Vivek Anand, MD

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.

Psychotherapy remains an important but underused modality with inconclusive relative differences. To examine the relative efficacy of psychotherapy for symptom improvement, a 

 of 48 randomized trials that included 3295 participants was conducted.

 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

 that included 342 patients with schizophrenia in 16 studies (3 open-label and 13 parallel sham-controlled) from 1998 to 2013.

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 

, which included 43,049 patients, was undertaken to determine the comparative usefulness of the antipsychotics for symptom reduction, discontinuation, and adverse effects.

 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 (

Melatonin for antipsychotic-induced metabolic adverse effects

Melatonin, commonly used as a sleep-promoting aid, was examined in a single-center, 

 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).

 involved 20 patients who were randomly assigned to sodium nitroprusside (0.5 µg/kg/min) or placebo infusion (5% glucose solution) over 4 hours.

 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.

 Turner DT, van der Gaag M, Karyotaki E, Cuijpers P. 

Psychological interventions for psychosis: a meta-analysis of comparative outcome studies

Revisiting the therapeutic effect of rTMS on negative symptoms in schizophrenia: a meta-analysis

 Leucht S, Cipriani A, Spineli L, et al. 

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

 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

 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

Articles

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. 

Research That Can Change Clinical Practice in Psychotic Disorders

[[{"type":"media","view_mode":"media_crop","fid":"23907","attributes":{"alt":"Top Research That May Change How You Treat Patients With Substance Use Disorders","class":"media-image media-image-right","id":"media_crop_6774306226148","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"3626","media_crop_rotate":"0","media_crop_scale_h":"139","media_crop_scale_w":"150","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]With the blizzard of clinical studies and ever-increasing pressure to stay current and evidence-based, the challenge to keep up with the ever-growing body of psychiatric literature is greater than ever. As clinical providers, we need help in sorting and evaluating the quality of information before we can apply it to clinical practice. Otherwise, when faced with information overload, the temptation is to take the most easily accessed, usually unappraised, biased information, which may lead to compromise in patient care.

We have identified and evaluated published research with findings that are ready for-and that have a direct bearing on-clinical practice. We used a 3-step process:

• Literature published July 2013 through June 2014 was searched for relevant study findings

• Psychiatric groups and colleagues were asked the following question: Of the research published July 1, 2013, through June 30, 2014, which had the most impact on the clinical practice of psychiatry?

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

Twenty papers were chosen on the basis of their clinical relevance, applicability, and quality.

Here we present, in the first of a series of brief articles, highlights from 4 studies and 1 review article.

Pharmacotherapy for alcohol use disorders

It is evident that alcohol use disorders (AUDs) are associated with considerable morbidity, mortality, and impaired quality of life. In a systematic review and meta-analysis to assess AUD treatments in an outpatient setting, the authors included 122 randomized controlled trials and 1 cohort study (N = 22,803).

 For all of the studies (reports published between 1970 and 2014), the duration of treatment was at least 12 weeks. Pooled analysis showed that oral acamprosate and naltrexone (50 mg/d) were the only FDA-approved treatments that were superior to placebo in preventing relapse.

The number needed to treat (NNT) to prevent return to any drinking was better for acamprosate than for naltrexone (12 vs 20, respectively); however, naltrexone was the superior treatment to prevent return to heavy drinking (NNT = 12). Both treatments also significantly decreased drinking days; naltrexone also reduced heavy drinking days and drinks per drinking day. Acamprosate and naltrexone did not differ on head-to-head comparison. Other effective treatments included naltrexone 100 mg/d for decreasing heavy drinking days; injectable naltrexone for reducing drinking days and heavy drinking days; nalmefene for reducing return to heavy drinking, heavy drinking days per month, and drinks per drinking day; valproic acid to prevent return to heavy drinking; and topiramate for decreasing drinking days, heavy drinking days, and drinks per drinking day. Acamprosate caused anxiety; naltrexone use led to dizziness and more GI adverse effects; topiramate was associated with neurological adverse effects; and there was a higher risk of withdrawal with naltrexone and nalmefene.

Given the mixed efficacy and underutilization of current FDA-approved treatments, development and examination of other drugs for AUDs is indicated. Gabapentin has lately been studied for AUDs. When used in association with alcohol consumption, gabapentin regulates neurotransmission, reduces cravings, and improves mood and sleep.

 undertook a 12-week, double blinded, 3-arm, parallel-group, placebo-controlled outpatient study. Treatment-seeking alcohol-dependent adults (N = 150) were randomized to placebo, 900 mg of gabapentin, or 1800 mg of gabapentin. Study participants also received 20-minute weekly manual-guided counseling to improve treatment adherence.

Alcohol use was assessed by timeline followback interview, drinking diary, weekly breathalyzer, monthly Î³-glutamyltransferase, and collateral information. This intent-to-treat analysis found that besides being well tolerated, gabapentin 1800 mg was the most effective treatment for abstinence (NNT = 8). It prevented heavy drinking (NNT = 5), and reduced heavy drinking days and drinks consumed per week. In addition, although the participants were minimally depressed at baseline, gabapentin 1800 mg showed statistically improved outcomes on mood, sleep, and craving measures.

Despite limitations such as higher heterogeneity, medium risk of bias among the studies in the meta-analysis

 along with attrition rate, and exclusion of comorbid substance use and psychiatric disorders in the gabapentin trial,

 these studies validated some already established treatments and provide insight into new ones.

