Clozapine use in patients with schizophrenia and a comorbid substance use disorder: A systematic review

Lifetime prevalence of substance use disorders (SUD) in patients with schizophrenia is nearly 50%. Nicotine, alcohol, and cannabis are the substances most frequently used, with a high percentage of poly-substance users. There are few available data about pharmacological approaches in this population. Amongst antipsychotics, clozapine shows positive evidence in the literature. The aim of the present article is to provide systematic review on the efficacy of clozapine in SUD improvement in schizophrenic patients. PRISMA recommendations were followed (PROSPERO id: CRD42017059299). Five studies for nicotine use and nine studies for SUD (other than nicotine) were analyzed. Regarding nicotine use, results from randomized controlled trials (RCT) have found a decrease in nicotine use after 12 weeks of 200–600 mg/day clozapine, as compared with lower doses. In SUD improvement (other than nicotine), RCT have shown superiority of clozapine when compared with risperidone, in short-term studies (from 4 to 12 weeks) performed in cannabis users. In long-term studies (1 year), clozapine was equal to ziprasidone in reducing cannabis use and equal to treatment as usual in reducing alcohol use. We conclude that positive results on nicotine use are scarce and derived from studies with a low degree of evidence. Evidence of clozapine on SUD (other than nicotine) is stronger, especially when clozapine is compared with first generation antipsychotics in poly-substance users. When compared with second generation antipsychotics, clozapine was superior to risperidone but equal to olanzapine or ziprasidone in poly-substance and cannabis users.     

Olanzapine treatment for patients with schizophrenia and substance abuse

The objective of this study was to evaluate the efficacy and safety of olanzapine in patients with schizophrenia and comorbid substance abuse disorders. Thirty patients who met DSM-IV criteria for schizophrenia or schizoaffective disorder as well as criteria for substance abuse or substance dependence, were treated in a 12-month prospective, open-label trial of olanzapine. Patients were evaluated with multiple efficacy and safety measures at baseline and then monthly thereafter. Statistically significant improvement was noted in psychopathology, levels of hope, and safety measures. Seventy percent (n = 21) of the patients achieved early full substance abuse remission at the end of the study period, while 30% (n = 9) achieved early partial substance abuse remission. Our results indicate that olanzapine treatment improved psychopathology, increased hopefulness, and reduced antipsychotic-associated side effects. The benefits observed with olanzapine treatment may contribute to the patients’ substance abuse remission.     

Reasons for substance use and vulnerability factors in patients with substance use disorder and anxiety or mood disorders

This cross-sectional study examined the reasons for substance use and the presence of vulnerability factors such as substance sensitivity, sensation seeking, and symptoms related to the attention deficit hyperactivity disorder (ADHD) in patients with substance use disorder (SUD) and comorbid mood and anxiety disorders by using the Structured Clinical Interview for the Spectrum of Substance Use (SCI-SUBS), a novel instrument designed to explore the spectrum of substance use and its clinical correlates. Study participants included 61 patients with SUD and mood or anxiety disorder, and two comparison groups including 35 patients with SUD only and 50 controls not in treatment for mental disorders or SUD. We found that patients with co-morbid mood or anxiety disorder had significantly higher scores on the SCI-SUBS domains 'substance sensitivity' and 'self-medication' as compared to those with SUD only. Scores on 'sensation seeking' and 'ADHD' domains were similar between both groups of patients and higher than in controls. Patients with comorbid mood or anxiety disorders showed a higher sensitivity to substances and were more prone to self-medication than those with SUD only. These characteristics should be taken into account in the diagnostic assessment and in long-term treatment to decrease the risk of relapse.     

