Neurocognitive deficits in depression: a systematic review of cognitive impairment in the acute and remitted state.

Previous research suggests a broad range of deficits in major depressive disorder. Our goal was to update the current assumptions and investigate the extent of cognitive impairment in depression in the acute and remitted state. A systematic review of the existing literature between 2009 and 2019 assessing the risk of bias within the included studies was performed. Of the 42 articles reviewed, an unclear risk of bias was shown overall. The risk of bias mainly concerned the sample selection, inadequate remedial measures, as well as the lack of blinding the assessors. In the acute phase, we found strong support for impairment in processing speed, learning, and memory. Follow-up studies and direct comparisons revealed less pronounced deficits in remission, however, deficits were still present in attention, learning and memory, and working memory. A positive correlation between the number of episodes and cognitive deficits as well as depression severity and cognitive deficits was reported. The results also demonstrate a resemblance between the cognitive profiles in bipolar disorder and depression. Comparisons of depression with schizophrenia led to unclear results, at times suggesting an overlap in cognitive performance. The main findings support the global deficit hypothesis and align with results from prior meta-analyses and reviews. Recommendations for future research are also presented.

Sex differences in pharmacological treatment of major depressive disorder: results from the AMSP pharmacovigilance program from 2001 to 2017.

Data on drug prescription for outpatients with major depressive disorder (MDD) suggest women are more likely to be treated with psychotropic drugs, while data on sex differences regarding pharmacological treatment of psychiatric inpatients are currently not available. Drug utilization data from the program "Drug Safety in Psychiatry" (German: Arzneimittelsicherheit in der Psychiatrie, AMSP) of 44,418 psychiatric inpatients with MDD were analyzed for sex differences between 2001 and 2017. Sex differences were analyzed using relative risks (RR) and 95% confidence intervals (95% CI). Time trends were analyzed by comparing the first (2001-2003) with the last time period (2015-2017). In general, men and women were equally likely to use psychotropic drugs. Monotherapy was more common in men. Women were more likely to utilize ≥ 4 psychotropic drugs. Antidepressant drugs (ADDs) were the most prescribed drug class. Men had a higher utilization of noradrenergic and specific serotonergic antidepressants (RR 1.15; 95% CI 1.12-1.19), especially mirtazapine (RR 1.16; 95% CI 1.12-1.19), but also of other ADDs such as bupropion (RR 1.50; 95% CI 1.35-1.68). Males had a slightly higher utilization of second-generation antipsychotic drugs (RR 1.06; 95% CI 1.03-1.09) and were less often treated with low-potency first-generation antipsychotic drugs (RR 0.86; 95% CI 0.83-0.90). Tranquilizing (e.g., benzodiazepines; RR 0.89; 95% CI 0.86-0.92) and hypnotic drugs (e.g., Z-drugs; RR 0.85; 95% CI 0.81-0.89) were less utilized in the treatment of male patients. Not all sex differences were stable over time. More sex differences were detectable in 2015-2017 than in 2001-2003. Findings suggest that certain psychotropic drugs are preferred in the treatment of men vs. women, however, sex differences found in this study are not as large as in ambulatory settings. To make evidence-based sex-specific recommendations in the treatment of MDD, differences in drug response and tolerability need to be further researched.

Cardiovascular Adverse Reactions During Antipsychotic Treatment: Results of AMSP, A Drug Surveillance Program Between 1993 and 2013.

BACKGROUND: Cardiovascular diseases are still the leading cause of global mortality. Some antipsychotic agents can show severe cardiovascular side effects and are also associated with metabolic syndrome. METHODS: This observational study was based on data of AMSP (Arzneimittelsicherheit in der Psychiatrie), a multicenter drug surveillance program in Austria, Germany and Switzerland, that recorded severe drug reactions in psychiatric inpatients. RESULTS: A total of 404 009 inpatients were monitored between 1993 and 2013, whereas 291 510 were treated with antipsychotics either in combination or alone. There were 376 cases of severe cardiovascular adverse reactions reported in the given timespan, yielding a relative frequency of 0.13%. The study revealed that incidence rates of cardiovascular adverse reactions were highest during treatment with ziprasidone (0.35%), prothipendyl (0.32%), and clozapine (0.23%). The lowest rate of cardiovascular symptoms occurred during treatment with promethazine (0.03%) as well as with aripiprazole (0.06%). The most common clinical symptoms were orthostatic collapse and severe hypotonia, sinustachycardia, QTc prolongation, myocarditis, and different forms of arrhythmia. The dosage at the timepoint when severe cardiovascular events occurred was not higher in any of the given antipsychotics than in everyday clinical practice and was in average therapeutic ranges. In terms of subclasses of antipsychotics, no significant statistical difference was seen in the overall frequencies of adverse reactions cases, when first-generation high potency, first-generation low potency, and second-generation antipsychotics were compared. Thirty percent of adverse events among second-generation antipsychotics were induced by clozapine. CONCLUSIONS: Our findings on cardiovascular adverse reactions contribute to a better understanding of cardiovascular risk profiles of antipsychotic agents in inpatients.

Severe parkinsonism under treatment with antipsychotic drugs.

