G. William MacEwan

Methamphetamine use: a comprehensive review of molecular, preclinical and clinical findings.

Methamphetamine (MA) is a highly addictive psychostimulant drug that principally affects the monoamine neurotransmitter systems of the brain and results in feelings of alertness, increased energy and euphoria. The drug is particularly popular with young adults, due to its wide availability, relatively low cost, and long duration of psychoactive effects. Extended use of MA is associated with many health problems that are not limited to the central nervous system, and contribute to increased morbidity and mortality in drug users. Numerous studies, using complementary techniques, have provided evidence that chronic MA use is associated with substantial neurotoxicity and cognitive impairment. These pathological effects of the drug, combined with the addictive properties of MA, contribute to a spectrum of psychosocial issues that include medical and legal problems, at-risk behaviors and high societal costs, such as public health consequences, loss of family support and housing instability. Treatment options include pharmacological, psychological or combination therapies. The present review summarizes the key findings in the literature spanning from molecular through to clinical effects.

Predictors and profiles of treatment non-adherence and engagement in services problems in early psychosis

Treatment adherence in early psychosis individuals is considered problematic. Some studies have tried to understand reasons for medication non-adherence in this population, though few have also considered engagement in services. We conducted a cross-sectional study with 118 early psychosis individuals, assessing multiple constructs (symptoms, insight, personality traits, alliance, childhood trauma, substance abuse, social functioning and sociodemographics) suggested in the literature as potentially linked to medication adherence or engagement in services. Forward Wald logistic regression suggested that more positive symptoms, having witnessed violence as a child and high agreeableness as a personality trait predicted poor medication adherence. Forward linear regression revealed that physical abuse as a child, lack of knowledge regarding consumer rights, difficulties in building an alliance, low neuroticism and high agreeableness predicted poor service engagement. Profiles of non-adherers or low service engagement were strongly linked to childhood trauma, and high agreeableness, as well as more severe symptoms and poor alliance. Males with histories of legal problems were also more prevalent in both groups. No significant differences were found for insight or substance abuse. Overall, individuals with early psychosis who adhered less to treatment in general could have issues with trusting authority and place more importance on peer acceptance. Results are presented in light of the existing literature and clinical implications are discussed.

The assessment of symptom severity and functional impairment with DSM-IV axis V.

OBJECTIVE The Global Assessment of Functioning scale (GAF) is included as axis V in the DSM-IV multiaxial diagnostic system. The GAF is simple to administer and routinely used in treatment planning and as a measure of program performance. The GAF assesses both symptom severity and functional impairment, but the resultant rating provides no information about the contribution of each of these domains. This study aimed to improve the clinical utility of the GAF by creating subscales. METHODS The authors divided the scale into its two principal domains: descriptors of social and occupational functioning (SOFAS) and descriptors of symptoms (GAF minus SOFAS descriptors). These and other measures of symptoms and functioning were used to assess 407 patients while acutely psychotic and again after treatment. RESULTS Symptom scores were of greater severity than functional impairment scores in most cases. Because of this, the GAF score tended to reflect symptom severity rather than functional impairment. The symptom rating was more strongly correlated with measures of positive symptoms, and the functional rating had higher associations with negative symptoms and functional impairment. Both scales were good indicators of clinical change. CONCLUSIONS Findings indicate that GAF ratings for patients with psychosis tend to reflect symptom severity rather than functional impairment. Splitting the GAF into two parts resulted in greater discrimination for this patient group yet retained ease of administration.

The Hotel Study: Multimorbidity in a Community Sample Living in Marginal Housing

OBJECTIVE The health of people living in marginal housing is not well characterized, particularly from the perspective of multimorbid illness. The authors investigated this population in a community sample. METHOD A prospective community sample (N=293) of adults living in single-room occupancy hotels was followed for a median of 23.7 months. Assessment included psychiatric and neurological evaluation, multimodal MRI, and viral testing. RESULTS Previous homelessness was described in 66.6% of participants. Fifteen deaths occurred during 552 person-years of follow-up. The standardized mortality ratio was 4.83 (95% CI=2.91-8.01). Substance dependence was ubiquitous (95.2%), with 61.7% injection drug use. Psychosis was the most common mental illness (47.4%). A neurological disorder was present in 45.8% of participants, with definite MRI findings in 28.0%. HIV serology was positive in 18.4% of participants, and hepatitis C virus serology in 70.3%. The median number of multimorbid illnesses (from a list of 12) was three. Burden of multimorbidity was significantly correlated with lower role functioning score. Comorbid addiction or physical illness significantly decreased the likelihood of treatment for psychosis but not the likelihood of treatment for opioid dependence or HIV disease. Participants who died during follow-up appeared to have profiles of multimorbidity similar to those of the overall sample. CONCLUSIONS This marginally housed cohort had greater than expected mortality and high levels of multimorbidity with adverse associations with role function and likelihood of treatment for psychosis. These findings may guide the development of effective health care delivery in the setting of marginal housing.