Dually diagnosed patients' responses to substance use disorder treatment

Few studies have investigated whether dually diagnosed patients with co-occurring substance use and psychiatric disorders (DD) respond as well to substance use disorder (SUD) treatments as patients with SUD do. Here we assessed whether male veteran DD and SUD patients with alcohol dependence diagnoses differed in the process and outcomes of residential SUD treatment. The main findings showed that (a) DD patients did not perceive SUD programs as positively as patients with SUD did and had worse proximal outcomes at discharge from treatment; (b) DD patients did as well as SUD patients on 1- and 5-year substance use outcomes but had worse psychiatric outcomes; and (c) patients who perceived treatment more positively and had better outcomes at discharge had better longer term outcomes. Thus, residential SUD programs are relatively effective in reducing DD patients' substance use problems; however, they are less successful in engaging DD patients in treatment and addressing their psychiatric problems.     

Naltrexone augmentation of neuroleptic treatment in alcohol abusing patients with schizophrenia

Objective Alcohol abuse in patients with schizophrenia is associated with psychiatric and social complications. While two medications have been approved by the Federal Drug Administration (FDA) for the treatment of alcoholism: disulfiram and naltrexone, no medications have been approved for individuals with alcohol dependence and comorbid schizophrenia. The purpose of this study was to evaluate the efficacy of naltrexone in alcohol-abusing schizophrenic patients.Method Thirty-one patients with schizophrenia and comorbid alcohol abuse or dependence were treated for 12 weeks in an outpatient study using naltrexone or placebo in a randomized, double-blind fashion in addition to their neuroleptic medication. Patients also participated in a weekly therapy using cognitive-behavioral drug relapse prevention strategies combined with skills training. Outcomes included drinking measured by the time line follow-back method, craving using the Tiffany Craving Questionnaire, psychotic symptoms using the Positive and Negative Symptoms Scale (PANSS), side effects and a measures of abnormal involuntary movements.Results There were no significant differences in treatment exposure or medication compliance between groups. Naltrexone treated patients had significantly fewer drinking days, heavy drinking days (>5 drinks) and reported less craving compared to the placebo treated patients. Naltrexone did not affect symptoms of schizophrenia, such as psychosis. The medication was well tolerated and there were no group differences in side effects.Conclusions These data suggest that naltrexone may be an effective medication for individuals with comorbid alcohol dependence and schizophrenia. Given the widespread problems associated with alcohol misuse in this population, and the lack of effective pharmacotherapies, these findings represent an exciting clinical development.An erratum to this article can be found at Preliminary results from this study were presented at the Society of Biological Psychiatry 57th Annual Scientific Convention, Philadelphia, Pa., USA in May 2002. The VA Naltrexone Study Collaboration Group: West Haven: Diana Congdon, Ned Cooney, Roberto Gil, Kathy Keegan, Debra Miles, Alison Oville, Barbara Peluse, Louis Trevisan; Northampton: Lynn Gordon, John Reino, Wayne Costello, Christopher Cryan; Bedford: Nitigna Desai, Marylee Losardo, Doreen Farrell, Barbara E. Rofman. W. Costello is deceased.     

Enhanced methamphetamine self-administration in a neurodevelopmental rat model of schizophrenia

RATIONALE: Substance abuse is more prevalent among patients with schizophrenia than in the general population. The considerable overlap in neurobiological disruptions thought to underlie each condition suggests that addictive behavior may represent a primary symptom of schizophrenia. OBJECTIVE: This study investigated drug-seeking in a neurodevelopmental animal model of schizophrenia, the neonatal ventral hippocampal lesion (NVHL) model. MATERIALS AND METHODS: At postnatal day 7, rats received an excitotoxic ventral hippocampus lesion or a sham procedure and were trained as adults to self-administer methamphetamine (0.1 mg/kg/infusion) or respond for natural reinforcement (water or food). RESULTS: NVHL rats were faster than shams to acquire the operant response for either drug self-administration or water reinforcement, suggesting that simple instrumental learning may be enhanced in these animals. NVHL and sham rats displayed no differences in fixed-ratio (FR) responding for either methamphetamine or food, and both groups of animals were equally sensitive to methamphetamine dose changes (0.05, 0.1, or 0.2 mg/kg/infusion). However, under a progressive-ratio (PR) schedule, NVHL animals reached significantly higher break points (NVHL 18 infusions; sham 12 infusions) for methamphetamine but not food reinforcement, suggesting enhanced motivation to acquire drug and/or elevated incentive value of the drug that did not generalize to another form of reinforcement. CONCLUSIONS: These data indicate that developmental disruption of the hippocampus elevates rats' vulnerability to drug-seeking behavior under PR conditions. Furthermore, drug self-administration in the NVHL animal emulates addictive behavior in schizophrenia, making this model useful for investigating the mechanisms of dual diagnosis, including the neurobiological and behavioral similarities between addiction and schizophrenia.     

