A Survey of Prescribers' Attitudes, Knowledge, Comfort, and Fear of Consequences Related to an Opioid Overdose Education and Naloxone Distribution Program.

CONTEXT: The alarming increase in opioid-related fatalities has placed the United States in the midst of an opioid epidemic. In an effort to reduce opioid-related fatalities, each Veterans Affairs (VA) hospital is responsible for development of an OEND (Overdose Education and Naloxone Distribution) program to enhance naloxone distribution. OBJECTIVE: To assess attitudes, knowledge, comfort level, and fear of consequences at the prescriber level related to the OEND program at VA Connecticut Healthcare System (VACHS). DESIGN: Anonymous surveys were administered to VACHS prescribers to assess attitude, knowledge, comfort level, and fear of consequences using a 5-point Likert scale. SETTING: VACHS. PARTICIPANTS: VACHS prescribers (primary care physicians/internists, psychiatrists, physician assistants/advanced practice registered nurses, pharmacists) in primary care/medicine, mental health, and substance use disorder (SUD). METHODS: Differences across 4 domains were analyzed using analysis of variance testing, and pairwise post hoc analysis was conducted using Tukey's HSD for all significant findings. Regression modeling was conducted to evaluate correlations between each group and survey responses. MAIN OUTCOME: Identify differences and potential barriers to program implementation across professions and practice specialty. RESULTS: While primary care/medicine, mental health, and SUD prescribers had positive attitudes toward dispensing naloxone, SUD clinicians reported being more comfortable, more knowledgeable, and less fearful of consequences. In general, psychiatrists reported to be more knowledgeable and comfortable prescribing naloxone. In addition, prescribers who received naloxone training reported themselves to be more comfortable, more knowledgeable, and less fearful of the consequences of dispensing naloxone. CONCLUSIONS: Results indicate that barriers to OEND implementation continue to exist, and not all clinicians or practice specialties at VACHS are comfortable with dispensing naloxone. A targeted approach to training health care clinicians may lead to increased acceptance of naloxone dispensing. Additional research is needed to elicit the best method of improved acceptance of naloxone to expand naloxone access.

Effects of the cannabinoid-1 receptor antagonist rimonabant on psychiatric symptoms in overweight people with schizophrenia: a randomized, double-blind, pilot study.

Weight gain is a major adverse effect of several second-generation antipsychotic medications. Rimonabant is a cannabinoid-1 receptor antagonist that promotes weight loss in the general population. We conducted a 16-week, double-blind, placebo-controlled study of rimonabant (20 mg/d) in people with schizophrenia or schizoaffective disorder, based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria, who were clinically stable on second-generation antipsychotics. Participants had a body mass index of 27 kg/m or higher with hyperlipidemia or body mass index of 30 kg/m or higher, and no current substance abuse/dependence (except nicotine), more than weekly cannabis use, or recent depressive symptoms/suicidality. An exercise and dietary counseling group was offered weekly. Target enrollment was 60; the trial was terminated early because of withdrawal of rimonabant from the European market. Fifteen participants were randomized (7 rimonabant, 8 placebo); 5 completed in each group. Rimonabant was associated with a greater reduction in Brief Psychiatric Rating Scale total score versus placebo (mean ± SE difference, -1.9 ± 0.8, P = 0.02), driven by differences in the Brief Psychiatric Rating Scale anxiety/depression (-1.4 ± 0.35, P = 0.0004) and hostility (-0.7 ± 0.3, P = 0.02) factors. Group differences were not significant for the Calgary Depression Scale total score (P = 0.24), Scale for the Assessment of Negative Symptoms total score (P = 0.13), weight, blood pressure, or fasting lipids or glucose. Rimonabant was well tolerated with no significant adverse events. No significant weight loss, metabolic effects, or adverse psychiatric effects were associated with the cannabinoid-1 receptor antagonist rimonabant in this small sample of people with schizophrenia. The endocannabinoid system remains a promising target for pharmacotherapy of schizophrenia and obesity.

Nonresponse to clozapine and premorbid functioning in treatment of refractory schizophrenia.

