreover, QTP-IR 600 mg was significantly less effective than QTP-ER at the same dose. Furthermore, QTP-IR 700 mg was significantly superior to placebo, but significantly inferior to QTP-ER 600 mg.

QTP-IR may reach comparable peak responses and exhibit enhanced antipsychotic effects at lower doses than QTP-ER; the converse may be true at relatively high doses. Collectively, we propose a novel strategy to enhance the efficacy of QTP administration.

Postpartum psychosis (PPP) is a psychiatric emergency that generally warrants acute inpatient care. PPP is marked by the sudden onset of affective and psychotic symptoms with a rapid deterioration in mental state. Evidence suggests that PPP is a discrete disorder on the bipolar disorder spectrum with a distinct treatment profile and prognosis.

We conducted a PubMed database search for various terms involving PPP and its treatment and included peer-reviewed articles published in English.

To provide a treatment algorithm for the management of PPP based on available evidence.

Pharmacological therapy is the mainstay of PPP management in the acute phase. Evidence points to a combination of antipsychotics and lithium in the acute treatment of PPP. Electroconvulsive therapy can offer a rapid treatment response where required. Lithium appears to have the best evidence for relapse prevention and prophylaxis in PPP. Psychoeducation is essential and psychosocial interventions used in bipolar disorder may be effective in PPP.

Early detection and prompt treatment with antipsychotics and lithium, followed by maintenance treatment with lithium, is associated with a favourable prognosis in PPP.

QTc prolongation is one of the possible complications in patients with schizophrenia taking antipsychotics, which leads to malignant cardiac arrhythmia. No meta-analysis has been reported assessing the prevalence and correlated risk factors for QTc prolongation.

This meta-analysis aimed to assess the evidence for the prevalence of QTc prolongation and correlated risk factors in patients with schizophrenia taking antipsychotics. Web of Science and PubMed were searched according to preset strategy. The quality of research was assessed by the Newcastle–Ottawa Scale (NOS).

In all, 15 studies covering 15,540 patients with schizophrenia taking antipsychotics were included. Meta-analysis showed that the prevalence of QTc prolongation in patients with schizophrenia taking antipsychotics was about 4.0% (95% confidence interval (CI): 3.0%–5.0%, p < 0.001). The prevalence was about 4.0% in Asia (95%CI: 3.0%–6.0%, p < 0.001), about 5.0% in Europe (95%CI: 2.0%–7.0%, p < 0.001), and about 2.0% in America (95%CI: 1.0%–3.0%, p < 0.001). Sensitivity analyses indicated the robustness of the result. Publication bias analysis reported a certain publication bias (t = 3.37, p = 0.012). Meta-regression suggested that female and elderly patients were clinically associated with a higher prevalence of QTc prolongation. According to included studies, smoking, comorbidity of cardiovascular disease, and abnormal levels of high-density lipoprotein/low-density lipoprotein might be related to QTc prolongation in patients with schizophrenia taking antipsychotics.

The prevalence of QTc prolongation in patients with schizophrenia taking antipsychotics was about 4.0%. Female and elderly patients were more likely to experience QTc prolongation. Close electrocardiogram monitoring was suggested in these at-risk populations.

Expert consensus-based clinically equivalent dose estimates and dosing recommendations can provide valuable support for the use of drugs for psychosis in clinical practice and research.

This second International Consensus Study of Antipsychotic Dosing provides dosing equivalencies and recommendations for newer drugs for psychosis and previously reported drugs with low consensus.

We used a two-step Delphi survey process to establish and update consensus with a broad, international sample of clinical and research experts regarding 26 drug formulations to obtain dosing recommendations (start, target range, and maximum) and estimates of clinically equivalent doses for the treatment of schizophrenia. Reference agents for equivalent dose estimates were oral olanzapine 20 mg/day for 15 oral and 7 long-acting injectable (LAI) agents and intramuscular haloperidol 5 mg for 4 short-acting injectable (SAI) agents. We also provide a contemporary list of equivalency estimates and dosing recommendations for a total of 44 oral, 16 LAI, and 14 SAI drugs for psychosis.

Survey participants (N = 72) from 24 countries provided equivalency estimates and dosing recommendations for oral, LAI, and SAI formulations. Consensus improved from survey stages I to II. The final consensus was highest for LAI formulations, intermediate for oral agents, and lowest for SAI formulations of drugs for psychosis.

As randomized, controlled, fixed, multiple-dose trials to optimize the dosing of drugs for psychosis remain rare, expert consensus remains a useful alternative for estimating clinical dosing equivalents. The present findings can support clinical practice, guideline development, and research design and interpretation involving drugs for psychosis.

