Building capacity for collaborative research on opioid and other substance use disorders through the Clinical and Translational Science Award Program.

The opioid crisis in the USA requires immediate action through clinical and translational research. Already built network infrastructure through funding by the National Institute on Drug Abuse (NIDA) and National Center for Advancing Translational Sciences (NCATS) provides a major advantage to implement opioid-focused research which together could address this crisis. NIDA supports training grants and clinical trial networks; NCATS funds the Clinical and Translational Science Award (CTSA) Program with over 50 NCATS academic research hubs for regional clinical and translational research. Together, there is unique capacity for clinical research, bioinformatics, data science, community engagement, regulatory science, institutional partnerships, training and career development, and other key translational elements. The CTSA hubs provide unprecedented and timely response to local, regional, and national health crises to address research gaps [Clinical and Translational Science Awards Program, Center for Leading Innovation and Collaboration, Synergy paper request for applications]. This paper describes opportunities for collaborative opioid research at CTSA hubs and NIDA-NCATS opportunities that build capacity for best practices as this crisis evolves. Results of a Landscape Survey (among 63 hubs) are provided with descriptions of best practices and ideas for collaborations, with research conducted by hubs also involved in premier NIDA initiatives. Such collaborations could provide a rapid response to the opioid epidemic while advancing science in multiple disciplinary areas.

Treatment of schizophrenia and comorbid substance abuse: pharmacologic approaches.

Co-occurring substance use disorder is common among patients with schizophrenia, and its presence greatly worsens the course of schizophrenia. A number of theories have been introduced to explain the increased rate of substance use disorder in these patients. These theories include the notion that substance use could trigger psychotic symptoms in vulnerable individuals and the idea that the substances are used to self-medicate symptoms of schizophrenia. Our group and others have advanced a neurobiological hypothesis to explain this comorbidity-that a mesocorticolimbic brain reward circuit underlies the substance use disorder in patients with schizophrenia. Treatment of substance use disorder in these patients is best done with integrated treatment programs that combine psychosocial interventions with pharmacotherapy. Recent data suggest that the atypical antipsychotic clozapine and perhaps other atypical agents may lessen substance use in patients with schizophrenia. My colleagues and I have proposed that clozapine's effect in these patients may be related to its ability to decrease the brain reward circuit dysfunction. Research is continuing on the use of atypical antipsychotics in patients with schizophrenia and comorbid substance abuse. The adjunctive use of naltrexone or other agents also may be helpful. Further research on the optimal pharmacologic approach to patients with dual diagnosis is needed.

Antipsychotic drug effects on brain morphology in first-episode psychosis.

BACKGROUND: Pathomorphologic brain changes occurring as early as first-episode schizophrenia have been extensively described. Longitudinal studies have demonstrated that these changes may be progressive and associated with clinical outcome. This raises the possibility that antipsychotics might alter such pathomorphologic progression in early-stage schizophrenia. OBJECTIVE: To test a priori hypotheses that olanzapine-treated patients have less change over time in whole brain gray matter volumes and lateral ventricle volumes than haloperidol-treated patients and that gray matter and lateral ventricle volume changes are associated with changes in psychopathology and neurocognition. DESIGN: Longitudinal, randomized, controlled, multisite, double-blind study. Patients treated and followed up for up to 104 weeks. Neurocognitive and magnetic resonance imaging (MRI) assessments performed at weeks 0 (baseline), 12, 24, 52, and 104. Mixed-models analyses with time-dependent covariates evaluated treatment effects on MRI end points and explored relationships between MRI, psychopathologic, and neurocognitive outcomes. SETTING: Fourteen academic medical centers (United States, 11; Canada, 1; Netherlands, 1; England, 1). PARTICIPANTS: Patients with first-episode psychosis (DSM-IV) and healthy volunteers. INTERVENTIONS: Random allocation to a conventional antipsychotic, haloperidol (2-20 mg/d), or an atypical antipsychotic, olanzapine (5-20 mg/d). MAIN OUTCOME MEASURES: Brain volume changes assessed by MRI. RESULTS: Of 263 randomized patients, 161 had baseline and at least 1 postbaseline MRI evaluation. Haloperidol-treated patients exhibited significant decreases in gray matter volume, whereas olanzapine-treated patients did not. A matched sample of healthy volunteers (n = 58) examined contemporaneously showed no change in gray matter volume. CONCLUSIONS: Patients with first-episode psychosis exhibited a significant between-treatment difference in MRI volume changes. Haloperidol was associated with significant reductions in gray matter volume, whereas olanzapine was not. Post hoc analyses suggested that treatment effects on brain volume and psychopathology of schizophrenia may be associated. The differential treatment effects on brain morphology could be due to haloperidol-associated toxicity or greater therapeutic effects of olanzapine.

Clozapine reconstructed: Haloperidol's ability to reduce alcohol intake in the Syrian golden hamster can be enhanced through noradrenergic modulation by desipramine and idazoxan.