Coping among military veterans with PTSD in substance use disorder treatment

We longitudinally investigated coping among male military veterans (n = 98) with posttraumatic stress disorder (PTSD) symptomatology and a co-occurring substance use disorder (SUD) who participated in a randomized controlled trial of seeking safety (SS). Participants were randomized to SS or intensive treatment-as-usual (TAU) for SUD. Coping (active, avoidant, emotional discharge), and PTSD and SUD symptomatology were measured prior to and at the end of treatment, and at 6- and 12-month follow-ups. Among the total sample, we found that: (a) avoidant and emotional discharge, but not active, coping tended to be positively associated with PTSD and SUD symptomatology at baseline; (b) active coping increased and avoidant and emotional discharge coping decreased during the 12-month time-period; and (c) avoidant and emotional discharge, but not active, coping longitudinally covaried with PTSD and SUD symptomatology. Results suggest the utility of targeting maladaptive coping in treatments for individuals with co-occurring PTSD and SUD.     

Accentuated behavioral sensitization to nicotine in the neonatal ventral hippocampal lesion model of schizophrenia

The prevalence of smoking in schizophrenia patients far exceeds that in the general population. Increased vulnerability to nicotine and other drug addictions in schizophrenia may reflect the impact of developmental limbic abnormalities on cortical-striatal mediation of behavioral changes associated with drug use. Rats with neonatal ventral hippocampal lesions (NVHLs), a neurodevelopmental model of schizophrenia, have previously been shown to exhibit altered patterns of behavioral sensitization to both cocaine and ethanol. This study explored nicotine sensitization in NVHLs by testing locomotor activity of NVHL vs. SHAM-operated controls over 3 weeks in response to nicotine (0.5 mg/kg) or saline injections (s.c.) followed by a nicotine challenge delivered to all rats 2 weeks later. At the beginning of the initial injection series, post-injection locomotor activation was indistinguishable among all treatment groups. However, nicotine but not saline injections produced a progressive sensitization effect that was greater in NVHLs compared to SHAMs. In the challenge session, rats with previous nicotine history showed enhanced locomotor activation to nicotine when compared to drug na?ve rats, with NVHL-nicotine rats showing the greatest degree of activity overall. These results demonstrate that NVHLs exhibit altered short- and long-term sensitization profiles to nicotine, similar to altered long-term sensitization profiles produced by cocaine and ethanol. Collectively, these findings suggest the neurodevelopmental underpinnings of schizophrenia produce enhanced behavioral sensitization to addictive drugs as an involuntary and progressive neurobehavioral process, independent of the acute psychoactive properties uniquely attributed to nicotine, cocaine, or alcohol.     

Pharmacological treatment of comorbid PTSD and substance use disorder: Recent progress