The aim of the study was to assess rates of severe parkinsonism related to different antipsychotic drugs (APDs) using data from an observational pharmacovigilance programme in German-speaking countries-Arzneimittelsicherheit in der Psychiatrie (AMSP). Data on APD utilization and reports of severe APD-induced parkinsonism were collected in 99 psychiatric hospitals in Austria, Germany and Switzerland during the period 2001-2016. Of 340,099 patients under surveillance, 245,958 patients were treated with APDs for the main indications of schizophrenic disorders, depression, mania and organic mental disorders. A total of 200 events of severe APD-induced parkinsonism were identified (0.08%). First-generation low-potency APDs were significantly less often implicated (0.02%) than second-generation APDs (0.07%) and first-generation high-potency APDs (0.16%). Among the second-generation APDs, amisulpride and risperidone ranked highest. The phenothiazines were associated with significantly lower rates of severe parkinsonism (0.02%) than those of the butyrophenones (0.11%) and thioxanthenes (0.12%). In 71 cases (35.5%), more than 1 drug was considered responsible for the induction of severe parkinsonism. In 44 patients (22.0%), the symptoms were extremely severe, leading to complete immobility and/or massive complications such as pneumonia and severe injuries due to falls. Higher age (> 60 years) was associated with significantly higher rates of severe parkinsonism, as were the diagnoses of schizophrenic disorder or mania. The large number of patients included in the present survey allows for the comparison of severe parkinsonism rates related to different APD classes and single APDs. The first-generation low-potency APDs had significantly reduced risk of severe parkinsonism compared not only to high potency but also to second-generation APDs.

Suicidal Ideation and Suicidal Behavior as Rare Adverse Events of Antidepressant Medication: Current Report from the AMSP Multicenter Drug Safety Surveillance Project.

Background: Suicidal ideations, suicide attempts, and fatal suicides are rare adverse drug reactions to antidepressant drugs, but they essentially are clinically relevant. Drawing on a larger dataset of the European drug surveillance program, the present naturalistic study updates a previous contribution (Stübner et al., 2010). Methods: First an analysis of the comprehensive data collected in 81 psychiatric hospitals from 1993 to 2014 by the European drug surveillance program Arzneimittelsicherheit in der Psychiatrie was made. All documented single cases of suicidal ideations or behavior judged as adverse drug reactions to antidepressant drugs were carefully assessed as to their clinical features and drug prescriptions. Results: Among 219,635 adult hospitalized patients taking antidepressant drugs under surveillance, 83 cases of suicidal adverse drug reactions occurred (0.04%): 44 cases of suicidal ideation, 34 attempted suicides, and 5 committed suicides were documented. Restlessness was present in 42 patients, ego-dystonic intrusive suicidal thoughts or urges in 39 patients, impulsiveness in 22 patients, and psychosis in 7 patients. Almost all adverse drug reactions occurred shortly after beginning antidepressant drug medication or increasing the dosage. Selective serotonin reuptake inhibitors caused a higher incidence of suicidal ideation and suicidal behavior as adverse drug reactions than noradrenergic and specific serotonergic antidepressants or tricyclic antidepressants, as did monotherapy consisting of one antidepressant drug, compared to combination treatments. Conclusions: The study supports the view that antidepressant drug-triggered suicidal ideation and suicidal behavior (primarily with selective serotonin reuptake inhibitors) are rare. Special clinical features (restlessness, ego-dystonic thoughts or urges, impulsiveness) may be considered as possible warning signs. A combination therapy might be preferable to antidepressant drug monotherapy when beginning treatment.

Use and safety of antiepileptic drugs in psychiatric inpatients-data from the AMSP study.

The psychiatric utilization patterns and risks of antiepileptic drugs (AEDs) were assessed by using data from the drug safety programme Arzneimittelsicherheit in der Psychiatrie over the time period 1993-2013. In a total of 432,215 patients, the main indications for AED use were acute mania, schizoaffective disorder, and schizophrenic and organic psychoses. Valproic acid (VPA) was the most common substance across all of those groups, reaching administration rates of up to 50% since 2005, at which time carbamazepine (CBZ) administration consistently dropped below a rate of 10%. Lamotrigine (LTG) and pregabalin (PGB) increased in relevance after 2005 and 2010, respectively (with administration rates of up to 9%), whereas oxcarbazepine (OXC) was least prevalent (<3%). The mean rates of severe adverse drug reactions (ADRs) ranged from 6 cases per 1000 patients treated (VPA) to 19/1000 (OXC) and were significantly lower with treatment with VPA compared to OXC and CBZ. Hyponatremia was the leading ADR during treatment with OXC; severe allergic skin reactions were most often observed during treatment with CBZ and LTG, and severe oedema was most common during treatment with PGB. Severe hyponatremia induced by OXC was observed significantly more often in female patients than in male patients.

Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.