Several studies have reported that a switch to the dopamine partial agonist (DPA) aripiprazole (ARP), especially when the switch is abrupt, is likely to fail and sometimes worsen psychosis in schizophrenia patients already under high-dose antipsychotic treatment. Such a switching failure is speculated to be related to be the dopamine supersensitivity state. The risks of switching to the DPA brexpiprazole (BREX) have not been reported.

We retrospectively analyzed the cases of 106 patients with schizophrenia to identify any factors related to the success or failure of switching to BREX.

The comparison between the patients with dopamine supersensitivity psychosis (n = 44) and those without (n = 62) revealed no significant difference in the switching failure judged at the sixth week. A comparison of the patients with successful switching (n = 80) and those who failed (n = 26) revealed that patients with treatment-resistant schizophrenia (TRS) were significantly more likely to fail. A logistic regression analysis also revealed that patients with past failure of switching to ARP are likely to succeed in switching to BREX. The 2-year follow-up of the patients with successful switching to BREX suggested that the patients who were treated with BREX, even temporarily, experienced some improvement in their Global Assessment of Functioning and Clinical Global Impression-Severity scores.

Overall, the results indicate that patients with schizophrenia can be switched more safely to BREX compared to ARP. However, the failure of switching to BREX could be higher in patients with TRS, and thus, starting BREX treatment in refractory patients warrants careful monitoring.

Due to the inflammatory factors in the pathophysiology of schizophrenia, Pentoxifylline, as anti-inflammatory medication, seems to improve the symptoms of schizophrenia. This study aims to evaluate the efficacy of Pentoxifylline as an adjunctive therapy on cognitive deficits and symptoms of schizophrenia.

This randomized double-blind placebo-controlled clinical trial was conducted on 52 patients diagnosed with chronic schizophrenia. All patients were divided into two, treatment and control groups. They received a 400 mg dose of Pentoxifylline and the placebo in the treatment and control groups, respectively, twice a day for 8 weeks. Then, they were tested with the Positive and Negative Syndrome Scale (PANSS), Wisconsin Card Sorting Test (WCST), digit span, Stroop test, and Rey Auditory and Verbal Learning Test at baseline and the end of the weeks 4 and 8. Data analysis was done by Kolmogorov–Smirnov test, t-test, Mann–Whitney test, chi-square test, and generalized estimating equation model.

After analyzing the data, it was revealed that the positive symptoms of PANSS, the number of errors in the incongruent Stroop test, and reaction time in the congruent Stroop test were significantly lower in the treatment group (p < 0.05). Moreover, the number of categories of WCST was significantly higher in the treatment group (p < 0.05). There was no statistically significant difference in other parameters between the control and treatment groups (p > 0.05).

As evidenced by the results of this study, Pentoxifylline can help alleviate schizophrenia cognitive deficits and can reduce psychotic symptoms. Therefore, it can potentially be useful for schizophrenia treatment.

The histamine-3 receptor (H3R) is an auto- and heteroreceptor that inhibits the release of histamine and other neurotransmitters. Post-mortem evidence has found altered H3R expression in patients with psychotic disorders, which may underlie cognitive impairment associated with schizophrenia (CIAS).

We used positron emission tomography (PET) imaging to compare brain uptake of an H3R selective tracer between patients with schizophrenia and matched controls (healthy individuals). Regions of interest included the dorsolateral prefrontal cortex (DLPFC) and striatum. We explored correlations between tracer uptake and symptoms, including cognitive domains.

A total of 12 patients and 12 matched controls were recruited to the study and were assessed with psychiatric and cognitive rating scales. They received a PET scan using the H3R-specific radioligand [¹¹C]MK-8278 to determine H3R availability.

There was no statistically significant difference in tracer uptake between patients and controls in the DLPFC (t₁₉ = 0.79, p = 0.44) or striatum (t₂₁ = 1.18, p = 0.25). An exploratory analysis found evidence for lower volume of distribution in the left cuneus (p_{FWE-corrected} = 0.01). DLPFC tracer uptake was strongly correlated with cognition in controls (trail making test (TMT) A: r = 0.77, p = 0.006; TMT B: rho = 0.74, p = 0.01), but not in patients (TMT A: r = −0.18, p = 0.62; TMT B: rho = −0.06, p = 0.81).

These findings indicate H3R in the DLPFC might play a role in executive function and this is disrupted in schizophrenia in the absence of major alterations in H3R availability as assessed using a selective radiotracer for H3R. This provides further evidence for the role of H3R in CIAS.