INTRODUCTION: It is recognized that early treatment can improve outcomes and generally improve recovery potential for those with schizophrenia. Data suggest that poor premorbid functioning has been found to be related to more severe symptoms and poor antipsychotic response; however, little is known about premorbid functioning in patients who have no response to clozapine treatment. METHODS: This study compares the premorbid functioning among patients who responded to clozapine treatment (20% decrease in total Brief Psychiatric Rating Scale [BPRS] score; n = 35) and those who did not respond (n = 50) to 8 weeks of clozapine treatment. Premorbid functioning was assessed using the Cannon-Spoor Premorbid Adjustment Scale. RESULTS: Patients who did not respond to clozapine had significantly lower total BPRS scores (P = .01) at baseline, driven primarily by lower ratings in hostility (P = .007) and activation (P = .02), compared with those who responded to clozapine. Responders and nonresponders did not differ in their age, race, level of education, marital status, age of onset, characterization of the deficit syndrome, and positive or negative symptoms. Nonresponders to clozapine did not improve in any area of symptoms or global functioning, whereas there were significant improvements in BPRS total scores (analysis of covariance) and all symptom domains in the responder groups (P < .0001). Level of functioning scores in those who responded to clozapine was significantly higher at end point (P = .02). As for premorbid functioning, there were no differences in scores between responders and nonresponders at the time of early and late adolescence; however, there was a trend toward lower premorbid functioning in the clozapine nonresponders on most childhood measures (before the age of 11 years). Clozapine nonresponders tended to be less social and more withdrawn as compared with those who responded to clozapine (P = .08), as well as tended to have poorer adaptation to school (P = .06) and fewer peer relationships (P = .08). These results did not reach significance. Work and/or school performance changed more insidiously in the nonresponders group before illness onset (P = .045). DISCUSSION: Clozapine is beneficial to many patients with treatment-resistant symptoms; however, nonresponse to this medication may represent a subtype of patients who may present differently with symptoms. These findings should encourage further examination of early childhood indicators and opportunities for appropriate and effective intervention.

Lack of beneficial galantamine effect for smoking behavior: a double-blind randomized trial in people with schizophrenia.

Cigarette smoking is in schizophrenia is prevalent and may be due to self-medicating attempts to improve cognitive deficits related to alpha7 and alpha4beta2 nicotinic receptor dysregulation. Galantamine is an acetylcholinesterase inhibitor that acts as a positive allosteric modulator of nicotine acetylcholine receptors including both the alpha4beta2 and alpha7 subunits. In a double-blind randomized clinical trial galantamine was compared to placebo for its effects on cognitive functioning in people with schizophrenia. This manuscript reports findings for galantamine's effect on smoking behavior in people from this 12-week trial who were smokers (18 galantamine, 25 placebo). Expired CO was measured every 2 weeks and the Fagerström Test for Nicotine Dependence (FTND) was administered at baseline and endpoint. Expired CO measures in galantamine subjects were 23.0+/-9.7 ppm and 21.1+/-10.3 ppm at baseline and Week 12, respectively, compared to 20.1+/-8.5 ppm and 21.0+/-10.3 ppm at baseline and Week 12 in placebo subjects. The mean tau-b correlation between expired CO level and visit was -0.05+/-0.41 in the galantamine group and 0.13+/-0.42 in the placebo group (F=0.73, df=1,38, p=0.40), suggesting that there were no trends toward increased or decreased smoking in either group. Mean FTND scores in the galantamine group were 4.9+/-2.5 at baseline and 5.2+/-2.2 at Week 12, compared to 4.1+/-2.6 at baseline and 3.7+/-2.6 at Week 12 in the placebo group (Mantel-Haenszel chi2=5.53, df=1, p=0.019), for an effect size of 0.4. These results suggest that galantamine has no effect on cigarette smoking and that during galantamine treatment nicotine dependency scores worsen.

Feasibility of reducing the duration of placebo-controlled trials in schizophrenia research.

Use of placebo-controlled trials in medical and psychiatric research has been controversial, although a consensus is emerging about conditions under which placebo-controlled trials are ethical. In schizophrenia research, the paradigm of slow onset of antipsychotic effects has led to a model in which placebo-controlled trials of 6-8 weeks duration have been used to demonstrate efficacy. Recent evidence that the largest symptom reductions are typically seen in the first weeks of treatment suggests that shorter placebo-controlled studies to demonstrate antipsychotic efficacy are possible. In a pilot study of the feasibility of shortening placebo-controlled studies, we reanalyzed data from placebo-controlled registry trials of olanzapine and risperidone and found that trials as short as 4 weeks could have similar power to longer term 6-8 week studies, given the estimated time course of treatment effects. Although fuller evaluation is required, the results suggest future antipsychotic trials could be shortened from 6-8 weeks to 3-4 weeks with a relatively low increase in sample size requirements. Shortening placebo-controlled trials would reduce patient burden and ethical objections to prolonged administration of placebo and reduce potential bias due to high dropout rates in longer clinical trials.