BACKGROUND: The question of which antipsychotic drug should be preferred for the treatment of schizophrenia is controversial, and conventional pairwise meta-analyses cannot provide a hierarchy based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs. METHODS: We did a Bayesian-framework, multiple-treatments meta-analysis (which uses both direct and indirect comparisons) of randomised controlled trials to compare 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia. We searched the Cochrane Schizophrenia Group's specialised register, Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for reports published up to Sept 1, 2012. Search results were supplemented by reports from the US Food and Drug Administration website and by data requested from pharmaceutical companies. Blinded, randomised controlled trials of patients with schizophrenia or related disorders were eligible. We excluded trials done in patients with predominant negative symptoms, concomitant medical illness, or treatment resistance, and those done in stable patients. Data for seven outcomes were independently extracted by two reviewers. The primary outcome was efficacy, as measured by mean overall change in symptoms. We also examined all-cause discontinuation, weight gain, extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation. FINDINGS: We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0·88, 0·73-1·03; amisulpride 0·66, 0·53-0·78; olanzapine 0·59, 0·53-0·65; risperidone 0·56, 0·50-0·63; paliperidone 0·50, 0·39-0·60; zotepine 0·49, 0·31-0·66; haloperidol 0·45, 0·39-0·51; quetiapine 0·44, 0·35-0·52; aripiprazole 0·43, 0·34-0·52; sertindole 0·39, 0·26-0·52; ziprasidone 0·39, 0·30-0·49; chlorpromazine 0·38, 0·23-0·54; asenapine 0·38, 0·25-0·51; lurasidone 0·33, 0·21-0·45; and iloperidone 0·33, 0·22-0·43. Odds ratios compared with placebo for all-cause discontinuation ranged from 0·43 for the best drug (amisulpride) to 0·80 for the worst drug (haloperidol); for extrapyramidal side-effects 0·30 (clozapine) to 4·76 (haloperidol); and for sedation 1·42 (amisulpride) to 8·82 (clozapine). Standardised mean differences compared with placebo for weight gain varied from -0·09 for the best drug (haloperidol) to -0·74 for the worst drug (olanzapine), for prolactin increase 0·22 (aripiprazole) to -1·30 (paliperidone), and for QTc prolongation 0·10 (lurasidone) to -0·90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses. INTERPRETATION: Antipsychotics differed substantially in side-effects, and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients. These findings should be considered by mental health policy makers and in the revision of clinical practice guidelines. FUNDING: None.

Cardiovascular adverse reactions during antidepressant treatment: a drug surveillance report of German-speaking countries between 1993 and 2010.

BACKGROUND: Antidepressants (ADs) are known to have the potential to cause various cardiovascular adverse drug reactions (ADRs). The tricyclic antidepressants (TCAs) were first revealed to be a possible source of cardiovascular ADRs. In recent years, newer classes of ADs were also suggested to have a higher risk of cardiovascular adverse effects. In particular, the selective serotonin reuptake inhibitors (SSRIs) were suspected to have the potential to induce QTc interval prolongation, and therefore increase the risk of ventricular arrhythmia. This descriptive study is based on the continuous pharmacovigilance program of German-speaking countries (Austria, Germany, and Switzerland), the Arzneimittelsicherheit in der Psychiatrie (AMSP), which assesses severe ADRs occurring in clinical routine situations. METHODS: Of 169,278 psychiatric inpatients treated with ADs between 1993 and 2010, 198 cases of cardiovascular ADRs (0.12%) were analyzed. RESULTS: Our study showed that the incidence rates of cardiovascular ADRs were highest during treatment with monoamine oxidase inhibitors (0.27%), TCAs (0.15%), and serotonin noradrenaline reuptake inhibitors (0.14%); the risk of occurring during treatment with SSRIs (0.08%) was significantly lower. The noradrenergic and specific serotonergic AD mirtazapine (0.07%) had a significantly lower risk of cardiovascular ADRs than all other ADs. Severe hypotension was the most frequent ADR, followed by hypertension, arrhythmia, and in some rare cases heart failure. CONCLUSIONS: Despite certain limitations due to the AMSP study design, our observations on cardiovascular ADRs can contribute to a better knowledge of the cardiovascular risk profiles of antidepressants in the clinical routine setting. However, prospective studies are needed to verify our findings.

Perphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia.

