The Relationship Between Self-Awareness and Psychotic-Like Experiences

The psychosis phenotype is thought to exist on a continuum, such that the same symptoms experienced by individuals diagnosed with psychotic disorders can also manifest in the general population to a less severe degree. The subclinical psychotic-like experiences reported by healthy individuals share a number of risk factors with psychotic disorders and confer greater risk of developing a psychotic disorder. Thus, healthy individuals with psychotic-like experiences comprise a valid population in which to study the underlying mechanisms of clinically significant psychotic symptoms. In this thesis, we aimed to further our understanding of psychotic-like experiences and the individuals who report them. We explored the relationships between tasks measuring different aspects of self-awareness and self-reported psychotic-like experiences using data obtained from 30 university students. We found that greater sensitivity to the difference between one’s own voice and another person’s voice predicted fewer symptoms of persecutory ideation. Additionally, we found that greater tendency to misattribute one’s own voice to an external source predicted greater symptoms of persecutory ideation.

Reasons for cannabis use in men with and without psychosis

Psychoses are relatively low prevalence disorders that have a disproportionately negative impact on individuals and society. Cannabis use is one factor that can exacerbate the negative consequences associated with psychotic disorders. Relatively few studies have examined the effects or reasons for using cannabis self-reported by individuals with psychosis. The present study is the first known to compare directly such factors in individuals with and without psychosis, within a single study. At baseline and follow-up participants with psychosis most commonly reported using cannabis for positive mood alteration (36% and 42%), coping with negative affect (27% and 29%) and for social activity reasons (38% and 29%). The control group most commonly reported using cannabis for relaxation (34% and 43%) and social activity reasons (49% and 51%). Participants with psychosis were less likely to report relaxation as the most important effect after use (27%) or expect it at follow-up (49%) compared to the control group (53% and 70%). In both groups, addiction and positive affect enhancement were the composite variable scores correlated most consistently with concurrent amount and frequency of use.

The future of cognitive and behavioral therapies in the prevention and early management of psychosis : opportunities and risks

Behavioral and cognitive interventions for people with psychosis have a long and distinguished history, although the evidence for their application to young people remains limited. We anticipate that the next decades will show substantial research into psychological intervention for this population. Important targets will include the management of environmental stressors, reduction of substance misuse, and promotion of early treatment. Psychological management of positive symptoms, depression, and suicidal behavior will continue to be critical objectives. Important secondary prevention goals will be the retention of cognitive functioning, vocational options, social skills, and social network support, including appropriate family support. We expect primary prevention to include both universal programs and interventions for adolescents at particularly high risk. Technical innovations will include increasing use of Internet-based intervention and behavior cueing devices. Pressures for intervention brevity will continue, as will problems with the systematic delivery of effective procedures.

A 1H-MRS investigation of the medial temporal lobe in antipsychotic-naïve and early-treated first episode psychosis

Schizophrenia is associated with significant brain abnormalities, including changes in brain metabolites as measured by proton magnetic resonance spectroscopy (MRS). What remains unclear is the extent to which these changes are a consequence of the emergence of psychotic disorders or the result of treatment with antipsychotic medication. We assessed 34 patients with first episode psychosis (15 antipsychotic naïve) and 19 age- and gender-matched controls using short-echo MRS in the medial temporal lobe bilaterally. Overall, there were no differences in any metabolite, regardless of treatment status. However, when the analysis was limited to patients with a diagnosis of schizophrenia, schizophreniform or schizoaffective disorder, significant elevations of creatine/phosphocreatine (Cr/PCr) and myo-inositol (mI) were found in the treated group. These data indicate a relative absence of temporal lobe metabolic abnormalities in first episode psychosis, but suggest that some treatment-related changes in mI might be apparent in patients with schizophrenia-spectrum diagnoses. Seemingly illness-related Cr/PCr elevations were also specific to the diagnosis of schizophrenia-spectrum disorder and seem worthy of future study.