Clinical and Preclinical Evidence for Functional Interactions of Cannabidiol and Δ9-Tetrahydrocannabinol.

The plant Cannabis sativa, commonly called cannabis or marijuana, has been used for its psychotropic and mind-altering side effects for millennia. There has been growing attention in recent years on its potential therapeutic efficacy as municipalities and legislative bodies in the United States, Canada, and other countries grapple with enacting policy to facilitate the use of cannabis or its constituents for medical purposes. There are >550 chemical compounds and >100 phytocannabinoids isolated from cannabis, including Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is thought to produce the main psychoactive effects of cannabis, while CBD does not appear to have similar effects. Studies conflict as to whether CBD attenuates or exacerbates the behavioral and cognitive effects of THC. This includes effects of CBD on THC-induced anxiety, psychosis, and cognitive deficits. In this article, we review the available evidence on the pharmacology and behavioral interactions of THC and CBD from preclinical and human studies, particularly with reference to anxiety and psychosis-like symptoms. Both THC and CBD, as well as other cannabinoid molecules, are currently being evaluated for medicinal purposes, separately and in combination. Future cannabis-related policy decisions should include consideration of scientific findings, including the individual and interactive effects of CBD and THC.

The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo controlled trial.

RATIONALE: Preliminary evidence suggests that cannabidiol (CBD) may be effective in the treatment of neurodegenerative disorders; however, CBD has never been evaluated for the treatment of cognitive impairments associated with schizophrenia (CIAS). OBJECTIVE: This study compared the cognitive, symptomatic, and side effects of CBD versus placebo in a clinical trial. METHODS: This study was a 6-week, randomized, placebo-controlled, parallel group, fixed-dose study of oral CBD (600 mg/day) or placebo augmentation in 36 stable antipsychotic-treated patients diagnosed with chronic schizophrenia. All subjects completed the MATRICS Consensus Cognitive Battery (MCCB) at baseline and at end of 6 weeks of treatment. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and biweekly. RESULTS: There was no main effect of time or drug on MCCB Composite score, but a significant drug × time effect was observed (p = 0.02). Post hoc analyses revealed that only placebo-treated subjects improved over time (p = 0.03). There was a significant decrease in PANSS Total scores over time (p < 0. 0001) but there was no significant drug × time interaction (p = 0.18). Side effects were similar between CBD and placebo, with the one exception being sedation, which was more prevalent in the CBD group. CONCLUSIONS: At the dose studied, CBD augmentation was not associated with an improvement in MCCB or PANSS scores in stable antipsychotic-treated outpatients with schizophrenia. Overall, CBD was well tolerated with no worsening of mood, suicidality, or movement side effects. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00588731.

Minimal effects of prolonged smoking abstinence or resumption on cognitive performance challenge the "self-medication" hypothesis in schizophrenia.

One prominent, long-standing view is that individuals with schizophrenia smoke cigarettes more than the general population to "self-medicate" cognitive deficits and other symptoms. This study tested the self-medication hypothesis by examining the effects of smoking abstinence and resumption on cognition in patients with schizophrenia. Nicotine-dependent smokers with schizophrenia (n=26) were trained on a cognitive battery and then hospitalized to achieve and maintain confirmed abstinence from smoking for ~1 week. Cognition was tested while smoking as usual (baseline), one day after smoking cessation (early abstinence), ~1 week later (extended abstinence), and within ~3 weeks of resuming smoking (resumption). The test battery included measures of processing speed, attention, conflict resolution, verbal memory, working memory, verbal fluency, and executive function to evaluate multiple cognitive domains affected by schizophrenia. Positive and negative symptoms of schizophrenia, depressive symptoms, and dyskinesia were also measured at baseline and after prolonged abstinence. There were no significant changes in global cognitive test performance with smoking cessation, abstinence, or resumption. There were small decreases in a measure of processing speed and delayed verbal recall with abstinence, but these findings failed to survive adjustments for multiple comparisons. Surprisingly, in this within subject "On-Off-Off-On" design, there were no significant effects of early or prolonged abstinence from smoking on cognitive and behavioral measures in smokers with schizophrenia. The results of this study challenge the widely held "self-medication" hypothesis of smoking and schizophrenia, question the extent of pro-cognitive effects of smoking and nicotine in schizophrenia, and support encouraging smoking cessation in schizophrenia.