BACKGROUND: Antipsychotic drugs are the core treatment for schizophrenia. Treatment guidelines state that there is no difference in efficacy between the various first-generation antipsychotics, however, low-potency first-generation antipsychotic drugs are sometimes perceived as less efficacious than high-potency first-generation compounds by clinicians, and they also seem to differ in their side effects. OBJECTIVES: To review the effects of high-potency, first-generation perphenazine compared with low-potency, first-generation antipsychotic drugs for people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (October 2010). SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing perphenazine with first-generation, low-potency antipsychotic drugs for people with schizophrenia or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis and using a random-effects model. MAIN RESULTS: The review currently includes four relevant randomised trials with 365 participants. The size of the included studies was between 42 and 158 participants with a study length between one and four months. Overall, the methods of sequence generation and allocation concealment were poorly reported. Most studies were rated as low risk of bias in terms of blinding. Overall, attrition bias in the studies was high.The effects of perphenazine and low-potency antipsychotic drugs seemed to be similar in terms of the primary outcome - response to treatment (perphenazine 58%, low-potency antipsychotics 59%, 2 RCTs, n = 138, RR 0.97 CI 0.74 to 1.26 - moderate quality of evidence). There was also no clear evidence of a difference in acceptability of treatment with the number of participants leaving the studies early due to any reason, however results were imprecise (perphenazine 30%, low-potency antipsychotics 28%, 3 RCTs, n = 323, RR 0.78 CI 0.35 to 1.76, very low quality of evidence).There were low numbers of studies available for the outcomes experiencing at least one adverse effect (perphenazine 33%, low-potency antipsychotics 47%, 2 RCTs, n = 165, RR 0.83 CI 0.36 to 1.95, low quality evidence) and experiencing at least one movement disorder (perphenazine 22%, low-potency first-generation antipsychotics 0%, 1 RCT, n = 69, RR 15.62 CI 0.94 to 260.49, low quality evidence), and the confidence intervals for the estimated effects did not exclude important differences. Akathisia was more frequent in the perphenazine group (perphenazine 25%, low-potency antipsychotics 22%, 2 RCTs, n = 227, RR 9.45 CI 1.69 to 52.88), whereas severe toxicity was less so (perphenazine 42%, low-potency antipsychotics 69%, 1 RCT, n = 96, RR 0.61 CI 0.41 to 0.89).There were three deaths in the low-potency group by four months but the difference between groups was not significant (perphenazine 0%, low-potency antipsychotics 2%, 1 RCT, n = 96, RR 0.14 CI 0.01 to 2.69, moderate quality evidence). No data were available for our prespecified outcomes of interest sedation or quality of life. Data were not available for other outcomes such as relapse, service use, costs and satisfaction with care.The event rates reported quote simple aggregates and are not based on the RRs. AUTHORS' CONCLUSIONS: The results do not show a superiority in efficacy of high-potency perphenazine compared with low-potency first-generation antipsychotics. There is some evidence that perphenazine is more likely to cause akathisia and less likely to cause severe toxicity, but most adverse effect results were equivocal. The number of studies as well as the quality of studies is low, with quality of evidence for the main outcomes ranging from moderate to very low, so more randomised evidence would be needed for conclusions to be made.

Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia.

BACKGROUND: Antipsychotic drugs are the core treatment for schizophrenia. Treatment guidelines state that there is no difference in efficacy between any other antipsychotic compounds, however, low-potency antipsychotic drugs are often perceived as less efficacious than high-potency compounds by clinicians, and they also seem to differ in their side effects. This review examined the effects of the high-potency antipsychotic fluphenazine compared to those of low-potency antipsychotics. OBJECTIVES: To review the effects of fluphenazine and low-potency antipsychotics for people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (November 2010). SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing fluphenazine with first-generation low-potency antipsychotic drugs for people with schizophrenia or schizophrenia-like psychosis. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. MAIN RESULTS: The review currently includes seven randomised trials and 1567 participants that compared fluphenazine with low-potency antipsychotic drugs. The size of the included studies was between 40 and 438 participants. Overall, sequence generation, allocation procedures and blinding were poorly reported. Fluphenazine was not significantly different from low-potency antipsychotic drugs in terms of response to treatment (fluphenazine 55%, low-potency drug 55%, 2 RCTs, n = 105, RR 1.06 CI 0.75 to 1.50, moderate quality evidence). There was also no significant difference in acceptability of treatment with equivocal numbers of participants leaving the studies early due to any reason (fluphenazine 36%, low-potency antipsychotics 36%, 6 RCTs, n = 1532, RR 1.00 CI 0.88 to 1.14, moderate quality evidence). There was no significant difference between fluphenazine and low-potency antipsychotics for numbers experiencing at least one adverse effect (fluphenazine 70%, low-potency antipsychotics 88%, 1 RCT, n = 65, RR 0.79 CI 0.58 to 1.07, moderate quality evidence). However, at least one movement disorder occurred significantly more frequently in the fluphenazine group (fluphenazine 15%, low-potency antipsychotics 10%, 3 RCTs, n = 971, RR 2.11 CI 1.41 to 3.15, low quality of evidence). In contrast, low-potency antipsychotics produced significantly more sedation (fluphenazine 20%, low-potency antipsychotics 64%, 1 RCT, n = 65, RR 0.31 CI 0.13 to 0.77, high quality evidence). No data were available for the outcomes of death and quality of life. The results of the primary outcome were robust in a number of subgroup and sensitivity analyses.Adverse effects such as akathisia (fluphenazine 15%, low-potency antipsychotics 6%, 5 RCTs, n = 1209, RR 2.28 CI 1.58 to 3.28); dystonia (fluphenazine 5%, low-potency antipsychotics 2%, 4 RCTs, n = 1309, RR 2.66 CI 1.25 to 5.64); loss of associated movement (fluphenazine 20%, low-potency antipsychotics 2%, 1 RCT, n = 338, RR 11.15 CI 3.95 to 31.47); rigor (fluphenazine 27%, low-potency antipsychotics 12%, 2 RCTs, n = 403, RR 2.18 CI 1.20 to 3.97); and tremor (fluphenazine 15%, low-potency antipsychotics 6%, 2 RCTs, n = 403, RR 2.53 CI 1.37 to 4.68) occurred significantly more frequently in the fluphenazine group.For other adverse effects such as dizziness (fluphenazine 8%, low-potency antipsychotics 17%, 4 RCTs, n = 1051, RR 0.49 CI 0.32 to 0.73); drowsiness (fluphenazine 18%, low-potency antipsychotics 25%, 3 RCTs, n = 986, RR 0.67 CI 0.53 to 0.86); dry mouth (fluphenazine 11%, low-potency antipsychotics 18%, 4 RCTs, n = 1051, RR 0.63 CI 0.45 to 0.89); nausea (fluphenazine 4%, low-potency antipsychotics 15%, 3 RCTs, n = 986, RR 0.25 CI 0.14 to 0.45); and vomiting (fluphenazine 3%, low-potency antipsychotics 8%, 3 RCTs, n = 986, RR 0.36 CI 0.18 to 0.72) results favoured fluphenazine with significantly more events occurring in the low-potency antipsychotic group for these outcomes. AUTHORS' CONCLUSIONS: The results do not show a clear difference in efficacy between fluphenazine and low-potency antipsychotics. The number of included studies was low and their quality moderate. Therefore, further studies would be needed to draw firm conclusions about the relative effects of fluphenazine and low-potency antipsychotics.

