Effect of long-acting injectable antipsychotics on 1-year hospitalization in bipolar disorder: a mirror-image study.

Long-acting injectable (LAI) antipsychotics are often used for the long-term management also of bipolar disorder (BD). Nonetheless, evidence on their effect on pragmatic outcomes such as hospitalization risk in BD is inconsistent. We carried out a mirror-image study comparing rates and number of days of hospitalization, one year before and after the initiation of LAI treatment, in a sample of subjects with BD. Participants were selected from the STAR Network Depot Study, a pragmatic, observational, multicenter research involving a cohort of inpatients and outpatients consecutively started on LAI treatment. Variations in rates and in total number of days of hospitalization between the 12 months before and those after treatment initiation were analyzed. Among 461 individuals screened for eligibility, we included 71 adults with BD, initiated either on first- (FGA) or second-generation (SGA) LAIs. We found a significant decrease in terms of 12-month hospitalization rates (p < 0.001) and number of days (p < 0.001) after LAI initiation, without any effect by age, gender, alcohol/substance use disorders, and symptom severity. Subgroup analyses based on antipsychotic class, history of LAI treatment, and concomitant oral medications, confirmed the decreasing trend on both hospitalization rates and number of days. However, these reductions were not significant among participants who continued this treatment for less than 6 months. Comprehensively, this study supports the role of LAIs as effective maintenance treatment options for BD. Further research is needed to identify clinical characteristics of people with BD who would most benefit from long-acting formulations of antipsychotics.

Therapeutic Interventions to Mitigate Mitochondrial Dysfunction and Oxidative Stress-Induced Damage in Patients with Bipolar Disorder.

Bipolar disorder (BD) is characterized by mood changes, including recurrent manic, hypomanic, and depressive episodes, which may involve mixed symptoms. Despite the progress in neurobiological research, the pathophysiology of BD has not been extensively described to date. Progress in the understanding of the neurobiology driving BD could help facilitate the discovery of therapeutic targets and biomarkers for its early detection. Oxidative stress (OS), which damages biomolecules and causes mitochondrial and dopamine system dysfunctions, is a persistent finding in patients with BD. Inflammation and immune dysfunction might also play a role in BD pathophysiology. Specific nutrient supplements (nutraceuticals) may target neurobiological pathways suggested to be perturbed in BD, such as inflammation, mitochondrial dysfunction, and OS. Consequently, nutraceuticals may be used in the adjunctive treatment of BD. This paper summarizes the possible roles of OS, mitochondrial dysfunction, and immune system dysregulation in the onset of BD. It then discusses OS-mitigating strategies that may serve as therapeutic interventions for BD. It also analyzes the relationship between diet and BD as well as the use of nutritional interventions in the treatment of BD. In addition, it addresses the use of lithium therapy; novel antipsychotic agents, including clozapine, olanzapine, risperidone, cariprazine, and quetiapine; and anti-inflammatory agents to treat BD. Furthermore, it reviews the efficacy of the most used therapies for BD, such as cognitive-behavioral therapy, bright light therapy, imagery-focused cognitive therapy, and electroconvulsive therapy. A better understanding of the roles of OS, mitochondrial dysfunction, and inflammation in the pathogenesis of bipolar disorder, along with a stronger elucidation of the therapeutic functions of antioxidants, antipsychotics, anti-inflammatory agents, lithium therapy, and light therapies, may lead to improved strategies for the treatment and prevention of bipolar disorder.

Demographic and clinical variables associated with response to clozapine in schizophrenia: a systematic review and meta-analysis.

Clozapine is the only licensed pharmacotherapy for treatment-resistant schizophrenia. However, response to clozapine is variable. Understanding the demographic and clinical features associated with response to clozapine may be useful for patient stratification for clinical trials or for identifying patients for earlier initiation of clozapine. We systematically reviewed the literature to investigate clinical and demographic factors associated with variation in clozapine response in treatment-resistant patients with schizophrenia spectrum disorders. Subsequently, we performed a random-effects meta-analysis to evaluate differences in duration of illness, age at clozapine initiation, age of illness onset, body weight and years of education between clozapine responders and non-responders. Thirty-one articles were eligible for qualitative review and 17 of these were quantitatively reviewed. Shorter duration of illness, later illness onset, younger age at clozapine initiation, fewer hospitalisations and fewer antipsychotic trials prior to clozapine initiation showed a trend to be significantly associated with a better response to clozapine. Meta-analysis of seven studies, totalling 313 subjects, found that clozapine responders had a significantly shorter duration of illness compared to clozapine non-responders [g = 0.31; 95% confidence interval (CI) 0.06-0.56; p = 0.01]. The results imply that a delay in clozapine treatment may result in a poorer response and that a focus on prompt treatment with clozapine is warranted.