BACKGROUND: Alcohol use disorder commonly occurs in patients with schizophrenia. Most antipsychotic drugs do not lessen alcohol use; although the atypical antipsychotic clozapine has been shown to reduce alcohol use in patients with schizophrenia, its toxicity severely limits its use in patients. With an eye toward creation of a safer clozapine-like drug, we have investigated the pharmacological basis of the clozapine's effects on alcohol drinking in the Syrian golden hamster. In this animal, as in patients with schizophrenia, clozapine reduces alcohol drinking while the typical antipsychotic haloperidol does not. We have suggested that clozapine decreases alcohol drinking due to its weak dopamine D2 receptor blockade, its potent norepinephrine α-2 receptor antagonism, as well as its ability to elevate plasma norepinephrine. METHODS: We recreated a clozapine-like drug to reduce alcohol drinking in the Syrian golden hamster by combining low dose haloperidol with a norepinephrine α-2 receptor antagonist, idazoxan, and a norepinephrine reuptake inhibitor, desipramine. Hamsters were given free access to water and alcohol (15% v/v) and were treated daily with each drug or with the three-drug combination for 23 days. RESULTS: The drug combination reduced alcohol drinking and preference significantly as compared to vehicle or to haloperidol, idazoxan or desipramine, while not altering food-intake or body-weight. CONCLUSION: These findings suggest that that haloperidol, which does not reduce alcohol drinking in patients with schizophrenia or the hamster, if combined with idazoxan and desipramine (producing a drug combination that mimics aspects of clozapine's pharmacology) is able to reduce alcohol drinking in the hamster.

Treating tobacco use disorder in pregnant women in medication-assisted treatment for an opioid use disorder: a systematic review.

Smoking is associated with adverse effects on pregnancy and fetal development, yet 88-95% of pregnant women in medication-assisted treatment for an opioid use disorder smoke cigarettes. This review summarizes existing knowledge about smoking cessation treatments for pregnant women on buprenorphine or methadone, the two forms of medication-assisted treatment for opioid use disorder indicated for prenatal use. We performed a systematic review of the literature using indexed terms and key words to capture the concepts of smoking, pregnancy, and opioid substitution and found that only three studies met search criteria. Contingency management, an incentive based treatment, was the most promising intervention: 31% of participants achieved abstinence within the 12-week study period, compared to 0% in a non-contingent behavior incentive group and a group receiving usual care. Two studies of brief behavioral interventions resulted in reductions in smoking but not cessation. Given the growing number of pregnant women in medication-assisted treatment for an opioid use disorder and the negative consequences of smoking on pregnancy, further research is needed to develop and test effective cessation strategies for this group.

Longer time to antipsychotic treatment discontinuation for any cause is associated with better functional outcomes for patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder.

OBJECTIVE: Time to all-cause treatment discontinuation is considered a composite proxy measure of treatment efficacy, safety, and tolerability. Longer time to discontinuation of antipsychotic medication for any cause has been shown to be associated with greater symptom improvements in the treatment of schizophrenia. This study examines whether longer time to all-cause medication discontinuation is also linked to better functional outcomes. METHOD: Using pooled data from 4 randomized, double-blind antipsychotic trials of 24- to 28-weeks' duration, this study examined the association between time to all-cause treatment discontinuation and functional outcomes, as assessed by a disease-specific, clinician-rated measure (Quality of Life Scale [QLS]) and a generic, patient-reported measure (Medical Outcomes Study Short Form 36 [SF-36]). Patients in these trials had a DSM-IV diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder. This post hoc analysis used Pearson partial correlations to assess relationships between time to treatment discontinuation and changes in functional scores, adjusting for baseline scores. Repeated measures analyses were also conducted to compare post-baseline functional outcome change over time between completers and noncompleters. RESULTS: Longer time to all-cause treatment discontinuation was found to be significantly associated with greater improvements in all assessed functional domains (p < .05). Patients who completed their respective trials (46.8%, 761/1627) experienced significantly greater improvement in functional outcome measures (in 4 QLS domains and SF-36 mental health component summary score; all, p < .001) compared to patients who discontinued for any cause. In addition, greater symptom improvement was significantly associated with greater functional improvements in assessed domains. CONCLUSIONS: Findings from this post hoc analysis illustrate the importance of longer treatment duration with antipsychotics for improving functional outcomes in the treatment of patients with schizophrenia.

Pharmacotherapy for schizophrenia and co-occurring substance use disorders.

Research on the optimal pharmacotherapy for people with schizophrenia and co-occurring substance use disorders remains in its infancy. This report reviews existing data and provides an update on recent research. The confluence of findings is consistent with a model of a reward dysfunction inherent in the neuropathology of schizophrenia, leading to a heightened vulnerability of people with schizophrenia to substance use disorders. Studies indicate that patients with dual disorders have difficulty tolerating conventional antipsychotics, have higher rates of medication nonadherence, and have greater impulsivity and sensation seeking. Limited evidence suggests that clozapine treatment may be associated with reduced substance abuse, with weaker evidence suggesting that other novel antipsychotics may have similar, but potentially less potent, effects. Controlled trials to test the effects of these medications are underway. A number of recent studies indicate that bupropion can facilitate reduced tobacco smoking among patients with schizophrenia. The preferential use of novel antipsychotics, a lower threshold for prescription of clozapine, the use of bupropion for smoking cessation, careful monitoring of compliance, and possible use of other medications for substance use disorders when indicated are recommended in pharmacologic management for people with co-occurring substance use disorders and schizophrenia.

The history of community mental health treatment and rehabilitation for persons with severe mental illness.

The authors review the evolution of the treatments for persons with severe mental illnesses over the past 40 years in three areas: pharmacological and other somatic treatments, psychosomatic treatments, and rehabilitation. Current treatments are based on a much stronger evidence base, are more patient-centered, and are more likely to target autonomy and recovery.