Flupenthixol versus low-potency first-generation antipsychotic drugs for schizophrenia.

BACKGROUND: Antipsychotic drugs are the core treatment for schizophrenia. Treatment guidelines state that there is no difference in efficacy between antipsychotic drugs, however, low-potency antipsychotic drugs are sometimes perceived as less efficacious than high-potency compounds by clinicians, and they also seem to differ in their side effects. OBJECTIVES: To review the effects in clinical response of flupenthixol and low-potency antipsychotics for people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (July 2010). SELECTION CRITERIA: Randomised controlled trials that compared flupenthixol with first-generation low-potency antipsychotic drugs for people with schizophrenia or schizophrenia-like psychosis. DATA COLLECTION AND ANALYSIS: We extracted data independently. For continuous data, we calculated mean differences (MD) based on a random-effects model. MAIN RESULTS: The review currently includes one randomised trial from mainland China with 153 participants that lasted two months and compared flupenthixol with chlorpromazine. The exact methods of sequence generation and allocation concealment were not reported, and medication was provided in an open manner. There were no data on the outcomes that we had a priori selected for a 'Summary of findings' table.There was no significant difference between flupenthixol and chlorpromazine in the participants' general mental state at endpoint as measured by the Brief Psychiatric Rating Scale (BPRS) total score (1 randomised controlled trial (RCT), n = 153, MD 2.20 95% confidence interval (CI) -1.25 to 5.65). Chlorpromazine was associated with significantly less dizziness (1 RCT, n = 153, MD 0.12 95% CI 0.01 to 0.23); dystonia (1 RCT, n = 153, MD 0.29 95% CI 0.13 to 0.45); unsteady gait (1 RCT, n = 153, MD 0.46 95% CI 0.28 to 0.64); reduced facial expression (1 RCT, n = 153, MD 0.27 95% CI 0.09 to 0.45); restlessness (1 RCT, n = 153, MD 0.69 95% CI 0.45 to 0.93); rigidity (elbow) (1 RCT, n = 153, MD 0.48 95% CI 0.28 to 0.68); and tremor (1 RCT, n = 153, MD 0.56 95% CI 0.34 to 0.78). Chlorpromazine produced more dryness of mouth than flupenthixol (1 RCT, n = 153, MD -0.14 95% CI -0.25 to -0.03). AUTHORS' CONCLUSIONS: The evidence base of flupenthixol versus low-potency first-generation antipsychotics is currently restricted to one randomised comparison with chlorpromazine. The few reported data do not suggest a difference in efficacy, but flupenthixol appeared to produce more movement disorders and dizziness, while chlorpromazine was associated with the anticholinergic side effect - dryness of mouth. More trials are needed to make conclusions about the relative effects of flupenthixol and low-potency antipsychotics.

Trifluoperazine versus low-potency first-generation antipsychotic drugs for schizophrenia.

BACKGROUND: Antipsychotic drugs are the core treatment for schizophrenia. Treatment guidelines state that there is no difference in efficacy between any other antipsychotic compounds, however, low-potency antipsychotic drugs are often perceived as less efficacious than high-potency compounds by clinicians, and they also seem to differ in their side-effects. OBJECTIVES: To review the effects in response to treatment of trifluoperazine and low-potency antipsychotics for people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Trials Register (November 2010). SELECTION CRITERIA: We included all randomised trials comparing trifluoperazine with first-generation low-potency antipsychotic drugs for people with schizophrenia or schizophrenia-like psychosis. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. MAIN RESULTS: The review currently includes seven randomised trials involving 422 participants that compared trifluoperazine with low-potency antipsychotic drugs. The size of the included studies was between 20 and 157 participants with a study length between four and 52 weeks. Overall, sequence generation, allocation procedures and blinding were poorly reported. Trifluoperazine was not significantly different from low-potency antipsychotic drugs in terms of response to treatment (trifluoperazine 26%, low-potency drug 27%, 3 RCTs, n = 120, RR 0.96 CI 0.59 to 1.56, moderate quality evidence). There was also no significant difference in acceptability of treatment with equivocal number of participants leaving the studies early due to any reason (trifluoperazine 20%, low-potency antipsychotics 16%, 3 RCTs, n = 239, RR 1.25, CI 0.72 to 2.17,low quality evidence). There was no significant difference in numbers with at least one adverse effect (trifluoperazine 60%, low-potency antipsychotics 38%, 1 RCT, n = 60, RR 1.60, CI 0.94 to 2.74, moderate quality evidence). However, at least one movement disorder was significantly more frequent in the trifluoperazine group (trifluoperazine 23%, low-potency antipsychotics 13%, 2 RCTs, n = 123, RR 2.08 CI 0.78 to 5.55, very low quality evidence) as well as incoordination (trifluoperazine 20%, low-potency antipsychotics 5%, 1 RCT, n = 60, RR 7.00, CI 1.60 to 30.66) and rigor (trifluoperazine 45%, low-potency antipsychotics 10%, 1 RCT, n = 60, RR 4.50, CI 1.58 to 12.84). No data were available for other outcomes of interest death, sedation and quality of life. AUTHORS' CONCLUSIONS: The results did not show a difference in efficacy between trifluoperazine and low-potency antipsychotics. Trifluoperazine produced more movement disorders. The number of randomised studies as well as their quality is low, the quality of evidence for outcomes of interest ranged from moderate to very low quality, so more, newer studies would be needed for conclusions about the relative effects of trifluoperazine and low-potency antipsychotics.