The dose-dependent psychomotor effects of intravenous delta-9-tetrahydrocannabinol (Δ9-THC) in humans.

BACKGROUND: Binding studies have demonstrated that levels of the cannabinoid receptor type-1 are highest in the basal ganglia and cerebellum, two areas critical for motor control. However, no studies have systematically examined the dose-related effects of intravenous delta-9-tetrahydrocannabinol, the primary cannabinoid receptor type-1 partial agonist in cannabis, on broad domains of psychomotor function in humans. AIMS: Therefore, three domains of psychomotor function were assessed in former cannabis users (cannabis abstinent for a minimum of three months; n=23) in a three test-day, within-subject, double-blind, randomized, cross-over, and counterbalanced study during which they received intravenous delta-9-tetrahydrocannabinol (placebo, 0.015 mg/kg, and 0.03 mg/kg). METHODS: Gross motor function was assessed via the Cambridge Neuropsychological Test Automated Battery Motor Screening Task, fine motor control via the Lafayette Instrument Grooved Pegboard task, and motor timing via a Paced Finger-Tapping Task. In addition, the Cambridge Neuropsychological Test Automated Battery Rapid Visual Processing Task was utilized to determine whether delta-9-tetrahydrocannabinol-induced motor deficits were confounded by disruptions in sustained attention. RESULTS/OUTCOMES: Delta-9-tetrahydrocannabinol resulted in robust dose-dependent deficits in fine motor control (Grooved Pegboard Task) and motor timing (Paced Finger-Tapping Task), while gross motor performance (Motor Screening Task) and sustained attention (Rapid Visual Processing Task) were unimpaired. Interestingly, despite the observed dose-dependent increases in motor impairment and blood levels of delta-9-tetrahydrocannabinol, subjects reported similar levels of intoxication in the two drug conditions. CONCLUSIONS/INTERPRETATION: These data suggest that while several domains of motor function are disrupted by delta-9-tetrahydrocannabinol, subjective feelings of intoxication are dissociable from cannabinoid-induced psychomotor effects. Results are discussed in terms of the potential neural mechanisms of delta-9-tetrahydrocannabinol in motor structures.

The Overdose Education and Naloxone Distribution Program at a VA Hospital.

A pilot program was developed to distribute naloxone kits, educate patients on opioid use risks, and reduce the number of overdose deaths.

Going up in smoke? A review of nAChRs-based treatment strategies for improving cognition in schizophrenia.

Cognitive impairment is known to be a core deficit in schizophrenia. Existing treatments for schizophrenia have limited efficacy against cognitive impairment. The ubiquitous use of nicotine in this population is thought to reflect an attempt by patients to selfmedicate certain symptoms associated with the illness. Concurrently there is evidence that nicotinic receptors that have lower affinity for nicotine are more important in cognition. Therefore, a number of medications that target nicotinic acetylcholine receptors (nAChRs) have been tested or are in development. In this article we summarize the clinical evidence of nAChRs dysfunction in schizophrenia and review clinical studies testing either nicotine or nicotinic medications for the treatment of cognitive impairment in schizophrenia. Some evidence suggests beneficial effects of nAChRs based treatments for the attentional deficits associated with schizophrenia. Standardized cognitive test batteries have failed to capture consistent improvements from drugs acting at nAChRs. However, more proximal measures of brain function, such as ERPs relevant to information processing impairments in schizophrenia, have shown some benefit. Further work is necessary to conclude that nAChRs based treatments are of clinical utility in the treatment of cognitive deficits of schizophrenia.

Cannabis withdrawal in chronic cannabis users with schizophrenia.