Beyond Dopamine Receptor Antagonism: New Targets for Schizophrenia Treatment and Prevention.

Treatment of schizophrenia (SCZ) historically relies on the use of antipsychotic drugs to treat psychosis, with all of the currently available antipsychotics acting through the antagonism of dopamine D2 receptors. Although antipsychotics reduce psychotic symptoms in many patients, they induce numerous undesirable effects and are not effective against negative and cognitive symptoms. These highlight the need to develop new drugs to treat SCZ. An advanced understanding of the circuitry of SCZ has pointed to pathological origins in the excitation/inhibition balance in regions such as the hippocampus, and restoring function in this region, particularly as a means to compensate for parvalbumin (PV) interneuron loss and resultant hippocampal hyperactivity, may be a more efficacious approach to relieve a broad range of SCZ symptoms. Other targets, such as cholinergic receptors and the trace amine-associated receptor 1 (TAAR1), have also shown some promise for the treatment of SCZ. Importantly, assessing efficacy of novel compounds must take into consideration treatment history of the patient, as preclinical studies suggest prior antipsychotic treatment may interfere with the efficacy of these novel agents. However, while novel therapeutic targets may be more effective in treating SCZ, a more effective approach would be to prevent the transition to SCZ in susceptible individuals. A focus on stress, which has been shown to be a predisposing factor in risk for SCZ, is a possible avenue that has shown promise in preclinical studies. Therefore, therapeutic approaches based on our current understanding of the circuitry of SCZ and its etiology are likely to enable development of more effective therapeutic interventions for this complex disorder.

The Benefits of Olanzapine in Palliating Symptoms.

OPINION STATEMENT: Olanzapine has become a major drug in the management of chemotherapy-induced nausea and vomiting as a prophylactic agent. In addition, a recent randomized trial has demonstrated its benefits in treating nausea and vomiting associated with advanced cancer. The added benefit to olanzapine is that it also stimulates appetite. As a result, since it treats multiple symptoms associated with advanced cancer, it is likely to become the antiemetic of choice in palliative care at least in the USA. The added benefit of treating insomnia and the avoidance of benzodiazepines should place olanzapine in at the top of the list of drugs to use for patients who do complain of insomnia. There is no good evidence that it potentiates the respiratory depression of opioids unlike benzodiazepines. The evidence is weak that olanzapine in as an adjuvant analgesic. Hopefully, future trials will explore this in greater depth. The benefits of adding olanzapine to potent opioids are that it may reduce craving, drug cues, and opioid misuse. Other symptoms like anxiety and depression may be addressed by the addition of olanzapine to standard antidepressants.

The Potential for Kratom as an Antidepressant and Antipsychotic.

Mitragyna speciosa, otherwise known as kratom, is a plant in the coffee family (Rubiaceae) native to Southeast Asia and Thailand whose leaves have been shown to cause opioid-like and stimulant responses upon ingestion. The major pharmacologically active compounds present in kratom, mitragynine and 7-hydroxymitragynine (7-HMG), are both indole alkaloids and are responsible for its opioid-like activity. While kratom is most commonly known for its affinity for mu-opioid receptors, research has shown one of its active components has effects on the same receptors to which some antipsychotics bind, such as D2 dopamine, serotonin (5-HT2C and 5-HT7), and alpha-2 adrenergic receptors displaying possible indications of kratom to be used as both antipsychotics and antidepressants. Although studies to evaluate this effect are still lacking, several online and in-person surveys note relief of depression and anxiety symptoms among those who consume kratom products, and in fact identify it as a common reason for consumption. This then highlights the dire need for further research to be conducted on kratom, its mechanism of action and the constituents that elicit these antidepressant, anxiolytic, and antipsychotic properties.

Brain volume changes over the first year of treatment in schizophrenia: relationships to antipsychotic treatment.