Regional cortical anatomy and clozapine response in refractory schizophrenia

Regional measures of cortical sulcal and ventricular enlargement on computed tomography scan were studied in a clinical sample of patients treated with clozapine. Cortical sulci were significantly enlarged in clozapine nonresponders compared to responders. The Clinical Global Impressions score at discharge was related to the size of the posterior frontal and lateral temporal sulci, with large sulci predicting a poorer response to clozapine treatment.

Effects of eight weeks of atypical antipsychotic treatment on middle frontal thickness in drug-naïve first-episode psychosis patients

Atypical antipsychotic medications generally maintain or increase gray matter amount and functioning. First-episode psychosis patients have lower gray matter volume in the middle frontal gyrus, as well as worse performance on spatial working memory tasks compared to controls. This study investigated the effects of short-term four- and eight-week atypical treatment on middle frontal thickness and spatial working memory in first-episode psychosis patients. Nineteen drug-naïve first-episode psychosis patients treated with risperidone or quetiapine and 26 controls completed structural magnetic resonance imaging, a spatial working memory task, and clinical assessment at three intervals (baseline, four weeks, and eight weeks; all patients and 23 controls completed all three assessments). Caudal and rostral middle frontal thicknesses were measured using the automated program Freesurfer. Positive, negative, and general symptoms of the Positive and Negative Syndrome Scale (PANSS) decreased significantly in patients, with most of the change occurring in the first four weeks of treatment. Patients demonstrated an increase in rostral middle frontal thickness over eight weeks of treatment compared to controls. There was a medium effect size relationship between reduction in negative symptoms at four and eight weeks, and a change in rostral middle frontal thickness over eight weeks. No changes were found in spatial working memory ability. Short-term atypical treatment with risperidone or quetiapine can increase prefrontal cortical thickness in psychosis. These findings are notable given the role of the rostral middle frontal region in cognition and the relationship between better cognitive functioning and better functional outcome in psychosis.

Conceptual and Methodological Issues in the Design of Clinical Trials of Antipsychotics for the Treatment of Schizophrenia

Schizophrenia is one of the most severe and disabling psychiatric disorders. Antipsychotic drugs offer considerable benefits in controlling symptoms and preventing relapse. The strategy for the present review of clinical trials was to ask ‘What are the features of schizophrenia and the existing treatments of the illness that have implications for future clinical trials’ ? Six key facts were identified.First, schizophrenia is genetically ‘complex’. Trials may benefit from designs including genetically related illnesses, by focussing on cross-cutting aspects of the phenotype such as psychosis or cognitive dysfunction, and by collecting information on possible moderators and mediators of treatment response.Second, schizophrenia affects multiple neurotransmitter systems. Mutiple signalling pathways may need to be considered, with different time courses of response. Outcome measures from clinical trials could be collected at more frequent intervals, particularly in the early phase of response.Third, the clinical features used to define the illness are a mix of symptoms and social-occupational dysfunction, yet treatment response is often defined only by changes in symptoms. Multiple measures of functioning need to be collected at baseline and at the endpoint of trials. Consensus definitions for response, remission, relapse, recovery and recurrence need to be developed.Fourth, schizophrenia is often highly disabling. Linking treatment response in clinical trials to measures of quality-adjusted life-years will allow comparison with other medical illnesses using common metrics.Fifth, the general health and care of individuals with schizophrenia is often poor. ‘Complex’ interventions, which include, but are not limited to, antipsychotic medications, need to be designed and tested for the problems facing these patients.Finally, large gaps exist between clinical trials, practice guidelines and patterns of practice. Trials need to be designed to investigate widely used approaches such as antipsychotic polypharmacy, where actual practice diverges from evidence-based guidelines.