BACKGROUND: Chronic users of cannabis often report withdrawal symptoms after abstinence from use, but little is known about cannabis withdrawal in people with schizophrenia. METHODS: Cannabis use patterns and withdrawal symptoms in adults with schizophrenia who had at least weekly cannabis use before attempting to quit without formal treatment were assessed with the Marijuana Quit Questionnaire (MJQQ), a 176-item, semi-structured questionnaire. RESULTS: 120 participants, predominantly African-American (62.5%) and male (76.7%), met inclusion criteria. 20.1% reported that their first regular cannabis use (median age 15 years [range 8-48]) preceded their age at first psychotic symptoms (20 [4-50] years). Twenty (16.7%) participants met lifetime criteria for cannabis abuse; 98 (81.7%) met surrogate criteria for lifetime cannabis dependence. Withdrawal symptoms were reported by 113 (94.2%) participants, with 74.2% reporting ≥4 symptoms. The most frequently reported withdrawal symptoms were craving for cannabis (59.2%), feeling anxious (52.57%), feeling bored (47.5%), feeling sad or depressed (45.8%), feeling irritable or jumpy (45.0%), feeling restless (43.3%), and trouble failing asleep (33.3%). One hundred-and-four (92.0%) participants took some action to relieve at least one of their withdrawal symptoms during their index-quit attempt, including 26 (23.0%) participants who reported resuming cannabis use. CONCLUSION: Cannabis withdrawal is a clinically significant feature of cannabis use among people with schizophrenia, may serve as a negative reinforcer for relapse, and deserves greater attention in treatment and research. Clinical Trials registration NCT00679016.

Diagnostic criteria for cannabis withdrawal syndrome.

OBJECTIVE: Cannabis withdrawal occurs in frequent users who quit, but there are no accepted diagnostic criteria for a cannabis withdrawal syndrome (CWS). This study evaluated diagnostic criteria for CWS proposed in DSM-V and two earlier proposals. METHOD: A convenience sample of 384 adult, non-treatment-seeking lifetime cannabis smokers provided retrospective self-report data on their "most difficult" quit attempt without formal treatment, which was used in this secondary analysis. Prevalence, time of onset, and peak intensity (5-point Likert scale) for 39 withdrawal symptoms (drawn from the literature) were assessed via computer-administered questionnaire. Subject groups were compared using chi-square or ANOVA. Symptom clustering was evaluated with principal components analysis. RESULTS: 40.9% of subjects met the DSM-V criterion of ≥3 symptoms from a list of 7. There were no associations with sex, race, or type of cannabis preparation used. There were significant positive associations between duration or frequency of cannabis use prior to the quit attempt and experiencing CWS. Subjects with CWS had a significantly shorter duration of abstinence. Alternative syndromal criteria (dropping physical symptoms from DSM-V list; requiring ≥2 or ≥4 symptoms from a list of 11) yielded a similar prevalence of CWS and similar associations with prior cannabis use and relapse. The PCA yielded 12 factors, including some symptom clusters not included in DSM-V. CONCLUSIONS: Findings support the concurrent and predictive validity of the proposed DSM-V CWS, but suggest that the list of withdrawal symptoms and number required for diagnosis warrant further evaluation.

Rimonabant for neurocognition in schizophrenia: a 16-week double blind randomized placebo controlled trial.

OBJECTIVE: To examine the effect of rimonabant on neurocognitive impairments in people with schizophrenia. METHODS: Participants entered a 16-week double-blind, placebo-controlled, randomized clinical trial. A neurocognitive battery was administered at baseline and end of study. RESULTS: In comparison to rimonabant (20mg/day), placebo-treated participants exhibited a significant improvement on the Repeatable Battery for the Assessment of Neuropsychological Status total score. In contrast, rimonabant was associated with significant improvement on a probabilistic learning task. There were no other significant treatment effects. CONCLUSIONS: Rimonabant did not improve global cognitive functioning, but did improve a specific learning deficit based on response to positive feedback.

Cigarette smoking and mortality risk in people with schizophrenia.

This study examined effects of cigarette smoking on mortality risk in 1213 persons aged 19-69 years with schizophrenia-related psychotic disorders admitted to State of Maryland Hospitals between 1994 and 2000. Inpatient medical records from 7 hospitals were reviewed to obtain demographic information, diagnosis, medication use, as well as smoking and other substance use. Social Security Death Index data were used to identify deaths in the study group between 1994 and 2004. Death records were reviewed to obtain manner of death and underlying disorders. Of the 1213, 55% were smokers and 71% abused substances. There was an age × smoking interaction (χ(2) = 14.6, df = 1, P = .0001) for mortality, with estimated hazard ratios (HRs) for smokers vs nonsmokers of 2.1 among 35- to 54-year olds and HR of 0.7 among those aged 55-69 years. Five- and 10-year mortality rates for smokers aged 35-54 years were 7.0% and 14.2%, compared with 3.3% and 10.0% for nonsmokers, respectively (χ(2) = 5.53, df = 1, P = .019). Cardiac causes were identified in 43% of deaths in smokers but only 19% of deaths in nonsmokers (P < .006). For those aged 35-54 years, the odds of cardiac related death was increased by 12 fold in smokers relative to nonsmokers (HR = 12.4, χ(2) = 12.0, df = 1, P = .0005). Among people aged 35-54 years, those smoking greater than one pack daily have a significantly increased total mortality risk (HR = 2.7) vs nonsmokers. Cigarette smoking, particularly in people aged 35-54 years, contributes to an increased risk of death. Greater smoking severity significantly increases this risk. Smoking cessation in people with schizophrenia deserves significant attention.

