Associations of premorbid adjustment with type and timing of childhood trauma in first-episode schizophrenia spectrum disorders.

BACKGROUND: Childhood trauma may contribute to poorer premorbid social and academic adjustment which may be a risk factor for schizophrenia. AIM: We explored the relationship between premorbid adjustment and childhood trauma, timing of childhood trauma's moderating role as well as the association of clinical and treatment-related confounders with premorbid adjustment. SETTING: We conducted a secondary analysis in 111 patients with first-episode schizophrenia (FES) disorders that formed part of two parent studies, EONKCS study (n =73) and the Shared Roots study (n =38). METHODS: Type of childhood trauma was assessed with the Childhood Trauma Questionnaire, short-form and premorbid adjustment using the Premorbid Adjustment Scale. Timing of childhood trauma was assessed using the Life Events Checklist and life events timeline. Linear regression analyses were used to assess the moderating effect of timing of childhood trauma. Clinical and treatment-related confounders were entered into sequential hierarchical regression models to identify independent predictors of premorbid adjustment across key life stages. RESULTS: Childhood physical neglect was associated with poorer premorbid academic functioning during childhood and early adolescence, and poorer premorbid social functioning during early and late adolescence. By hierarchical regression modelling (r 2 = 0.13), higher physical neglect subscale scores (p = 0.011) independently predicted poorer premorbid social adjustment during early adolescence. Timing of childhood trauma did not moderate the relationship between childhood trauma and premorbid functioning. CONCLUSION: In patients with FES, childhood physical neglect may contribute to poorer premorbid social functioning during early adolescence. This may provide us with an opportunity to identify and treat at-risk individuals earlier.

Factors associated with poor satisfaction with treatment and trial discontinuation in chronic schizophrenia.

IntroductionDespite consistently high discontinuation rates due to withdrawal of consent (WOC) and insufficient therapeutic effect (ITE) in schizophrenia trials, insight into the underlying factors contributing to poor satisfaction with treatment and dropout is limited. A better understanding of these factors could help to improve trial design and completion rates. METHODS: Using data from 1,136 trial participants with schizophrenia or schizoaffective disorder, we explored associations between predictor variables with (1) dropout due to WOC and ITE and (2) satisfaction with treatment among patients and investigators by means of hierarchic multiple regression analyses. RESULTS: ITE was associated with poor clinical improvement, poor investigator satisfaction with treatment, and poor patient insight into their own disease, whereas WOC only showed a meaningful association with poor patient satisfaction with treatment. Investigator satisfaction with treatment appeared most strongly associated with Positive and Negative Syndrome Scale (PANSS) positive factor endpoint scores, whereas patient satisfaction with treatment was best predicted by the endpoint score on the PANSS emotional distress factor. The occurrence of severe side effects showed no meaningful association to satisfaction with treatment among investigators and patients, and neither did a patient's experienced psychopathology, nor their self-rating of functional impairment. CONCLUSIONS: Whereas trial discontinuation due to ITE is associated with poor treatment effectiveness, a patient's decision to withdraw from an antipsychotic trial remains unpredictable and may occur even when the investigator observes a global clinical improvement and is satisfied with the treatment.

Predictors of abnormal involuntary movement in an african schizophrenia population.

As little is known about the risk factors for abnormal involuntary movements in African patients with schizophrenia, 170 Xhosa participants with schizophrenia were rated with the abnormal involuntary movement scale. Abnormal involuntary movements occurred in 19.4% of this group. Modeling of the data set showed that combining age at interview, age-squared, cannabis use or abuse, and anhedonia successfully identified 82.35% of cases of involuntary movements overall. Abnormal involuntary movements increased with increasing age (in a nonlinear manner), the presence of a cannabis use or abuse history seems to be protective against involuntary movements, and anhedonia is associated with the group that displayed fewer involuntary movements.

Crisis discharges and readmission risk in acute psychiatric male inpatients.