Incipient neurovulnerability and neuroprotection in early psychosis : a proton spectroscopy study of the anterior hippocampus at 3Tesla

Programmed cell death (PCD) and progenitor cell generation (of glial and in some brain areas also neuronal fate) in the CNS is an active process throughout life and is generally not associated with gliosis which means that PCD can be pathologically silent. The striking discovery that progenitor cell generation (of glial and in some brain areas neuronal fate) is widespread in the adult CNS (especially the hippocampus) suggest a much more dynamic scenario than previously thought and transcends the dichotomy between neurodevelopmental and neurodegenerative models of schizophrenia and related disorders. We suggest that the regulatory processes that control the regulation of PCD and the generation of progenitor cells may be disturbed in the early phase of psychotic disorders underpinning a disconnectivity syndrom at the onset of clinically overt disorders. An ongoing 1H-MRS study of the anterior hippocampus at 3 Tesla in mostly drug-naive first-episode psychosis patients suggests no change in NAA, but significant increases in myo-inositol and lactate. The data suggests that neuronal integrity in the anterior hippocampus is still intact at the early stage of illness or mainly only functionally impaired. However the increase in lactate and myo-inositol may reflect a potential disturbance of generation and PCD of progenitor cells (of glial and in selected brain areas also neuronal fate) at the onset of psychosis. If true the use of neuroprotective agents such as lithium or eicosapentaenoic acid (which inhibit PCD and support cell generation)in the early phase of psychotic disorders may be a potent treatment avenue to explore.

Cortisol and dehydroepiandrosterone-sulphate levels correlate with symptom severity in first-episode psychosis

Dehydroepiandrosterone (DHEA) and its sulphate form (DHEA) are neuroactive steroids with antiglucocorticoid properties. An imbalance in the ratio of cortisol to DHEA(S) has been implicated in the pathophysiology of stress-related psychiatric disorders. This study prospectively investigated circulating cortisol, DHEAS and their ratio in first-episode psychosis (FEP) patients compared to healthy controls, and their relationship to perceived stress, psychotic, negative and mood symptoms. METHODS: Blood cortisol and DHEAS levels were obtained in 39 neuroleptic-naïve or minimally-treated FEP patients and 25 controls. Twenty-three patients and 15 controls received repeat assessments after 12 weeks. Perceived stress was assessed using the Perceived Stress Scale and symptoms were assessed in patients using standard rating scales. RESULTS: At baseline, no differences were observed in cortisol, DHEAS or the cortisol/DHEAS ratio between patients and controls. There were also no group differences in the change in these biological variables during the study period. Within FEP patients, decreases in cortisol and the cortisol/DHEAS ratio over time were directly related to the improvement in depression (r = 0.45; p = 0.031, r = 0.52; p = 0.01), negative (r = 0.51; p = 0.006, r = 0.55; p = 0.008) and psychotic symptoms (cortisol only, r = 0.53; p = 0.01). Perceived stress significantly correlated with DHEAS (r = 0.51; p = 0.019) and the cortisol/DHEAS ratio (r = -0.49; p = 0.024) in controls, but not patients, possibly reflecting an impaired hormonal response to stress in FEP patients. CONCLUSIONS: These findings further support the involvement of the stress system in the pathophysiology of psychotic disorders, with implications for treatment strategies that modulate these neurosteroids.

The effect of atypical antipsychotics on pituitary gland volume in patients with first-episode psychosis: A longitudinal MRI study