Haloperidol versus low-potency first-generation antipsychotic drugs for schizophrenia.

BACKGROUND: Antipsychotic drugs are the core treatment for schizophrenia. Treatment guidelines state that there is no difference in efficacy between antipsychotic compounds, however, low-potency antipsychotic drugs are often clinically perceived as less efficacious than high-potency compounds, and they also seem to differ in their side-effects. OBJECTIVES: To review the effects in clinical response of haloperidol and low-potency antipsychotics for people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (July 2010). SELECTION CRITERIA: We included all randomised trials comparing haloperidol with first-generation low-potency antipsychotic drugs for people with schizophrenia or schizophrenia-like psychosis. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data, we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. For continuous data, we calculated mean differences (MD), again based on a random-effects model. MAIN RESULTS: The review currently includes 17 randomised trials and 877 participants. The size of the included studies was between 16 and 109 participants. All studies were short-term with a study length between two and 12 weeks. Overall, sequence generation, allocation procedures and blinding were poorly reported. We found no clear evidence that haloperidol was superior to low-potency antipsychotic drugs in terms of clinical response (haloperidol 40%, low-potency drug 36%, 14 RCTs, n = 574, RR 1.11, CI 0.86 to 1.44 lowquality evidence). There was also no clear evidence of benefit for either group in acceptability of treatment with equivocal difference in the number of participants leaving the studies early due to any reason (haloperidol 13%, low-potency antipsychotics 17%, 11 RCTs, n = 408, RR 0.82, CI 0.38 to 1.77, low quality evidence). Similar equivocal results were found between groups for experiencing at least one adverse effect (haloperidol 70%, low-potency antipsychotics 35%, 5 RCTs n = 158, RR 1.97, CI 0.69 to 5.66, very low quality evidence ). More participants from the low-potency drug group experienced sedation (haloperidol 14%, low-potency antipsychotics 41%, 2 RCTs, n = 44, RR 0.30, CI 0.11 to 0.82, moderate quality evidence), orthostasis problems (haloperidol 25%, low-potency antipsychotics 71%, 1 RCT, n = 41, RR 0.35, CI 0.16 to 0.78) and weight gain (haloperidol 5%, low-potency antipsychotics 29%, 3 RCTs, n = 88, RR 0.22, CI 0.06 to 0.81). In contrast, the outcome 'at least one movement disorder' was more frequent in the haloperidol group (haloperidol 72%, low-potency antipsychotics 41%, 5 RCTs, n = 170, RR 1.64, CI 1.22 to 2.21, low quality evidence). No data were available for death or quality of life. The results of the primary outcome were robust in several subgroup and sensitivity analyses. AUTHORS' CONCLUSIONS: The results do not clearly show a superiority in efficacy of haloperidol compared with low-potency antipsychotics. Differences in adverse events were found for movement disorders, which were more frequent in the haloperidol group, and orthostatic problems, sedation and weight gain, which were more frequent in the low-potency antipsychotic group. The quality of studies was low, and the quality of evidence for the main outcomes of interest varied from moderate to very low, so more newer studies would be needed in order to draw a definite conclusion about whether or not haloperidol is superior or inferior to low-potency antipsychotics.

Understanding effect size: an international online survey among psychiatrists, psychologists, physicians from other medical specialities, dentists and other health professionals.

BACKGROUND AND OBJECTIVE: Various ways exist to display the effectiveness of medical treatment options. This study examined various psychiatric, medical and allied professionals' understanding and perceived usefulness of eight effect size indices for presenting both dichotomous and continuous outcome data. METHODS: We surveyed 1316 participants from 13 countries using an online questionnaire. We presented hypothetical treatment effects of interventions versus placebo concerning chronic pain using eight different effect size measures. For each index, the participants had to judge the magnitude of the shown effect, to indicate how certain they felt about their own answer and how useful they found the given effect size index. FINDINGS: Overall, 762 (57.9%) participants fully completed the questionnaire. In terms of understanding, the best results emerged when both the control event rate (CER) and the experimental event rate (EER) were presented. The difference in minimal importance difference units (MID unit) was understood worst. Respondents also found CER and EER to be the most useful presentation approach while they rated MID unit as the least useful. Confidence in the risk ratio ranked high, even though it was rather poorly understood. CONCLUSIONS AND CLINICAL IMPLICATIONS: For dichotomous outcomes, presenting the effects in terms of the CER and EER could lead to the most correct interpretation. Relative measures including the risk ratio must be supplemented with absolute measures such as the CER and EER. Effects on continuous outcomes were better understood through standardised mean differences than mean differences. These can also be supplemented by dichotomised CER and EER.