BACKGROUND: Severe pressures on beds in psychiatric services have led to the implementation of an early ("crisis") discharge policy in the Western Cape, South Africa. The study examined the effect of this policy and length of hospital stay (LOS) on readmission rates in one psychiatric hospital in South Africa. METHODS: Discharge summaries of adult male patients (n = 438) admitted to Stikland Psychiatric Hospital during 2004 were retrospectively examined. Each patient's clinical course was then analysed for the period between January 1st, 2004, and August 31st, 2006. RESULTS: Although shorter LOS was associated with decreased readmission rates, the effect of crisis discharges was far more powerful. Patients discharged as usual had a far lower risk of readmission than those discharged due to bed pressures (i.e. crisis discharge). CONCLUSION: Increased risks associated with the early discharge policy necessitate the urgent review of the current management of bed shortages in this inpatient facility. The strengthening of community initiatives, particularly assertive outreach could be a way forward.

DNA methylation and antipsychotic treatment mechanisms in schizophrenia: Progress and future directions.

Antipsychotic response in schizophrenia is a complex, multifactorial trait influenced by pharmacogenetic factors. With genetic studies thus far providing little biological insight or clinical utility, the field of pharmacoepigenomics has emerged to tackle the so-called "missing heritability" of drug response in disease. Research on psychiatric disorders has only recently started to assess the link between epigenetic alterations and treatment outcomes. DNA methylation, the best characterised epigenetic mechanism to date, is discussed here in the context of schizophrenia and antipsychotic treatment outcomes. The majority of published studies have assessed the influence of antipsychotics on methylation levels in specific neurotransmitter-associated candidate genes or at the genome-wide level. While these studies illustrate the epigenetic modifications associated with antipsychotics, very few have assessed clinical outcomes and the potential of differential DNA methylation profiles as predictors of antipsychotic response. Results from other psychiatric disorder studies, such as depression and bipolar disorder, provide insight into what may be achieved by schizophrenia pharmacoepigenomics. Other aspects that should be addressed in future research include methodological challenges, such as tissue specificity, and the influence of genetic variation on differential methylation patterns.

Fine-mapping of antipsychotic response genome-wide association studies reveals novel regulatory mechanisms.

AIM: Noncoding variation has demonstrated regulatory effects on disease treatment outcomes. This study investigated the potential functionality of previously implicated noncoding variants on schizophrenia treatment response. MATERIALS & METHODS: Predicted regulatory potential of variation identified from antipsychotic response genome-wide association studies was determined. Prioritized variants were assessed for association(s) with treatment outcomes in a South African first episode schizophrenia cohort (n = 103). RESULTS: Bioinformatic and association results implicated a relationship between regulatory variants, expression of MANBA, COL9A2 and NFKB1, and treatment response. Three SNPs were associated with poor outcomes (rs230493: p = 1.88 × 10-6; rs3774959: p = 1.75 × 10-5; and rs230504: p = 1.48 × 10-4). CONCLUSION: This study has thoroughly investigated previous GWAS to pinpoint variants that may play a causal role in poor schizophrenia treatment outcomes, and provides potential candidate genes for further study in the field of antipsychotic response.

A systematic review of genetic variants associated with metabolic syndrome in patients with schizophrenia.

Metabolic syndrome (MetS) is a cluster of factors that increases the risk of cardiovascular disease (CVD), one of the leading causes of mortality in patients with schizophrenia. Incidence rates of MetS are significantly higher in patients with schizophrenia compared to the general population. Several factors contribute to this high comorbidity. This systematic review focuses on genetic factors and interrogates data from association studies of genes implicated in the development of MetS in patients with schizophrenia. We aimed to identify variants that potentially contribute to the high comorbidity between these disorders. PubMed, Web of Science and Scopus databases were accessed and a systematic review of published studies was conducted. Several genes showed strong evidence for an association with MetS in patients with schizophrenia, including the fat mass and obesity associated gene (FTO), leptin and leptin receptor genes (LEP, LEPR), methylenetetrahydrofolate reductase (MTHFR) gene and the serotonin receptor 2C gene (HTR2C). Genetic association studies in complex disorders are convoluted by the multifactorial nature of these disorders, further complicating investigations of comorbidity. Recommendations for future studies include assessment of larger samples, inclusion of healthy controls, longitudinal rather than cross-sectional study designs, detailed capturing of data on confounding variables for both disorders and verification of significant findings in other populations. In future, big genomic datasets may allow for the calculation of polygenic risk scores in risk prediction of MetS in patients with schizophrenia. This could ultimately facilitate early, precise, and patient-specific pharmacological and non-pharmacological interventions to minimise CVD associated morbidity and mortality.