BACKGROUND: Pituitary volume is currently measured as a marker of hypothalamic-pituitary-adrenal hyperactivity in patients with psychosis despite suggestions of susceptibility to antipsychotics. Qualifying and quantifying the effect of atypical antipsychotics on the volume of the pituitary gland will determine whether this measure is valid as a future estimate of HPA-axis activation in psychotic populations. AIMS: To determine the qualitative and quantitative effect of atypical antipsychotic medications on pituitary gland volume in a first-episode psychosis population. METHOD: Pituitary volume was measured from T1-weighted magnetic resonance images in a group of 43 first-episode psychosis patients, the majority of whom were neuroleptic-naive, at baseline and after 3months of treatment, to determine whether change in pituitary volume was correlated with cumulative dose of atypical antipsychotic medication. RESULTS: There was no significant baseline difference in pituitary volume between subjects and controls, or between neuroleptic-naive and neuroleptic-treated subjects. Over the follow-up period there was a negative correlation between percentage change in pituitary volume and cumulative 3-month dose of atypical antipsychotic (r=-0.37), i.e. volume increases were associated with lower doses and volume decreases with higher doses. CONCLUSIONS: Atypical antipsychotic medications may reduce pituitary gland volume in a dose-dependent manner suggesting that atypical antipsychotic medication may support affected individuals to cope with stress associated with emerging psychotic disorders.

Medication adherence of individuals with a first episode of psychosis

Objective To determine rates of adherence to antipsychotic medication in first episode patients and the correlates of adherence in this group. Method Subjects were the first 200 admissions to an Early Psychosis Program. Adherence was determined on a three-point scale. Symptoms, medication side-effects, quality of life, substance use and family involvement were examined longitudinally. Results In their first year in the program 39% were non-adherent, 20% inadequately adherent, and 41% adherent. Non-adherent patients demonstrated more positive symptoms, more relapses, more alcohol and cannabis use, reduced insight, and poorer quality of life. They were younger, had an earlier age of onset and less likely to have a family member involved in treatment. Conclusion Results for this group are similar to those reported in the literature. Correlates are often the consequence of non-adherence. Non-compliance has to be anticipated and relationships maintained with patients and families to intervene as soon as possible to minimize the consequence of non-compliance.

Mice lacking the serotonin Htr2B receptor gene present an antipsychotic-sensitive schizophrenic-like phenotype

Impulsivity and hyperactivity share common ground with numerous mental disorders, including schizophrenia. Recently, a population-specific serotonin 2B (5-HT2B) receptor stop codon (ie, HTR2B Q20*) was reported to segregate with severely impulsive individuals, whereas 5-HT2B mutant (Htr2B−/−) mice also showed high impulsivity. Interestingly, in the same cohort, early-onset schizophrenia was more prevalent in HTR2B Q*20 carriers. However, the putative role of 5-HT2B receptor in the neurobiology of schizophrenia has never been investigated. We assessed the effects of the genetic and the pharmacological ablation of 5-HT2B receptors in mice subjected to a comprehensive series of behavioral test screenings for schizophrenic-like symptoms and investigated relevant dopaminergic and glutamatergic neurochemical alterations in the cortex and the striatum. Domains related to the positive, negative, and cognitive symptom clusters of schizophrenia were affected in Htr2B−/− mice, as shown by deficits in sensorimotor gating, in selective attention, in social interactions, and in learning and memory processes. In addition, Htr2B−/− mice presented with enhanced locomotor response to the psychostimulants dizocilpine and amphetamine, and with robust alterations in sleep architecture. Moreover, ablation of 5-HT2B receptors induced a region-selective decrease of dopamine and glutamate concentrations in the dorsal striatum. Importantly, selected schizophrenic-like phenotypes and endophenotypes were rescued by chronic haloperidol treatment. We report herein that 5-HT2B receptor deficiency confers a wide spectrum of antipsychotic-sensitive schizophrenic-like behavioral and psychopharmacological phenotypes in mice and provide first evidence for a role of 5-HT2B receptors in the neurobiology of psychotic disorders