Two Sides of the Same Coin in Female Borderline Personality Disorder: Self-Reported Guilt and Shame and Their Neurofunctional Correlates.

OBJECTIVE: Patients with borderline personality disorder (BPD) report to be especially prone to social emotions like shame and guilt. At the same time, these emotions seem to play an important role in BPD pathology. The present study aimed to deepen the knowledge about the processes behind shame and guilt in patients with BPD. METHODS: Twenty patients with BPD and twenty healthy controls (HCs) took part in an experiment that induced shame and guilt by imagining scenarios during scanning using functional brain imaging. Participants also filled out self-report questionnaires and took part in diagnostic interviews. RESULTS: BPD patients reported more proneness to guilt but not to shame than the HCs. There was no difference in the self-reported intensity rating of experimentally induced emotions between the groups. Between-group contrast of neural signals in the shame condition revealed a stronger activation of cingulate and fusiform gyrus for the BPD patients compared to the controls, and a more pronounced activation in the lingual gyrus and cuneus for the HCs. In the guilt condition, activation in the caudate nucleus, the fusiform gyrus, and the posterior cingulate cortex was stronger in BPD patients, while HC showed stronger activations in cuneus, lingual gyrus, and fronto-temporal regions. CONCLUSIONS: Differences in the neuro-functional processes between BPD patients and HC were found, even though the two groups did not differ in their self-report of subjective proneness to guilt and emotional intensity of shame and guilt during the experiment. While the HCs may be engaged more by the emotional scenarios themselves, the BPD patients may be more occupied with cognitive regulatory and self-referential processing.

Two Sides of Theory of Mind: Mental State Attribution to Moving Shapes in Paranoid Schizophrenia Is Independent of the Severity of Positive Symptoms.

BACKGROUND: Theory of Mind (ToM) impairment has repeatedly been found in paranoid schizophrenia. The current study aims at investigating whether this is related to a deficit in ToM (undermentalizing) or an increased ToM ability to hyperattribute others' mental states (overmentalizing). METHODS: Mental state attribution was examined in 24 patients diagnosed with schizophrenia (12 acute paranoid (APS) and 12 post-acute paranoid (PPS)) with regard to positive symptoms as well as matched healthy persons using a moving shapes paradigm. We used 3-T-functional magnetic resonance imaging (fMRI) to provide insights into the neural underpinnings of ToM due to attributional processes in different states of paranoid schizophrenia. RESULTS: In the condition that makes demands on theory of mind skills (ToM condition), in patients with diagnosed schizophrenia less appropriate mental state descriptions have been used, and they attributed mental states less often to the moving shapes than healthy persons. On a neural level, patients suffering from schizophrenia exhibited within the ToM network hypoactivity in the medial prefrontal cortex (MPFC) and hyperactivity in the temporo-parietal junction (TPJ) as compared to the healthy sample. CONCLUSIONS: Our results indicate both undermentalizing and hypoactivity in the MPFC and increased overattribution related to hyperactivity in the TPJ in paranoid schizophrenia, providing new implications for understanding ToM in paranoid schizophrenia.

Relapse in clinically stable adult patients with schizophrenia or schizoaffective disorder: evidence-based criteria derived by equipercentile linking and diagnostic test accuracy meta-analysis.

BACKGROUND: There is no consensus on defining relapse in schizophrenia, and scale-derived criteria with unclear clinical relevance are widely used. We aimed to develop an evidence-based scale-derived set of criteria to define relapse in patients with schizophrenia or schizoaffective disorder. METHODS: We searched the Yale University Open Data Access (YODA) for randomised controlled trials (RCTs) in clinically stable adults with schizophrenia or schizoaffective disorder, and obtained individual participant data on Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Severity (CGI-S), Personal and Social Performance (PSP), and Social and Occupational Functioning Assessment Scale (SOFAS). Our main outcomes were PANSS-derived criteria based on worsening in PANSS total score. We examined their relevance using equipercentile linking with CGI-S and functioning scales, and their test-performance in defining relapse with diagnostic test accuracy meta-analysis against CGI-S worsening (≥1-point increase together with a score ≥4 points) and psychiatric hospitalisation. FINDINGS: Based on data from seven RCTs (2354 participants; 1348 men [57·3%] and 1006 women [42·7%], mean age of 39·5 years [SD 12·0, range 17-89]; 303 Asian [12.9%], 255 Black [10.8%], 1665 White [70.7%], and other or unspecified 131 [5.6%]), an increase of 12 points or more in PANSS total (range 30-210 points) corresponded to clinically important deterioration in global severity of illness (≥1 point increase in CGI-S, range 1-7) and functioning (≥10 points decline in PSP or SOFAS, range 1-100). The interpretation of percentage changes varied importantly across different baseline scores. An increase of 12 points or more in PANSS total had good sensitivity and specificity using CGI-S as reference standard (sensitivity 82·1% [95% CI 77·1-86·4], specificity 86·9% [82·9-90·3]), as well as good sensitivity but lower specificity compared to hospitalisation (sensitivity 81·7% [74·1-87·7], specificity 69·2% [60·5-76·9]). Requiring either an increase in PANSS total or in specific items for positive and disorganization symptoms further improved test-performance. Cutoffs for situations where high sensitivity or specificity is needed are presented. INTERPRETATION: An increase of either 12 points or more in the PANSS total score, or worsening of specific positive and disorganisation symptom items could be a reasonable evidence-based definition of relapse in schizophrenia, potentially linking symptoms used to define remission and relapse. Percentage changes should not be used to define relapse because their interpretation depends on baseline scores. FUNDING: German Research Foundation (grant number: 428509362).

