Research That Can Change Clinical Practice in Psychotic Disorders

July 28, 2015

The need to stay up-to-date with the most current evidence-based information is becoming harder than ever. For this reason, the authors identify and evaluate published research that may have a direct bearing on clinical practice.

Because psychiatrists need to stay up-to-date with the most current evidence-based information is becoming harder than ever, we attempted to identify and evaluate published research that may have a direct bearing on clinical practice. We used the following process:

• Literature published between July 1, 2013, and June 30, 2014, was searched for relevant study findings

• Psychiatric groups and colleagues were asked which research published July 1, 2013, through June 30, 2014, had had the greatest impact on the clinical practice of psychiatry

• Post-publication reviews and commentaries in peer-reviewed journals helped assess the final choices

The articles were chosen on the basis of the clinical relevance, applicability, and quality of the research.

Here we present data from 3 meta- analyses and 2 double-blind, randomized, placebo-controlled trials.

Psychological treatments

Psychotherapy remains an important but underused modality with inconclusive relative differences. To examine the relative efficacy of psychotherapy for symptom improvement, a comparative meta-analysis of 48 randomized trials that included 3295 participants was conducted.1 All the studies in the analysis involved a comparison of at least 2 interventions: befriending, CBT, cognitive remediation, psychoeducation, social skills training, and supportive counseling. The studies ranged from 3 to 104 weeks in duration. Most CBT and social skills training studies had no bias of risk; heterogeneity was moderate to high in most psychotherapy meta-analyses other than CBT.

For all symptom improvement, CBT was most and befriending was least effective (Hedges’ g = 0.16; 95% CI, 0.04, 0.28, and Hedges’ g = −0.37; 95% CI, −0.60, −0.13, respectively). CBT had significant but small benefits for positive symptoms compared with other treatments; these benefits remained after excluding biased trials but lost significance after sensitivity analyses for researcher allegiance. Social skills training provided mild to moderate benefits over other therapies (Hedges’ g = 0.27; 95% CI, 0.01, 0.53) for negative symptom improvement; the benefits remained after excluding biased studies. On head-to-head comparison, CBT was statistically superior to supportive counseling for positive symptoms (Hedges’ g = 0.23; 95% CI, 0.01, 0.44). Among CBT subtypes, generic CBT was more effective than coping enhancement.

Repetitive transcranial magnetic stimulation

Quality-of-life measures along with other functional outcomes in schizophrenia are largely predicted by negative symptom resolution; however, treatment of negative symptoms continues to be a challenge, even with atypical antipsychotics. To fill this gap, other treatment alternatives have been investigated. Among them, repetitive transcranial magnetic stimulation (rTMS) has been found to provide symptomatic relief. This was examined in a meta-analysis that included 342 patients with schizophrenia in 16 studies (3 open-label and 13 parallel sham-controlled) from 1998 to 2013.2

In half of the studies, the participants were receiving typical antipsychotics. The duration of illness among the participants was 5.3 to 22.7 years. Participants received 5 to 20 sessions of rTMS at 1 to 20 Hz with 80% to 110% motor threshold. Most studies used the left dorsolateral prefrontal cortex as the treatment site; SANS (Scale for the Assessment of Negative Symptoms) and PANSS (Positive and Negative Syndrome Scale) scores were used as outcome measures.

On pre-post rTMS treatment outcomes, active rTMS yielded a moderate effect on negative symptoms (Cohen’s d = 0.62; 95% CI, 0.22, 1.02); however, pooled analysis of the open-label studies failed to show any significant difference. The pre-post sham treatment difference, indicative of placebo effect, also showed small effect (Cohen’s d = 0.39; 95% CI, 0.15, 0.67). Compared with sham treatments, rTMS induced moderate negative symptom improvement (Cohen’s d = 0.53; 95% CI, 0.19, 0.87). In addition, rTMS treatment was found to have statistically significant effect when the following moderators were in place: shorter duration of illness, longer treatment duration, 10-Hz frequency, left dorsolateral prefrontal cortex treatment site, 110% motor threshold intensity, and a higher baseline PANSS score.

Relative efficacy of oral antipsychotic monotherapy

Inconclusive efficacy hierarchy of oral antipsychotic monotherapy prompted a pooled analysis of 212 blinded, randomized, controlled trials published from 1955 to 2012. The meta-analysis, which included 43,049 patients, was undertaken to determine the comparative usefulness of the antipsychotics for symptom reduction, discontinuation, and adverse effects.3 Thirteen atypical antipsychotics (including zotepine, amisulpride, sertindole) and 2 typical antipsychotics (haloperidol, chlorpromazine) were compared with placebo during the acute treatment phase, defined as the initial 6 weeks. The mean duration of psychotic illness was 12.4 years and the mean age of the participants was 38.4 years.

All the medications were statistically superior to placebo for symptom reduction. Clozapine was most effective for providing symptom relief (SMD [standard mean difference] = −0.88; 95% CrI [credible interval], −1.03, −0.73); besides being most effective, haloperidol (SMD = −0.45) also outperformed quetiapine (SMD = −0.44), aripiprazole (SMD = −0.43), and ziprasidone (SMD = −0.39). In addition, chlorpromazine (SMD = −0.38) was found to be better than lurasidone (SMD = −0.33) and iloperidone (SMD = −0.33).