BACKGROUND: Progressive brain volume reductions have been described in schizophrenia, and an association with antipsychotic exposure has been reported. METHODS: We compared percentage changes in grey and white matter volume from baseline to month 12 in 23 previously antipsychotic-naïve patients with a first episode of schizophrenia or schizophreniform disorder who were treated with the lowest effective dose of flupenthixol decanoate depot formulation, with 53 matched healthy individuals. Total antipsychotic dose was precisely calculated and its relationship with brain volume changes investigated. Relationships between volumetric changes and treatment were further investigated in terms of treatment response (changes in psychopathology and functionality) and treatment-related adverse-events (extrapyramidal symptoms and weight gain). RESULTS: Excessive cortical volume reductions were observed in patients [-4.6 (6.6)%] v. controls [-1.12 (4.0)%] (p = 0.009), with no significant group differences for changes in subcortical grey matter and white matter volumes. In a multiple regression model, the only significant predictor of cortical volume change was total antipsychotic dose received (p = 0.04). Cortical volume change was not significantly associated with the changes in psychopathology, functionality, extrapyramidal symptoms and body mass index or age, gender and duration of untreated psychosis. CONCLUSIONS: Brain volume reductions associated with antipsychotic treatment are not restricted to poor outcome patients and occur even with the lowest effective dose of antipsychotic. The lack of an association with poor treatment response or treatment-related adverse effects counts against cortical volume reductions reflecting neurotoxicity, at least in the short term. On the other hand, the volume reductions were not linked to the therapeutic benefits of antipsychotics.

Clozapine Safety and Efficacy for Interictal Psychotic Disorder in Pharmacoresistant Epilepsy.

Since the middle of the 19th century, both neurologists and psychiatrists have linked psychosis and epilepsy. Clozapine, the most effective antipsychotic drug, alters electroencephalographic activity and carries a significant risk of causing seizures. Unfortunately, this risk limits the drug's potential use in treating pharmacoresistant psychosis in patients with epilepsy. We present a unique case in which we used clozapine successfully as a last resort treatment for chronic interictal psychosis in a 43-year-old woman with severe pharmacoresistant epilepsy and recurrent status epilepticus. Her psychotic symptoms improved markedly without an increase in the frequency of seizures despite gradual titration of the clozapine dose up to 300 mg daily. Her response demonstrates that, properly monitored, clozapine can be an effective treatment for psychosis even in patients with daily seizures.

Long-acting injectable antipsychotics for prevention and management of violent behaviour in psychotic patients.

BACKGROUND AND AIMS: It has been well established that long-term antipsychotic treatment prevents relapse, lowers number of rehospitalisations, and also effectively reduces violent behaviour. Although violent behaviour is not a typical manifestation of schizophrenia or other psychotic disorders, the diagnosis of psychosis increases the overall risk of violence. One of the few modifiable factors of violence risk is adherence with medication. In contrast, non-adherence with drug treatment and subsequent relapse increases risk of violent acts. Non-adherence can be addressed partially by long-acting injectable antipsychotics (LAI). The aim of our review was to examine the role of antipsychotic drugs, especially LAI, in prevention and management of violent behaviour in psychosis. METHODS: This is a non-systematic, narrative review of the data from open, naturalistic, retrospective, and population studies, case series, and post hoc analyses of randomised controlled trials. Search of electronic databases (PubMed, Embase) was performed to identify relevant papers. RESULTS: Nine published papers (3 cross-sectional chart reviews, 4 retrospective studies, 2 prospective, randomised trials) were found. The results indicated positive clinical and antiaggressive effects of LAI in psychotic patients with high risk of violent behaviour. DISCUSSION: Reviewed evidence suggests that secured drug treatment with LAI may have clinical benefit in schizophrenia patients with high risk of violent behaviour. LAI significantly reduced the severity of hostility, aggressivity, number of violent incidents, and criminal offences. These findings are supported further by the empirical evidence from clinical practice, high rates of prescribed LAI to schizophrenia patients in high-security and forensic psychiatric facilities. CONCLUSIONS: Available data encourage the use of LAI in forensic psychiatry, especially during court-ordered commitment treatment.

Raising the standard of care in the treatment of schizophrenia: Yes we can!