A 12-week, double-blind comparison of olanzapine vs haloperidol in the treatment of acute mania.

BACKGROUND: This randomized controlled trial compares the efficacy and safety of olanzapine vs haloperidol, as well as the quality of life of patients taking these drugs, in patients with bipolar mania. METHODS: The design consisted of 2 successive, 6-week, double-blind periods and compared flexible dosing of olanzapine (5-20 mg/d, n = 234) with haloperidol (3-15 mg/d, n = 219). RESULTS: Rates of remission (Young-Mania Rating Scale score of < or =12 and 21-item Hamilton Rating Scale for Depression score of < or =8 at week 6) were similar for olanzapine- and haloperidol-treated patients (52.1% vs 46.1%, respectively; P =.15). For the subgroup of patients whose index episode did not include psychotic features, rates of remission were significantly greater for the olanzapine group compared with the haloperidol group (56.7% vs 41.6%, P =.04). Relapse into an affective episode (mania and/or depression) occurred in 13.1% and 14.8% of olanzapine- and haloperidol-treated patients, respectively (P =.56). Switch to depression occurred significantly more rapidly with haloperidol than with olanzapine when using survival analysis techniques (P =.04), and significantly more haloperidol-treated patients experienced worsening of extrapyramidal symptoms, as indicated by several measures. Weight gain was significantly greater in the olanzapine group compared with the haloperidol group (2.82 vs 0.02 kg, P<.001). The olanzapine group had significant improvement in quality of life on several dimensions compared with the haloperidol group. CONCLUSIONS: These data suggest that olanzapine does not differ from haloperidol in achieving overall remission of bipolar mania. However, haloperidol carries a higher rate of extrapyramidal symptoms, whereas olanzapine is associated with weight gain.

Incidence of tardive dyskinesia in first-episode psychosis patients treated with low-dose haloperidol.

BACKGROUND: Previous studies suggest that the risk of tardive dyskinesia is increased with higher doses of conventional antipsychotics. This study evaluates the 12-month incidence of tardive dyskinesia in subjects with first-episode psychosis who were treated with very low doses of haloperidol. METHOD: Fifty-seven subjects with first-episode psychosis and a DSM-IV diagnosis of schizophreniform disorder, schizophrenia, or schizoaffective disorder were treated according to a fixed protocol with a mean dose of haloperidol of 1.68 mg/day and prospectively studied for 12 months. Subjects were assessed for extrapyramidal symptoms and psychiatric symptoms at 3-month intervals. Data were gathered from 1999 to 2001. RESULTS: Twelve-month incidence of probable or persistent tardive dyskinesia according to Schooler and Kane criteria was 12.3% (N = 7). Subjects with tardive dyskinesia did not differ from the rest of the sample regarding gender, race, duration of untreated psychosis, or baseline clinical characteristics. Subjects with tardive dyskinesia were older compared with subjects without tardive dyskinesia (37.14 +/- 9.23 vs. 27.30 +/- 8.09 years, respectively; t = -2.77, df = 30, p = .01) and received higher mean doses of haloperidol at 12 months (2.80 +/- 1.64 vs. 1.39 +/- 0.69 mg/day, respectively; t = -3.13, df = 25, p = .004). Cox regression analysis revealed that age at inclusion (p = .031), percentage change in negative symptoms (p = .028), and dose of haloperidol at 12 months (p = .016) were significant predictors of risk for tardive dyskinesia. CONCLUSION: Incidence of tardive dyskinesia was at least as high as in other samples treated with standard doses of conventional antipsychotics. Subjects at risk for tardive dyskinesia could not be identified on the basis of initial clinical features or acute treatment response. Risk of tardive dyskinesia was related to age, antipsychotic dose, and worsening of negative, depressive, and parkinsonian symptoms.

Ethnicity and treatment response in schizophrenia: a comparison of 3 ethnic groups.