Previous research has identified a strong association between posttraumatic stress disorder (PTSD) and substance use disorder (SUD), necessitating the development of treatments that address both conditions. Some pharmacotherapies are effective for the treatment of PTSD and SUD alone, however; no medications have been proven to be effective for the combination of these conditions. We review the recent advances in pharmacological treatment of comorbid PTSD and SUD. A randomized clinical trial of sertraline, a serotonin reuptake inhibitor (SSRI), did not show overall efficacy for comorbid PTSD and alcohol dependence (AD), although it may have efficacy among light drinkers. Another clinical trial demonstrated the efficacy of both disulfiram and naltrexone for the treatment of AD in individuals with PTSD. A more recent clinical trial suggested that norepinephrine uptake inhibitors may also have efficacy for the treatment of comorbid PTSD and AD. In animal and preliminary human studies, brain norepinephrine and glutamate/GABA have emerged as potential treatment targets for comorbid PTSD and SUD. Noradrenergic medications that are promising for comorbid PTSD and SUD include prazosin, guanfacine, and atomoxetine. Promising glutamate/GABA medications include topiramate, memantine, acamprosate, N-acetylcysteine (NAC), and ketamine. The safety and efficacy of these medications for the treatment of PTSD and SUD need to be tested in controlled clinical trials.     

Pathological and problem gambling in substance use treatment: A systematic review and meta-analysis

Pathological and problem gambling refer to a class of disorders, including those meeting criteria for a psychiatric diagnosis (i.e., pathological gambling), and others comprising a spectrum of severity defined by significant personal and social harm (i.e., problem gambling), that may be common in substance use treatment but are frequently unrecognized. This paper presents a systematic review and meta-analysis of available evidence indicating the prevalence of such gambling disorders in substance use treatment. It provides weighted mean estimates from across studies of clinical samples of substance users, and suggests around 14% of patients that demonstrate comorbid pathological gambling. Around 23% suffer conditions along the broader spectrum of problem gambling. The review also highlights important limitations of existing evidence, including scant data on current versus lifetime comorbidity, as well as reliance on convenience samples and self-administered measures of gambling problems. Notwithstanding a concomitant need for caution when applying these results, the findings suggest a strong need to identify and manage gambling comorbidity in substance use treatment. Strategies for identification of gambling disorders, and therapies that may provide useful adjunctive interventions in substance use treatment are discussed.     

Personality risk profile for conduct disorder and substance use disorders in youth

The five factor model of personality is a useful metric to describe personality profiles associated with maladaptive functioning. Using the NEO-Five Factor Inventory (NEO-FFI), we examined a conceptually based profile of high neuroticism, low agreeableness and low conscientiousness among 243 youth (aged 13-18 years) with varying degrees of conduct disorder (CD) and substance use disorders (SUD). Comparisons of the NEO-FFI personality dimensions between CD/SUD youth and adolescent siblings (N=173), and relations between the personality dimensions and behavioral indicators of conduct disorder and substance involvement were examined. Youth with CD and SUD had greater neuroticism, lower agreeableness, and lower conscientiousness than siblings of a similar age. The NEO-FFI scales predicted aggression and substance involvement for both probands and siblings in this cross-sectional investigation. These findings support the role for personality in models of the etiology and persistence of conduct disorder and substance use disorders.     

Comorbid depression and substance use disorder: Longitudinal associations between symptoms in a controlled trial

This study examined the longitudinal association between substance use and depressive symptoms in veterans receiving outpatient treatment for comorbid substance use disorder and major depression. Veterans (N = 237, mean age = 48.2 years, 90% male, 70% Caucasian) received either 6 months of group integrated cognitive-behavioral therapy or twelve-step facilitation. Hamilton Depression Rating Scale scores and percent days using any substance were assessed every 3 months up to 1 year posttreatment. Greater substance use predicted time-varying elevations in depression above individual patterns of change in depression. Moreover, change in depressive symptoms was associated with change in both the likelihood of any substance use and the frequency of use during the treatment and follow-up periods. Changes in these symptoms appear to be linked, such that individuals with greater reductions in substance use have greater reductions in depressive symptoms (and vice versa).     

Service utilization during and after outpatient treatment for comorbid substance use disorder and depression

Patients with comorbid substance use disorder (SUD) and depression incur greater treatment costs than those with either disorder alone. Integrated treatment targeting both issues concurrently has been shown to reduce substance use and depression in this population, but little is known about the effects of such treatment on the utilization of costly health services. This study compared 18-month patterns of service utilization for 236 veterans with comorbid SUD depression randomly assigned to 6 months of either Integrated Cognitive Behavioral Therapy (ICBT) or Twelve-Step Facilitation Therapy. Treatment group differences were found for the utilization of psychotropic medication services and inpatient hospitalization. Higher rates of therapy attendance, lower baseline depression, and receiving ICBT all predicted shorter admissions for those hospitalized during treatment. Ethnicity and gender predicted medication service use both during and following treatment. The findings provide evidence supporting the long-term cost-effectiveness of integrated treatment for this high-risk population.     