OBJECTIVE: In response to evidence of deteriorating outcomes of people with schizophrenia we recently published a critical review in the journal concerning why outcomes for schizophrenia are not improving. A published commentary on our review raised criticisms that we aim to address herein. METHOD: Published data related to four issues raised in the commentary were reviewed. RESULTS: There is a body of evidence that supports the possibility of dramatic improvements in treatment effectiveness, presented in our critical review, and these can be achieved within existing financial resources and present day understanding of the pathophysiology of schizophrenia. However, the commentary leads us to highlight four current obstacles to improving treatment effectiveness: (1) the belief of many psychiatrists that long-term antipsychotic medication raises the cardiovascular mortality rate in schizophrenia when the opposite is almost certainly the case; (2) the need to improve psychiatrist training in diagnostic and communication skills, especially with first episode presentations; (3) the requirement for comprehensive and structured assessment of the highly prevalent deficits in insight and decision making capacity associated with schizophrenia; and (4) the need for improved intervention design to minimise the impact of these deficits on treatment choice and refusal. CONCLUSION: With a sense of professional urgency, a genuinely respectful and caring partnership between clinicians, affected individuals and their families, and researchers, with relative little innovation, we conclude that the standard of care can definitely be raised now in the treatment of schizophrenia.

Should psychiatrists be more cautious about the long-term prophylactic use of antipsychotics?

Patients who recover from an acute episode of psychosis are frequently prescribed prophylactic antipsychotics for many years, especially if they are diagnosed as having schizophrenia. However, there is a dearth of evidence concerning the long-term effectiveness of this practice, and growing concern over the cumulative effects of antipsychotics on physical health and brain structure. Although controversy remains concerning some of the data, the wise psychiatrist should regularly review the benefit to each patient of continuing prophylactic antipsychotics against the risk of side-effects and loss of effectiveness through the development of supersensitivity of the dopamine D2 receptor. Psychiatrists should work with their patients to slowly reduce the antipsychotic to the lowest dose that prevents the return of distressing symptoms. Up to 40% of those whose psychosis remits after a first episode should be able to achieve a good outcome in the long term either with no antipsychotic medication or with a very low dose.

Effectiveness of Risperidone Augmentation in Obsessive-Compulsive Disorder: Experience From a Specialty Clinic in India.

Risperidone is the most widely used augmenting agent in the treatment of obsessive-compulsive disorder (OCD). However, a recent controlled study found risperidone to be no different from placebo, raising doubts about its effectiveness. In this context, we sought to examine the real-world effectiveness of risperidone from the large database of an OCD clinic in India. A total of 1314 consecutive patients who registered at the OCD clinic between 2004 and 2014 were evaluated with structured interviews and scales. Patients with OCD initiated on risperidone augmentation without concurrent cognitive behavior therapy and who were on stable and adequate doses of serotonin reuptake inhibitors for at least 12 preceding weeks were included for analysis. The primary outcome measure was all-cause discontinuation. Logistic regression was performed to identify the factors predicting improvement with risperidone augmentation. A total of 92 patients were eligible for analysis. Risperidone continued to be used in 23 patients (25%) at the time of last follow-up, and the remaining discontinued either because of ineffectiveness or intolerability. The fall in the Yale-Brown Obsessive-Compulsive Scale scores was significantly greater in patients who continued to take risperidone when compared with those who did not (41.6% vs 3.7%, t = 6.95, P < 0.001). A total of 22 patients (24%) were noted to have at least a 25% reduction on the Yale-Brown Obsessive-Compulsive Scale scores. On regression analysis, no predictors of improvement with risperidone augmentation could be identified. The study demonstrated, in a real-world setting, that risperidone may be a useful augmenting agent in a proportion of patients with partial/poor response to serotonin reuptake inhibitors.

Different mechanisms of risperidone result in improved interpersonal trust, social engagement and cooperative behavior in patients with schizophrenia compared to trifluoperazine.