BACKGROUND: Numerous cultural and ethnic factors may directly and indirectly influence treatment outcome in schizophrenia. The present study compared the response to antipsychotic treatment in 3 ethnic groups of patients with schizophrenia. METHOD: Fifty black, 63 mixed descent, and 79 white patients with DSM-IV-diagnosed schizophrenia or schizophreniform disorder who were participants in multinational clinical drug trials were assessed by means of the Positive and Negative Syndrome Scale (PANSS). Treatment response was measured by the change in PANSS total scores and the change in positive, negative, and general psychopathology subscale scores from baseline to 6 weeks. Also, the percentage of responders (defined as > or = 40% reduction in PANSS total scores) was calculated for each group. RESULTS: Baseline PANSS scores differed significantly, being higher for black and mixed descent patients. Mixed descent patients showed the greatest mean +/- SD percentage reduction in PANSS total score (29.4 +/- 21.6) followed by black (28.4 +/- 14.7) and white (11.4 +/- 27.6) patients. Analysis of covariance revealed a significant effect of ethnicity on the reduction in PANSS total scores (p < .0001). The numbers of responders were 20 mixed descent (32%), 12 black (24%), and 7 white (9%) patients (p = .002). CONCLUSION: Significant ethnic differences in acute antipsychotic treatment response are demonstrated by this study. Factors such as diet, nutritional status, body mass, and substance use could be important, as well as genetically determined ethnospecific pharmacokinetic and pharmacodynamic differences. Delayed help-seeking may account for the higher baseline scores in the black and mixed descent patients.

Open trial of citalopram in adults with post-traumatic stress disorder.

The selective serotonin reuptake inhibitors (SSRIs) are rapidly emerging as preferred first-line drugs in the pharmacological management of post-traumatic stress disorder (PTSD). Citalopram, an SSRI with highly potent and selective serotonin reuptake inhibition, may be a useful agent for treating the intrusive, avoidance, and arousal symptoms that characterize PTSD. Fourteen adult subjects (12 with civilian-related post-traumatic stress disorder, and 2 with combat-related post-traumatic stress disorder) were entered into an 8 wk, open- label, fixed-dose trial of citalopram, commencing with 20 mg/d, and increasing to 40 mg/d after 2 wk. Eleven subjects completed 8 wk treatment and were included in the data analysis. Based on the Clinician-Administered Post-traumatic Stress Disorder Scale (CAPS-2), there was significant reduction in all core PTSD symptoms (re-experiencing, hyperarousal, and avoidance) by week 8. Nine of the 11 completers were classified as 'responders' on Clinical Global Impression Improvement scores. Secondary measures of depression (Montgomery-Asberg Depression Rating Scale) and anxiety (Hamilton Anxiety Scale) also improved significantly by week 8. Citalopram was tolerated well, and there were no dropouts due to adverse effects. Data from this preliminary open trial suggests that citalopram, an SSRI, may be effective for reducing the key symptoms of PTSD, however, these findings need confirmation in double-blind, placebo-controlled trials.

Treatment of schizophrenia in low-income countries.

The introduction of the novel antipsychotics has had a major impact upon the treatment of schizophrenia. However, the greater acquisition costs of these drugs puts them beyond the reach of large sectors of the world's population. Consequently, the gap between the levels of care in high-income and low-income countries is likely to widen even further. Co-ordinated global action is necessary to ensure greater accessibility of these drugs. Cost-effectiveness studies in low-income countries need to be undertaken. The considerable evidence for improved safety and efficacy of low-dose compared to high-dose classical antipsychotics offers an alternative that could be implemented immediately in low-income countries.

Obsessive-compulsive disorder and the promoter region polymorphism (5-HTTLPR) in the serotonin transporter gene (SLC6A4): a negative association study in the Afrikaner population.

A polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4) has been reported to have functional significance and to be associated with obsessive-compulsive disorder (OCD). However, other studies have generated confounding results. A study was undertaken to re-evaluate this association in subjects drawn from the relatively genetically homogeneous Afrikaner population of South Africa. Fifty-four OCD patients of Afrikaner descent and 82 ethnically matched control individuals were phenotyped and genotyped. No significant association was found between the distribution of the 5-HTTLPR genotypes at the SLC6A4 locus and OCD. A similar result (p = 0.108) was generated when a meta-analysis of the 5-HTTLPR polymorphism, combining the current study with a previously reported Caucasian group, was performed; the meta-study comprised 129 OCD patients and 479 control individuals. However, both studies lacked power. Therefore, evidence that variation in SLC6A4 plays a significant role in the development of OCD in the population groups studied is inconclusive. Future association studies in Caucasian populations may extend the power of such meta-analyses and assist in delineating the role of SLC6A4 in OCD.