Young adults with co-occurring disorders: substance use disorder treatment response and outcomes

Compared to other life stages, young adulthood (ages 18–24) is characterized by qualitative differences including the highest rates of co-occurring substance use and psychiatric disorders (COD). Little is known, however, regarding young adults' response to substance use disorder (SUD) treatment, especially those with COD. Greater knowledge in this area could inform and enhance the effectiveness and efficiency of SUD care for this patient population. The current study investigated differences between 141 COD and 159 SUD-only young adults attending psychiatrically-integrated residential SUD treatment on intake characteristics, during-treatment changes on clinical targets (e.g., coping skills; abstinence self-efficacy), and outcomes during the year post-discharge. Contrary to expectations, despite more severe clinical profiles at intake, COD patients showed similar during-treatment improvements on clinical target variables, and comparable post-treatment abstinence rates and psychiatric symptoms. Clinicians referring young adults with COD to specialized care may wish to consider residential SUD treatment programs that integrate evidence-based psychiatric services.     

Childhood and adolescent risk factors for comorbid depression and substance use disorders in adulthood

The comorbidity of major depression and substance use disorders is well documented. However, thorough understanding of prevalence and early risk factors for comorbidity in adulthood is lacking, particularly among urban African Americans. With data from the Woodlawn Study, which follows a community cohort of urban African Americans from ages 6 to 42, we identify the prevalence of comorbidity and childhood and adolescent risk factors of comorbid depression and substance use disorders, depression alone, and substance use disorders alone. Prevalence of comorbid substance use disorders and major depression in adulthood is 8.3% overall. Comorbidity in cohort men is twice that for women (11.1% vs. 5.7%). Adjusted multinomial regression models found few differences in risk factors for comorbidity compared to either major depression or a substance use disorder on its own. However, results do suggest distinct risk factors for depression without a substance use disorder in adulthood compared to a substance use disorder without depression in adulthood. In particular, low socioeconomic status and family conflict was related to increased risk of developing major depression in adulthood, while dropping out of high school was a statistically significant predictor of adult-onset substance use disorders. Early onset of marijuana use differentiated those with a substance use disorder with or without depression from those with depression without a substance use disorder in adjusted models. In conclusion, comorbid substance use disorders and depression are highly prevalent among these urban African Americans. Insight into the unique childhood and adolescent risk factors for depression compared to substance use disorders is critical to intervention development in urban communities. Results suggest that these programs must consider individual behaviors, as well as the early family dynamic.     

Screening for posttraumatic stress disorder in civilian substance use disorder patients: Cross-validation of the Jellinek-PTSD screening questionnaire

This study aimed to cross-validate earlier findings regarding the diagnostic efficiency of a modified version of the Primary Care Posttraumatic Stress Disorder (PC-PTSD) screening questionnaire (A. Prins, P. Ouimette, R. Kimerling, R. P. Cameron, D. S. Hugelshofer, J. Shaw-Hegwer, et al., 2004). The PC-PTSD is a four-item screening questionnaire for Posttraumatic Stress Disorder (PTSD). Based on former research, we adapted the PC-PTSD for use among civilian substance use disorder (SUD) patients (D. Van Dam, T. Ehring, E. Vedel, & P. M. G. Emmelkamp, 2010). This version will be referred to as the Jellinek-PTSD (J-PTSD) screening questionnaire. Results showed a high sensitivity (.87), specificity (.75), and overall efficiency (.77) of the J-PTSD in detecting PTSD when using a cutoff score of 2. This confirms findings in former research, and suggests that the J-PTSD is a useful screening instrument for PTSD within a civilian SUD population. Both PTSD and SUD are severe and disabling disorders causing great psychological distress. An early recognition of PTSD among SUD patients makes it possible to address PTSD symptoms in time, which may ultimately lead to an improvement of symptoms in this complex patient group.     