AIM: Atypical antipsychotic treatment (e.g. risperidone) has been found to improve social functioning more than standard antipsychotic treatment. However, it is unclear which specific social behaviors are implicated in this improvement. The current study employed an interactive puzzle game to examine how social behaviors contribute to the improvement of social functioning by comparing patients receiving risperidone with those receiving trifluoperazine. METHODS: Scores on the Positive and Negative Syndrome Scale, executive functioning, and social functioning were obtained from 24 patients with schizophrenia receiving either risperidone (n = 12) or trifluoperazine (n = 12), before their social behavior was measured in the interactive Tangrams Game. Immediately after the Tangrams Game, participants filled in two questionnaires measuring their interpersonal trust and rejection toward their game partner. RESULTS: Patients receiving risperidone showed more social engagement, cooperative behavior and interpersonal trust toward their game partners than those receiving trifluoperazine. Additional multivariate analysis of variance revealed that lower affiliative behavior was a function of positive symptoms; interpersonal trust had an impact on social engagement but executive functioning did not explain lower interpersonal trust or social disengagement. CONCLUSION: Improvement of social competence by risperidone might be related to the enhancement of both social behaviors and interpersonal trust as well as better symptom resolution.

Aripiprazole adjunct treatment in bipolar I or II disorder, depressed state: a 2-year clinical study.

The symptomatic course of bipolar disorder (BPD) is chronic and dominated by depression. As recurrence rates are high, maintenance therapy is required. Although efficacious, mood stabilizers may be hampered by poor adherence, and second-generation antipsychotic medications may be associated with weight gain and metabolic abnormalities. There is evidence to suggest that aripiprazole is beneficial in major depressive disorder and BPD with depression. We therefore investigated 2-year clinical outcomes with aripiprazole adjunct therapy at 5 to 15 mg once daily alongside a mood stabilizer in 40 patients with BPD. All patients experienced marked improvements in Montgomery-Åsberg Depression Rating Scale scores by 6 weeks and substantial reductions in Clinical Global Impressions Scale scores by 6 months. All patients were able to return to optimal or premorbid functioning by 6 months to 1 year. By 1 year, all patients made a complete functional recovery on the Sheehan Disability Scale. Improvements were maintained on all measures up to 2 years. There were minimal adverse events, all of which decreased during therapy. Our findings indicate that aripiprazole adjunct treatment is safe and effective as an acute and maintenance therapy for BPD. However, the findings will need to be replicated by larger studies.

Is it time to call it quits on low-dose quetiapine?

The mandate of the Centers for Medicare & Medicaid Services to decrease the use of antipsychotics in long-term care facilities requires creative solutions. Low-dose quetiapine is used for a multitude of behavioral disorders and sleep problems in the nursing facility population. Yet, at doses of 25 mg per day or less, it doesn't have strong affinity (if any) for the dopamine-2 (D2) receptor, but it does maintain affinity for the histamine-1 and alpha-1 receptors. This begs the question: If it's not antagonizing the D2 receptor, could the use of something with similar receptor-affinity produce the same result, allowing discontinuation of the antipsychotic altogether? Using knowledge of receptor affinities and the pharmacologic action of low-dose quetiapine, consultant pharmacists may have one additional tool in their armamentarium of fighting inappropriate antipsychotic use.

Prevention of First-Episode Psychosis in People at Clinical High Risk: A Randomized Controlled, Multicentre Trial Comparing Cognitive-Behavioral Therapy and Clinical Management Plus Low-Dose Aripiprazole or Placebo (PREVENT).

BACKGROUND: There is limited knowledge of whether cognitive-behavioral therapy (CBT) or second-generation antipsychotics (SGAs) should be recommended as the first-line treatment in individuals at clinical high risk for psychosis (CHRp). HYPOTHESIS: To examine whether individual treatment arms are superior to placebo and whether CBT is non-inferior to SGAs in preventing psychosis over 12 months of treatment. STUDY DESIGN: PREVENT was a blinded, 3-armed, randomized controlled trial comparing CBT to clinical management plus aripiprazole (CM + ARI) or plus placebo (CM + PLC) at 11 CHRp services. The primary outcome was transition to psychosis at 12 months. Analyses were by intention-to-treat. STUDY RESULTS: Two hundred eighty CHRp individuals were randomized: 129 in CBT, 96 in CM + ARI, and 55 in CM + PLC. In week 52, 21 patients in CBT, 19 in CM + ARI, and 7 in CM + PLC had transitioned to psychosis, with no significant differences between treatment arms (P = .342). Psychopathology and psychosocial functioning levels improved in all treatment arms, with no significant differences. CONCLUSIONS: The analysis of the primary outcome transition to psychosis at 12 months and secondary outcomes symptoms and functioning did not demonstrate significant advantages of the active treatments over placebo. The conclusion is that within this trial, neither low-dose aripiprazole nor CBT offered additional benefits over clinical management and placebo.