Efficacy and tolerability of quetiapine in poorly responsive, chronic schizophrenia.

With the notable exception of clozapine, there is at present insufficient information on the efficacy of atypical antipsychotic medications in patients with poorly responsive schizophrenia. The present study reports on the efficacy and tolerability of quetiapine and haloperidol in patients with schizophrenia who showed no response to treatment with fluphenazine. This study is a post hoc subanalysis of an 8-week, double-blind study of patients receiving quetiapine 600 mg/day or haloperidol 20 mg/day. The proportion of patients classified as "Clinical Global Impression responders" (defined as Clinical Global Impression Severity of Illness score of < or = 3 at study end) was greater in the quetiapine group compared with the haloperidol group (51% vs. 25%; P = 0.023). Overall, quetiapine was well tolerated with less extrapyramidal side-effects and reduction in prolactin when compared to haloperidol. Weight gain was modest but more apparent in quetiapine-treated patients. Quetiapine is an appropriate treatment choice in patients who do not respond to prior antipsychotic treatment.

Depressive symptoms at baseline predict fewer negative symptoms at follow-up in patients with first-episode schizophrenia.

There is uncertainty regarding the prognostic value of depressive symptoms in schizophrenia, having previously been associated with both favourable and poor outcome. This study investigated the relationship between baseline depressive symptoms and treatment outcome at 6, 12 and 24 weeks in 80 subjects with first-episode schizophrenia or schizophreniform disorder in terms of PANSS total and subscale score changes. No significant association was found between baseline PANSS depression factor scores and PANSS total and subscore changes. However, a significant inverse correlation between baseline depression scores and negative scores at 6, 12 and 24 weeks was found (p=0.044, 0.023 and 0.012, respectively). Multiple regression analysis indicated that this finding could not be explained on the basis of age, gender or duration of untreated psychosis. These findings support previous work suggesting that high baseline depressive scores predict favourable outcome.

Differential effect of quetiapine on depressive symptoms in patients with partially responsive schizophrenia.

While atypical antipsychotics appear to be effective in reducing depressive symptoms in the acute phase of schizophrenia, little is known about their efficacy in patients with ongoing symptoms. The present study assessed whether quetiapine (Seroquel) is more effective than haloperidol in treating depressive symptoms in patients with persistent positive symptoms, and investigated whether this effect is independent, or secondary to, reductions in other symptoms such as positive, negative or extrapyramidal symptoms. Patients with schizophrenia and a history of partial refractoriness to conventional antipsychotics who had not responded to 4 weeks of fluphenazine treatment (20 mg/day) were randomized to receive either quetiapine (600 mg/day) or haloperidol (20 mg/day) for a further 8 weeks. Change in the Positive and Negative Syndrome Scale depression factor score from baseline to endpoint was calculated and path analyses were performed on data from 269 patients. Quetiapine produced a greater reduction in depressive scores than haloperidol (-1.60 versus -0.54; p = 0.006). The path analyses indicated that this was a direct effect on depressive symptoms. These findings extend the evidence for an antidepressant effect for the novel antipsychotics in schizophrenia, and suggest that this is not limited to acutely psychotic patients.

Comparison of response to a selective serotonin reuptake inhibitor in children, adolescents, and adults with posttraumatic stress disorder.