Intentions to quit smoking among youth in substance abuse treatment

Introduction

Smoking cessation interventions for adolescents in substance abuse treatment have shown promise. However, a better understanding of the correlates of substance use disordered (SUD) youths’ intentions toward smoking cessation will help tailor cessation interventions to this population. The current study examined tobacco use, smoking-related self-efficacy, substance use and intentions to quit using alcohol and illicit drugs as correlates of intentions to quit smoking among youth in SUD treatment.

Methods

Participants were 178 adolescents who were in inpatient (n = 90) or outpatient (n = 88) SUD treatment and had smoked at least once in the past 30 days. The sample was 44% female, 72% non-Hispanic Caucasian, with a mean age of 16.2 years (SD = 1.2). Participants rated the likelihood that they would be nonsmokers in the next year (9-point scale).

Results

SUD youth intention to quit smoking averaged 4.9 out of 10 (SD = 3.2), comparable to intention to quit drinking (M = 5.3, SD = 3.6), but lower than their intention to quit using drugs (M = 6.0, SD = 3.4). Teens’ intentions to quit smoking were associated with nicotine dependence (r = −.30, p < .01) and smoking cessation related self-efficacy (r = .36, p < .01), but not with pretreatment substance use severity (r = −.15). Controlling for nicotine dependence, teens’ intentions to quit smoking were positively related to smoking cessation self-efficacy (pr = .26, p < .01) and intention to quit using illicit drugs (pr = .15, p < .05), but unrelated to intention to quit drinking.

Discussion

Findings highlight the appropriateness of addressing adolescent tobacco use during SUD treatment, but emphasize the importance of assessing intention and other cognitions for each substance, as they may differ markedly.     

Emerging adult outcomes of adolescent psychiatric and substance use disorders

This study investigates the age 25 outcomes of late adolescent mental health and substance use disorders. A hierarchical cluster analysis of age 19 DSM-III-R mental health and substance diagnoses placed participants into one of 9 clusters: Anxious, Depressed, Antisocial, Drug Abuser, Problem Drinker, Anxious Drinker, Depressed Drug Abuser and Antisocial Drinker, and No Diagnosis. Diagnoses were generated from the University of Michigan Composite International Diagnostic Interview. Repeated measures multivariate analyses of variance revealed distinct trajectories of improvement and decline among the 9 clusters. Clusters with co-occurring substance and mental health disorders improved over adolescent levels, but continued to have higher levels of depression symptoms, poorer global functioning, and higher levels of substance use than the No Diagnosis cluster. Members of the The Problem Drinkers cluster, who tended to have alcohol use disorders only at age 19, did not differ from their peers with no diagnoses. Drug use disorders in adolescence, with or without a co-occurring mental health disorders, were associated with a poor prognosis in emerging adulthood. Clinical interventions should distinguish among these diverse clinical presentations.     

The DrugCheck Problem List: a new screen for substance use disorders in people with psychosis

Despite considerable recent interest in the issue of comorbid substance use disorders in people with serious mental illness, there remains a need to refine approaches to screening. This paper describes the development and testing of a new screen for substance-related comorbidity, the 12-item DrugCheck Problem List (PL). Exploratory factor analysis with inpatient samples suggested a single-factor structure, although confirmatory factor analysis in a further sample found similar fit from a two-factor model. Sensitivity and specificity in detecting DSM-IV substance use disorders were both high and comparable to performances of the Severity of Dependence Scale and Alcohol Use Disorders Identification Test (Australian version). The list of problem areas provided by the PL has utility in driving further assessment and treatment planning, and offers suggested foci for motivational interviewing. While further testing is indicated, these data provide strong initial support for its use.