Study findings highlight the importance of identification and use of effective tobacco cessation treatments among persons with mental illness. Two studies examined the effects of motivationally targeted treatment or maintenance of pharmacological treatment on tobacco consumption outcomes.

In the first study, 224 inpatients who were moderately nicotine-dependent smokers were randomized into either a smoking cessation intervention or usual care.

 Randomization was stratified by number of cigarettes smoked daily and state of change. The motivationally tailored intervention was initiated during inpatient stay and included an individually tailored computer-delivered program and tobacco cessation counseling as well as access to nicotine patches, support from an outpatient provider, and computer intervention post-hospitalization.

The study assessed biochemically verified 7-day point abstinence at follow-up and re-hospitalization rates during the 18-month period. Most study completers were in the contemplation stage of change and the retention rates were comparable in both groups. The abstinence rates were higher for the intervention group over 18 months (odds ratio [OR] = 3.15; 95% confidence interval [CI], 1.22 - 8.14). Psychiatric and substance use disorders did not predict abstinence at follow-up. More participants in usual care were hospitalized over the 18-month period (56% and 44%, respectively; OR = 1.92; 95% CI, 1.06 - 3.49). Abstinence status was not found to be associated with re-hospitalization, unlike other biopsychosocial variables.

Results from this study demonstrated that individually tailored, motivationally designed interventions along with nicotine replacement can lead to better rates of abstinence and fewer re-hospitalizations. This important finding may change practice, given that the abstinence rates have been found to decline considerably after discontinuation of pharmacological therapy.

In the double-blind, placebo-controlled second study, 87 patients who had achieved 2 weeks of continuous abstinence at week 12 on open treatment were randomized to cognitive-behavioral therapy (CBT) and varenicline (1 mg twice daily) or placebo.

 Patients continued treatment until week 52, after which treatment was discontinued; these patients were followed up to week 76. The outcome measures included 7-day continuous abstinence confirmed by exhaled carbon monoxide at week 52, biochemically confirmed continuous abstinence from weeks 12 through 64, and self-reported smoking behaviors until week 76. About 70% completed the relapse prevention phase (weeks 12 to 52).

The active-treatment group (varenicline and CBT) had tripling of 7-day continuous abstinence rates at week 52 (60% vs 19%; OR = 6.2; 95% CI, 2.2 - 19.2) and continuous abstinence from weeks 12 through 64 (45% vs 15%; OR = 4.6; 95% CI, 1.5 - 15.7). In addition, continuous abstinence as measured by patient self-report was higher in the active-treatment group (OR = 3.5; 95% CI, 1.02 - 13.6). Severity of psychiatric symptoms, overall health self-report, and nicotine withdrawal symptoms did not differ between groups. The active-treatment group had more headaches (P ≤ .05), less agitation or excitement (P ≤ .05), and fewer hospitalizations (risk ratio = 0.45; 95% CI, 0.04 - 2.9).

This study provides much-needed evidence for continuing maintenance combination treatment to achieve better tobacco cessation outcomes among psychiatric patients.

To help educate patients and their families in face of the ever-increasing acceptability of cannabis, Volkow and colleagues

 from the National Institute on Drug Abuse (NIDA) summarized the effect of heavy or long-term marijuana use. Adolescent exposure to tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, alters the sensitivity of the brain’s reward regions to other substances. Moreover, brain circuitry is impaired; there is increased risk of mental illness as well as respiratory and cardiovascular problems; and academic performance and quality of life decline while higher school dropout and delinquent behavior rates increase.

The researchers also raised concerns about a possible correlation between increasing THC content and higher number of emergency department visits and motor vehicle accidents. Since adolescent marijuana use has been shown to be inversely related to the perceived risk of marijuana, Volkow and colleagues

 also speculated about the negative impact of new age permissiveness and the dynamic socio-politico-legal changes regarding marijuana on adolescent and adult health outcomes.

These studies emphasize established treatments and also provide information about new therapies that may improve outcomes. In our opinion, naltrexone and acamprosate should be the first-line treatments along with psychosocial interventions in isolated or comorbid AUD, and gabapentin may be used as a second-line treatment in a primary care population.

Pharmacological agents in combination with psychosocial support beyond the acute treatment phase of tobacco cessation are well tolerated and reduce recidivism.

Given pop culture and ever-changing legality, marijuana use continues to be a challenge. The review article by researchers at the NIDA is essential to our understanding the adverse effects of cannabis use not only by the pediatric population but by adults as well.

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 and Dr Stanciu is a Second-Year Resident in the department of psychiatry and behavioral medicine at the Brody School of Medicine. The authors report no conflicts of interest concerning the subject matter of this article.

 Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. 

 Mason BJ, Quello S, Goodell V, et al. Gabapentin treatment for alcohol dependence: a randomized clinical trial. 

 Prochaska JJ, Hall SE, Delucchi K, Hall SM. Efficacy of initiating tobacco dependence treatment in inpatient psychiatry: a randomized controlled trial. 

 Evins AE, Cather C, Pratt SA, et al. Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder: a randomized clinical trial. 

 Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. 

The authors use a 3-step process to identify and evaluate published research with findings that are ready for-and that have a direct bearing on-clinical practice.