BACKGROUND: Although the pathophysiology of posttraumatic stress disorder (PTSD) is considered multifactorial, empirical evidence suggests that serotonergic dysregulation may characterize the disorder. The efficacy of the selective serotonin reuptake inhibitors (SSRIs) in treating essential symptoms (re-experiencing, avoidance, numbing, hyperarousal) in both adults and children is likely to involve potentiation of this neurotransmitter. OBJECTIVE: This study compared outcome in an 8-week open trial of citalopram (an SSRI) in children/adolescents and adults with a Diagnostic and Statistical Manual of Mental Disorders (4th ed.) diagnosis of PTSD. METHODS: Twenty-four children/adolescents and 14 adults assessed for PTSD severity at baseline were followed up on citalopram treatment (20-40 mg/day) at two-weekly intervals over 8 weeks. The Clinician-Adminstered PTSD Scale (CAPS) and the Clinical Global Improvement Scale (CGI) were used as outcome measures. RESULTS: Although there were no significant differences in outcome measures between children/adolescents (n = 24) and adults (n = 14), both groups had significant reductions in mean CAPS total scores, symptom cluster scores, and CGI ratings at endpoint. CONCLUSION: Although the SSRIs have established efficacy and safety in the treatment of adult PTSD, literature on their use in child and adolescent PTSD is sparse. Controlled data are needed to support the clinical perception that SSRIs are agents of choice in the treatment of pediatric PTSD.

Chromosome 22q11 in a Xhosa schizophrenia population.

Chromosome 22q11 aberrations substantially increase the risk for developing schizophrenia. Although micro-deletions in this region have been extensively investigated in different populations across the world, little is known of their prevalence in African subjects with schizophrenia. We screened 110 African Xhosa-speaking participants with schizophrenia for the presence of micro-deletions. As further verification for the presence or absence of 22q11 microdeletions, we screened 238 Xhosa schizophrenia patients and 240 healthy Xhosa individuals from a larger schizophrenia candidate 22q11 gene study using molecular analyses. Data from molecular and cytogenetic analyses confirmed the absence of 22q11 microdeletions in the Xhosa schizophrenia samples. Although the absence of chromosome 22q11 micro-deletions in this group of patients does not exclude the possibility that it may occur in Xhosa schizophrenia patients, we concluded an extremely low prevalence. Our findings suggest that unique susceptibility loci may be present in this group.

Causal attributions, pathway to care and clinical features of first-episode psychosis: a South African perspective.

BACKGROUND: Causal belief systems and help-seeking practices may impact on pathway to care and features of first-episode psychosis (FEP) that have prognostic value. This is particularly relevant in South Africa where many people subscribe to traditional belief systems and consult traditional healers. AIM: To evaluate the relationship between causal attributions and pathway to care and features of FEP that have prognostic value. METHOD: We tested associations between causal attributions and pathway to care and duration of untreated psychosis (DUP), age of onset, PANSS-rated positive, negative and general symptoms and depressive symptoms (Calgary Depression Scale) in a sample of 54 FEP patients. RESULTS: Spiritual attribution of cause (49% of patients) was associated with long DUP, while consultation with a traditional healer (39% of patients) was associated with long DUP and high negative symptoms. Only 19% had consulted a psychiatrist. Seventy nine per cent (79%) were referred to hospital by family, police were involved in 44% of admissions, and 81% were admitted involuntarily. CONCLUSIONS: Spiritual attributions of cause and previous consultation with traditional healers may delay entry to psychiatric care and thereby negatively impact on prognosis of FEP. This highlights the importance of mental health education and developing a positive collaborative relationship with traditional healers, especially in low- and middle-income countries.

Whole-genome resequencing in pharmacogenomics: moving away from past disparities to globally representative applications.

Africa suffers from a high burden of disease; nonetheless, it has been one of the most under-represented continents with regard to genomic research. It can be argued that this disproportionate research is related to the fact that the genome architecture of African individuals is poorly suited to SNP-based genome-wide association studies, given existing genotyping platforms. However, this argument is no longer plausible with the arrival of next-generation sequencing technologies, which allow for the analysis of entire genomes. Using pharmacogenes to critically examine the merit of next-generation sequencing technologies in pharmacogenomics, we found a substantial amount of novel/uncharacterized variation, which was predicted to alter protein function. This variation was predominantly observed in African individuals, emphasizing the benefit of next-generation sequencing technologies specifically for these individuals. We also observed an improvement in the reliability of sequencing technologies in a relatively short time. Therefore, as sequencing technologies develop and decrease in cost, the ability to reliably detect variation will improve and these technologies will begin to replace other less comprehensive genotyping assays.