Between 25% and 50% of patients suffering from treatment-resistant schizophrenia fail to achieve a clinical response with clozapine. The rapid identification and treatment of this subgroup of patients represents a challenge for healthcare practice.

To evaluate the relationship between metabolic alterations and the clinical response to clozapine.

A multicenter, observational, case–control study was performed. Patients diagnosed with schizophrenia treated with clozapine were eligible (minimum dose 400 mg/d for at least 8 weeks and/or clozapine plasma levels ⩾ 350 µg/mL). According to the Positive and Negative Syndrome Scale (PANSS) total score, patients were classified as clozapine-responsive (CR) (<80 points) or clozapine non-responsive (CNR) (⩾80 points). Groups were compared based on demographic and treatment-related characteristics, together with body mass index (BMI), waist circumference, insulin, leptin, and C-reactive protein plasma levels. Plasma levels of clozapine and its main metabolite, nor-clozapine, were measured in all the participants. In addition, the potential relationship between PANSS scores and leptin or insulin plasma levels was assessed.

A total of 46 patients were included: 25 CR and 21 CNR. BMI and waist circumference, fasting insulin and leptin plasma levels were lower in the CNR group, while C-reactive protein was not different. Moreover, significant negative correlations were observed between PANSS positive and general psychopathology subscores, on one hand, and insulin and leptin plasma levels, on the other hand, as well as between PANSS negative subscores and leptin plasma levels.

Our results suggest that the lack of metabolic effect induced by clozapine is associated with the lack of clinical response.

Clozapine is the most effective antipsychotic but requires careful titration to therapeutic blood levels. Methods to predict therapeutic doses are based on population data.

We aimed to construct a model based on genetic variants which accurately predicted plasma levels for clozapine.

We measured clozapine plasma levels in patients on a stable dose of clozapine who were known to be fully compliant. Measured plasma levels were adjusted for sampling time and dose. Hepatic enzyme variants were analysed and models were constructed to predict the required dose. These predictions were compared with a standard population-based algorithm.

We measured plasma clozapine concentrations in 18 adherent patients on stable doses of clozapine and recorded the exact timing of sampling. For the algorithm-predicted dose, the mean difference was −49.9 mg/day ((SD 155.9), r = 0.36) from the actual dose required to give a plasma concentration of 0.35 ng/ml. The gene variant activity score predicted a dose for which the mean difference was −43.5 mg/day ((SD 140.1), r = 0.55). For the gene variant activity score with omeprazole correction predicted dose, the mean difference was −31.0 mg/day ((SD 140.8), r = 0.54), and with the gene variant CYP1A2 inducibility predicted dose the mean difference was 44.9 mg/day ((SD 160.8), r = 0.32).

Our gene variant activity score with omeprazole correction gave the best estimate of the clozapine dose required to achieve a minimum therapeutic plasma concentration. The use of this model will allow safer titration of clozapine and may reduce the need for plasma-level monitoring during titration.

Preliminary evidence suggest clozapine is associated with more favorable impact on concurrent substance use disorder related outcomes in patients with concurrent schizophrenia spectrum disorders (SSD). At the same time, there is a dearth of evidence with regards to clozapine outcomes in the context of concurrent methamphetamine or amphetamine use disorder (MAUD).

To examine whether clozapine use decreases rate of methamphetamine or amphetamine (MA) relapses and increases the likelihood of maintaining abstinence from any MA use.

A descriptive-analytic retrospective cohort study was conducted on individuals with SSD-MAUD in an inpatient provincial treatment and rehabilitation center for concurrent disorders. Antipsychotic exposure was categorized as “on clozapine” or “on other antipsychotic(s).” Data were collected using electronic health records. Logistic regression was used to examine association of clozapine treatment with likelihood of complete abstinence from MA use for the duration of antipsychotic exposure. Negative binomial regression was used to examine association of clozapine treatment with rate of MA relapses for the duration of antipsychotic exposure.

The majority of the 87 included patients were male. Ethnicity was diverse, with the largest groups self-identifying as Indigenous and European. Clozapine use was both associated with increased likelihood of maintaining abstinence from MA use (adjusted odds ratio (aOR) = 3.05, 95% confidence intervals (CI) = 1.15–8.1, p = 0.025), and decreased rate of MA relapses (aRR = 0.45, 95% CI = 0.25–0.82, p = 0.009) for the duration of antipsychotic exposure. Co-prescription of psychostimulants was associated with increased rate of MA relapses (aRR = 2.43, 95% CI = 1.16–5.10, p = 0.019).

In this study, clozapine use compared with other antipsychotics in SSD was associated with improved outcomes related to severe concurrent MAUD. Co-prescription of psychostimulant medications was associated with a poor outcome.