Neuropsychological functioning in inpatients with major depression or schizophrenia.

BACKGROUND: Studies that compare neuropsychological functioning in inpatients with mood disorder or schizophrenia come to heterogeneous results. This study aims at investigating the question whether there are different neuropsychological test profiles in stabilised post-acute inpatients with affective disorders or schizophrenia. METHOD: We were interested in evaluating impairment in specific areas of cognitive functioning in patients with schizophrenia or depression. In clinical reality, patients with depression and schizophrenia are often treated together with little attention to their specific needs. 74 patients with major depression and 38 patients with schizophrenia were assessed in a comprehensive neuropsychological battery. All patients were in a post-acute stage of their illness, i.e. remission of acute symptoms. RESULTS: In spite of a comparable mean score of psychopathological symptoms in the Brief Psychiatric Rating Scale-Expanded (BPRS-E) as well as in the Global Assessment Functioning Scale (GAF), patients with depressive disorder showed significantly better results in verbal and visual short-term memory, verbal fluency, visual-motor coordination, information processing in visual-verbal functioning and selective attention compared to patients with schizophrenia. No significant differences between both samples were found in practical reasoning, general verbal abstraction, spatial-figural functioning, speed of cognitive processing. CONCLUSIONS: These results show that there are differences in scores in psychopathology (BPRS-E, GAF) in patients with affective disorders or schizophrenia and different neuropsychological test profiles in the post-acute stage of their illness.

Neurocognitive Deficits in First-Episode and Chronic Psychotic Disorders: A Systematic Review from 2009 to 2022.

Cognitive impairment in patients suffering from schizophrenia spectrum disorders has been discussed as a strong predictor for multiple disease outcome variables, such as response to psychotherapy, stable relationships, employment, and longevity. However, the consistency and severity of cognitive deficits across multiple domains in individuals with first-episode and chronic psychotic disorders is still undetermined. We provide a comprehensive overview of primary research from the years 2009 to 2022. Based on a Cochrane risk assessment, a systematic synthesis of 51 out of 3669 original studies was performed. Impairment of cognitive functioning in patients diagnosed with first-episode psychotic disorders compared with healthy controls was predicted to occur in all assessed cognitive domains. Few overall changes were predicted for chronically affected patients relative to those in the first-episode stage, in line with previous longitudinal studies. Our research outcomes support the hypothesis of a global decrease in cognitive functioning in patients diagnosed with psychotic disorders, i.e., the occurrence of cognitive deficits in multiple cognitive domains including executive functioning, memory, working memory, psychomotor speed, and attention. Only mild increases in the frequency of cognitive impairment across studies were observed at the chronically affected stage relative to the first-episode stage. Our results confirm and extend the outcomes from prior reviews and meta-analyses. Recommendations for psychotherapeutic interventions are provided, considering the broad cognitive impairment already observed at the stage of the first episode. Based on the risk of bias assessment, we also make specific suggestions concerning the quality of future original studies.

The relationship between blood-brain barrier dysfunction and neurocognitive impairments in first-episode psychosis: findings from a retrospective chart analysis.

BACKGROUND: Even before the onset of psychotic symptoms, individuals with schizophrenia display cognitive impairments. Simultaneously, increasing amounts of individuals exhibit dysfunction of the blood-brain barrier (BBB). However, the impact of BBB dysfunction on neurocognitive impairment in people with first-episode psychosis has not yet been investigated. AIMS: To advance understanding of said relationship, we considered one of the largest first-episode psychosis cohorts with cerebrospinal fluid parameters available, and investigated whether BBB dysfunction is related to working memory, working speed and attention. METHOD: We conducted a retrospective chart review of 121 in-patients diagnosed with a first episode of a schizophrenia spectrum disorder. Patients underwent neurocognitive testing and a lumbar puncture within routine clinical care. To define BBB dysfunction, albumin cerebrospinal fluid/serum quotients, immunoglobulin G ratios and oligoclonal band types were evaluated, and gender-specific differences investigated. Neurocognitive functioning was assessed by the Wechsler Adult Intelligence Scale, Test of Attentional Performance and Repeatable Battery for the Assessment of Neuropsychological Status. We performed simple and multiple linear regression analyses to interpret associations of interest. RESULTS: Of those tested, 16% showed an alteration in albumin quotients and 12% had an oligoclonal band type indicating BBB dysfunction. Notably, male patients were more likely to have an increased albumin quotient and a higher immunoglobulin G ratio than female patients. We found no significant association between BBB dysfunction and neurocognitive assessments. CONCLUSIONS: The hypothesised relationship between BBB and neurocognitive impairments was not detectable in our retrospective cohort. Further cerebrospinal fluid-based studies with a longitudinal assessment of cognitive functioning and disease trajectory are urgently needed.