Hippocampal volume and the brain-derived neurotrophic factor Val66Met polymorphism in first episode psychosis

INTRODUCTION Small hippocampi and impaired memory are common in patients with psychosis and brain-derived neurotrophic factor (BDNF) plays a critical role in hippocampal neuroplasticity and memory. A common BDNF allele (Val66Met) has been the focus of numerous studies but results from the few BDNF-imaging studies are complex and contradictory. The objective of this study was to determine the association between Val66Met and hippocampal volume in patients with first episode psychosis. Secondary analyses explored age-related associations and the relationship between Val66Met and memory. METHOD Hippocampal volume and BDNF genotyping were obtained for 58 patients with first-episode psychosis and 39 healthy volunteers. Patients were recruited from an early psychosis program serving a catchment-area population. RESULTS Hippocampal volume was significantly smaller in patients than controls (F(1,92)=4.03, p<0.05) and there was a significant group-by-allele interaction (F(1,92)=3.99, p<0.05). Hippocampal volume was significantly smaller in patients than controls who were Val-homozygotes but no group differences were found for Met carriers. Findings were not affected by diagnosis, antipsychotic medication, or age, and there was no change in hippocampal volume during a one-year follow-up. Val-homozygous patients had worse immediate and delayed memory than their Met counterparts. CONCLUSIONS Results suggest the effects of the BDNF Val66Met allele may be different in patients with psychosis than in healthy adults. Hippocampal volume in patient and control Met allele carriers was very similar suggesting that illness-related factors have minimal influence in this group. In contrast, Val homozygosity was related to smaller hippocampi and poorer memory functioning only in patients with psychosis.

Predictors of starting to smoke cigarettes in patients with first episode psychosis.

INTRODUCTION Cigarette smoking is common in psychotic disorders and may be initiated in an attempt to control features of illness. However, genetic, obstetric and early life conditions are risks for starting to smoke in the general population but their role in psychotic patients is unclear. METHOD Smoking history and the putative predictors of starting to smoke were assessed in a community-wide sample of 115 first episode psychosis patients. The proportion that initiated smoking was compared with that from population surveys and the impact of risk factors was assessed within the patient sample. RESULTS Most patients began smoking before illness onset and the proportion who initiated smoking was significantly high by the onset of a functional decline. Gestational tobacco exposure was a risk for smoking and was also associated with low birthweight, poor academic achievement, and obesity. Low familial socioeconomic position but not familial psychiatric problems also predicted smoking initiation. DISCUSSION In most cases, smoking preceded illness onset and was not a response to early features of illness. General population predictors of starting to smoke were also associated with smoking initiation in psychotic patients. Of these risks, exposure to tobacco during gestation is noteworthy in that it affects brain development and is associated with cognitive, behavioral, psychiatric and general health problems. In addition, nicotine interacts with other substances of abuse. The initiation of smoking before illness onset and the association with developmental problems raises the question of whether cigarette smoking influences some aspects of illness in patients with psychosis.

A randomized, double-blind, placebo-controlled study of the safety and tolerability of high-dose quetiapine in patients with persistent symptoms of schizophrenia or schizoaffective disorder.

OBJECTIVE Quetiapine is often prescribed at higher than approved doses. We investigated the safety, tolerability, and efficacy of quetiapine > 800 mg/d. METHOD A trial was carried out from October 2003-September 2005 in 19 referral centers. Patients with DSM-IV schizophrenia or schizoaffective disorder were randomized on the basis of persistent symptoms of moderate severity (< 30% improvement in total Positive and Negative Syndrome Scale score after ≥ 4 weeks of quetiapine). The 8 week, double-blind study compared continuation of quetiapine 800 mg/d (n = 43) versus 1,200 mg/d (n = 88). The primary outcome measure was emergent or worsening parkinsonism (Simpson-Angus Scale). Secondary outcomes were adverse events, metabolic side effects, and symptom severity. RESULTS Mean doses obtained were 799 mg/d and 1,144 mg/d in the 800-mg/d and > 800-mg/d groups, respectively. Emergent or deteriorating parkinsonism in the high-dose group was 3.1% greater (95% CI, -7.8% to 14.0%; P = .76) than in the 800-mg/d group, a value that was within the a priori limit of 16% defined as noninferiority. Both doses of quetiapine were safe and well tolerated. Weight gain was greater in the high-dose group (1.7 kg over 12 weeks; ≥ 7% body weight, n = 11 [12.5%]) versus the 800-mg/d group (1.1 kg over 12 weeks; ≥ 7% body weight, n = 4 [9.3%]). The mean adjusted difference in weight gain (1.3 kg) was greater in the high-dose group (95% CI, 0.0-2.5; P = .044). Symptom severity declined, with no significant difference between groups. CONCLUSIONS The results did not demonstrate any advantage for use of quetiapine outside the approved dose range. TRIAL REGISTRATION www.clinicaltrials.gov Identifier: NCT00328978.