Questioning the 'neuroprotective' hypothesis: does drug treatment prevent brain damage in early psychosis or schizophrenia?

The idea that psychotic disorders are characterised by progressive neurodegeneration that can be reversed by drug treatment is used to justify early treatment of increasing numbers of mostly young people. I argue that there is little evidence to support the view that old- or new-generation antipsychotics are 'neuroprotective', and some evidence that the drugs themselves may be responsible for the decline in brain matter observed in some studies.

Pharmacological agents for developmental stuttering in children and adolescents: a systematic review.

Stuttering affects approximately 5% of children up to the teenage years. There are many possible forms of intervention, one of which is pharmacotherapy. No review about the treatment of stuttering with pharmacological agents in children and adolescents has been undertaken. The objectives of this review were to determine the extent of previous research in this area and to assess the success of pharmacological agents in reducing the frequency of disfluency in child and adolescent stutterers (<18 years). A systematic search of MEDLINE, PsychInfo, Embase, and Cochrane Systematic Review databases was carried out to identify potential studies for the review. Studies that met specified criteria were selected for detailed examination, and the quality of evidence they provided was assessed according to 7 criteria that pertained to study design and data provision. Seven publications met the inclusion criteria for the review. Only 1 publication was classified as strong evidence quality, and this reported that clonidine did not reduce the frequency of disfluency in a group of 25 individuals who stuttered. All further publications were classified as either very low or low evidence quality. The agents examined were risperidone, olanzapine, clonidine, tiapride, haloperidol, and chlorpromazine.

Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis.

CONTEXT: Atypical antipsychotic medications are commonly used for off-label conditions such as agitation in dementia, anxiety, and obsessive-compulsive disorder. OBJECTIVE: To perform a systematic review on the efficacy and safety of atypical antipsychotic medications for use in conditions lacking approval for labeling and marketing by the US Food and Drug Administration. DATA SOURCES AND STUDY SELECTION: Relevant studies published in the English language were identified by searches of 6 databases (PubMed, EMBASE, CINAHL, PsycInfo, Cochrane DARE, and CENTRAL) from inception through May 2011. Controlled trials comparing an atypical antipsychotic medication (risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, asenapine, iloperidone, or paliperidone) with placebo, another atypical antipsychotic medication, or other pharmacotherapy for adult off-label conditions were included. Observational studies with sample sizes of greater than 1000 patients were included to assess adverse events. DATA EXTRACTION: Independent article review and study quality assessment by 2 investigators. DATA SYNTHESIS: Of 12 228 citations identified, 162 contributed data to the efficacy review. Among 14 placebo-controlled trials of elderly patients with dementia reporting a total global outcome score that includes symptoms such as psychosis, mood alterations, and aggression, small but statistically significant effects sizes ranging from 0.12 and 0.20 were observed for aripiprazole, olanzapine, and risperidone. For generalized anxiety disorder, a pooled analysis of 3 trials showed that quetiapine was associated with a 26% greater likelihood of a favorable response (defined as at least 50% improvement on the Hamilton Anxiety Scale) compared with placebo. For obsessive-compulsive disorder, risperidone was associated with a 3.9-fold greater likelihood of a favorable response (defined as a 25% improvement on the Yale-Brown Obsessive Compulsive Scale) compared with placebo. In elderly patients, adverse events included an increased risk of death (number needed to harm [NNH] = 87), stroke (NNH = 53 for risperidone), extrapyramidal symptoms (NNH = 10 for olanzapine; NNH = 20 for risperidone), and urinary tract symptoms (NNH range = 16-36). In nonelderly adults, adverse events included weight gain (particularly with olanzapine), fatigue, sedation, akathisia (for aripiprazole), and extrapyramidal symptoms. CONCLUSIONS: Benefits and harms vary among atypical antipsychotic medications for off-label use. For global behavioral symptom scores associated with dementia in elderly patients, small but statistically significant benefits were observed for aripiprazole, olanzapine, and risperidone. Quetiapine was associated with benefits in the treatment of generalized anxiety disorder, and risperidone was associated with benefits in the treatment of obsessive-compulsive disorder; however, adverse events were common.