The role of antihistaminic effects in the misuse of quetiapine: a case report and review of the literature.

Recent case reports and case series suggest that the atypical antipsychotic quetiapine has the potential for misuse. This includes drug-seeking behaviors motivated by quetiapine as well as inappropriate (intranasal or intravenous) administration. We present an additional case of quetiapine misuse and review other published cases. In general, quetiapine misuse is associated with prior CNS depressant use and is more common in forensic settings. The mechanism of reinforcement for this misuse is unknown, but we hypothesize that it is related to quetiapine's pharmacological profile as an antihistamine with a relative low affinity for dopamine receptors. The risks to individuals and society of exaggerating/simulating symptoms to obtain high-dose quetiapine in the absence of a clinical indication are discussed. This includes the unwelcome possibility of restricting access to this effective medication.

Cannabis withdrawal symptoms in non-treatment-seeking adult cannabis smokers.

BACKGROUND: Cannabis withdrawal is not recognized in DSM-IV because of doubts about its clinical significance. OBJECTIVES: Assess the phenomenon of cannabis withdrawal and its relationship to relapse in non-treatment-seeking adults. SUBJECTS: Convenience sample of 469 adult cannabis smokers who had made a quit attempt while not in a controlled environment. METHODS: Subjects completed a 176-item Marijuana Quit Questionnaire collecting information on sociodemographic characteristics, cannabis use history, and their "most difficult" cannabis quit attempt. RESULTS: 42.4% of subjects had experienced a lifetime withdrawal syndrome, of whom 70.4% reported using cannabis in response to withdrawal. During the index quit attempt, 95.5% of subjects reported > or =1 individual withdrawal symptom (mean [SD] 9.5 [6.1], median 9.0); 43.1% reported > or =10. Number of withdrawal symptoms was significantly associated with greater frequency and amount of cannabis use, but symptoms occurred even in those using less than weekly. Symptoms were usually of > or = moderate intensity and often prompted actions to relieve them. Alcohol (41.5%) and tobacco (48.2%) were used more often than cannabis (33.3%) for this purpose. There was little change during withdrawal in use of other legal or illegal substances. CONCLUSIONS: Cannabis withdrawal is a common syndrome among adults not seeking treatment. The intention to relieve withdrawal symptoms can drive relapse during quit attempts, giving cannabis withdrawal clinical significance as a target of treatment.

The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements.

In light of the large number of studies published since the 2004 update of Schizophrenia Patient Outcomes Research Team psychopharmacological treatment recommendations, we conducted an extensive literature review to determine whether the current psychopharmacological treatment recommendations required revision and whether there was sufficient evidence to warrant new treatment recommendations for prespecified outcomes of interest. We reviewed over 400 articles, which resulted in 16 treatment recommendations: the revision of 11 previous treatment recommendations and 5 new treatment recommendations. Three previous treatment recommendations were eliminated. There were 13 interventions and/or outcomes for which there was insufficient evidence for a treatment recommendation, and a statement was written to summarize the current level of evidence and identify important gaps in our knowledge that need to be addressed. In general, there was considerable consensus among the Psychopharmacology Evidence Review Group and the expert consultants. Two major areas of contention concerned whether there was sufficient evidence to recommend specific dosage ranges for the acute and maintenance treatment of first-episode and multi-episode schizophrenia and to endorse the practice of switching antipsychotics for the treatment of antipsychotic-related weight gain. Finally, there continue to be major gaps in our knowledge, including limited information on (1) the use of adjunctive pharmacological agents for the treatment of persistent positive symptoms or other symptom domains of psychopathology, including anxiety, cognitive impairments, depressive symptoms, and persistent negative symptoms and (2) the treatment of co-occurring substance or medical disorders that occur frequently in individuals with schizophrenia.