The all-cause discontinuation was highest for haloperidol, whereas clozapine and olanzapine were among the most acceptable antipsychotics. Although tolerable, olanzapine and clozapine caused the most weight gain; haloperidol, ziprasidone, and lurasidone did not differ statistically from placebo in causing weight gain. Haloperidol caused the most extrapyramidal adverse effects, while clozapine produced fewer adverse effects than all medications and placebo. Paliperidone was associated with the highest prolactin elevation followed by risperidone, whereas quetiapine and aripiprazole did not differ from placebo. All medications except lurasidone, aripiprazole, paliperidone, and asenapine caused QTc prolongation. Also, clozapine and chlorpromazine were the most sedating, whereas iloperidone and paliperidone were found to be similar to placebo (Table).

Melatonin for antipsychotic-induced metabolic adverse effects

Melatonin, commonly used as a sleep-promoting aid, was examined in a single-center, 8-week study.4 All 48 participants received olanzapine (15 to 25 mg/d) and clonazepam (2 mg) for sleep enhancement; they were then randomized to bedtime melatonin 3 mg (n = 24) or placebo (n = 24). The adherence rates were high (> 90%) and did not differ between the two groups. In the modified intent-to-treat analysis, the melatonin group had significant time- treatment effect and less weight gain than the placebo group (MD [mean difference] = 3.2 kg; 95% CI, 0.5, 6.0). Other significant favorable outcomes in the melatonin group included smaller increase in BMI (MD = 1.07 kg/m2; 95% CI, 0.15, 1.99) and in waist circumference (MD = 2.83 cm; 95% CI, 0.12, 5.54). Furthermore, the melatonin group achieved higher total PANSS reduction than the placebo group (MD = 12.9; 95% CI, 2.8, 23.0).

Intravenous sodium nitroprusside

A double-blind, randomized, placebo-controlled trial involved 20 patients who were randomly assigned to sodium nitroprusside (0.5 µg/kg/min) or placebo infusion (5% glucose solution) over 4 hours.5 Most of the participants were male and were receiving antipsychotic medication, the mean age was 25 years, and the duration of the illness ranged from 2.85 to 3.2 years. The study participants were interviewed using the BPRS-18 (18-item Brief Psychiatric Rating Scale) and the PANSS negative symptom subscale (primary outcome measures) every hour during the infusion. Changes to supplemental medications (benzodiazepines and analgesics) and antipsychotics were permitted 2 days and 7 days post-infusion.

The sodium nitroprusside group showed statistically significant improvement on the total BPRS-18 score from the second hour of the infusion until the fourth week of observation. Significant improvement on the BPRS-18 score was noted on the anxiety-depression and thinking disorder subscales from the second and third hour of infusion until the second and fourth weeks of the observation period.

Other significant changes were found on withdrawal-retardation (days 2 through 14) and activation (days 1 through 7) subscales. Similar gains were observed on PANSS (from the third hour of infusion until the fourth week of observation). Furthermore, sodium nitroprusside did not differ from placebo on physiological parameters and the AIMS (Abnormal Involuntary Movement Scale). Other desirable effects included fewer number of medications or dose changes after 1 week.


Schizophrenia, as a major cause of disability-adjusted life years, continues to be a treatment challenge. The results of these meta-analyses and experimental studies provide understanding of relative efficacies of established modalities and emerging effective treatments. Psychotherapy, in particular CBT and social skills training, may help in achieving better outcomes along with standard medical management. Although the relative differences were clinically small with indication of publication bias and heterogeneity, this meta-analysis yielded evidence for adopting a multimodal approach.

rTMS appeared to be superior in combating the constellation of negative symptoms that affect functionality in patients with psychotic disorders. Although the meta-analysis did not include patients receiving atypical antipsychotics, rTMS along with an atypical antipsychotic may lead to enhanced symptom relief.

In the comparative efficacy analyses, newer medications, such as lurasidone and iloperidone, did not appear as effective as other, older drugs. This finding leaves a large gap for more effective drug development. Melatonin as an adjunctive treatment appears to be a cost-effective intervention to prevent metabolic adverse effects. Lastly, sodium nitroprusside as a glutamate–nitric oxide–cyclic guanosine monophosphate network modulator may emerge as a safe treatment with rap-id and long-lasting effects, which are certainly desirable for our psychotic patients. However, further research is needed before this find-ing can be translated into clinical application.


Dr Saeed is Professor and Chairman in the department of psychiatric medicine at the Brody School of Medicine at East Carolina University, Director of the ECU Center for Telepsychiatry and e-Behavioral Health as well as of the North Carolina Statewide Telepsychiatry Program (NC-STeP), and Chief of Psychiatry at the Vidant Medical Center in Greenville, NC. Dr Anand is an Assistant Professor in the department of psychiatry and behavioral medicine at the Brody School of Medicine.


1. Turner DT, van der Gaag M, Karyotaki E, Cuijpers P. Psychological interventions for psychosis: a meta-analysis of comparative outcome studies. Am J Psychiatry. 2014;171:523-538.

2. Shi C, Yu X, Cheung EF, et al. Revisiting the therapeutic effect of rTMS on negative symptoms in schizophrenia: a meta-analysis. Psychiatry Res. 2014;215:505-513.

3. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis [published correction appears in Lancet. 2013; 382:940]. Lancet. 2013;382:951-962.

4. Modabbernia A, Heidari P, Soleimani R, et al. Melatonin for prevention of metabolic side-effects of olanzapine in patients with first-episode schizophrenia: randomized double-blind placebo-controlled study. J Psychiatr Res. 2014;53:133-140.

5. Hallak JE, Maia-de-Oliveira JP, Abrao J, et al. Rapid improvement of acute schizophrenia symptoms after intravenous sodium nitroprusside: a randomized, double-blind, placebo-controlled trial. JAMA Psychiatry. 2013;70:668-676.