The profile of psychiatric symptoms exacerbated by methamphetamine use

Background Methamphetamine use can produce symptoms almost indistinguishable from schizophrenia. Distinguishing between the two conditions has been hampered by the lack of a validated symptom profile for methamphetamine-induced psychiatric symptoms. We use data from a longitudinal cohort study to examine the profile of psychiatric symptoms that are acutely exacerbated by methamphetamine use. Methods 164 methamphetamine users, who did not meet DSM-IV criteria for a lifetime primary psychotic disorder, were followed monthly for one year to assess the relationship between days of methamphetamine use and symptom severity on the 24-item Brief Psychiatric Rating Scale. Exacerbation of psychiatric symptoms with methamphetamine use was quantified using random coefficient models. The dimensions of symptom exacerbation were examined using principal axis factoring and a latent profile analysis. Results Symptoms exacerbated by methamphetamine loaded on three factors: positive psychotic symptoms (suspiciousness, unusual thought content, hallucinations, bizarre behavior); affective symptoms (depression, suicidality, guilt, hostility, somatic concern, self-neglect); and psychomotor symptoms (tension, excitement, distractibility, motor hyperactivity). Methamphetamine use did not significantly increase negative symptoms. Vulnerability to positive psychotic and affective symptom exacerbation was shared by 28% of participants, and this vulnerability aligned with a past year DSM-IV diagnosis of substance-induced psychosis (38% vs. 22%, _2 (df1) = 3.66, p = 0.056). Conclusion Methamphetamine use produced a symptom profile comprised of positive psychotic and affective symptoms, which aligned with a diagnosis of substance-induced psychosis, with no evidence of a negative syndrome.

The prevalence and correlates of childhood trauma in patients with early psychosis

Objective: To describe the prevalence and demographic, clinical and functional correlates of childhood trauma in patients attending early psychosis clinics. Method: Participants were recruited from outpatients attending four early psychosis services. Exposure to childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Psychopathology was measured using the Positive and Negative Syndrome Scale and the Depression, Anxiety and Stress Scale. Social and vocational functioning and substance use were also assessed. Results: Over three-quarters of the 100 patients reported exposure to any childhood trauma. Emotional, physical and sexual abuse were reported by 54%, 23% and 28% of patients, respectively, while 49% and 42% of patients reported emotional and physical neglect, respectively. Female participants were significantly more likely to be exposed to emotional and sexual abuse. Exposure to childhood trauma was correlated with positive psychotic symptoms and higher levels of depressive, anxiety and stress symptoms; however, it had no impact on social or vocational functioning or recent substance use. Conclusion: Exposure to childhood trauma was common in patients with early psychosis, and associated with increased symptomatology. Existing recommendations that standard clinical assessment of patients with early psychosis should include inquiry into exposure to childhood trauma are supported.

Cognitive functioning and its heritability in bipolar I disorder

Bipolar I disorder is a severe psychiatric disorder characterized by episodic mood alterations that can be manic, depressive or mixed. Bipolar disorder seems to be highly genetic, but the etiology of this complex disorder has remained elusive. In recent years, studies have found that euthymic patients with bipolar disorder may have impairments particularly in executive functioning, verbal learning and memory. These impairments may be present also among some of the relatives of these patients, who may be vulnerable to the disorder. Using neuropsychological variables as endophenotypes, i.e. intermediate phenotypes between genes and the phenotypes, has been suggested to aid search for the etiological background of the disorder, but evidence is sparse on whether these variables fulfill the criteria for endophenotypes. The present thesis is part of the Genetic Epidemiology and Molecular Genetics of Severe Mental Disorders in Finland project. The specific aim was to investigate whether neuropsychological test variables would indicate genetic liability to the disorder and could therefore be regarded as endophenotypes. Thus, cognitive functions and their heritability were studied in bipolar I disorder patients and in their unaffected first-degree relatives from a population-based sample of families, comparing them to a population-based control group. In order to add homogeneity to the subgroups of bipolar disorder patients and their relatives, cognitive functions and their heritability were further studied in a group of families affected by bipolar I disorder only (bipolar families) and another group of families affected by both bipolar I disorder and schizophrenia or schizoaffective disorders (mixed families). Finally, the effect of processing speed on other cognitive functions was investigated. The study showed that especially executive functioning and processing speed fulfilled the endophenotype criteria. Impairments in these functions were found in bipolar patients and in their relatives irrespective of other severe psychopathology in the family. These functions were highly heritable in these families. Study also showed that generalized impairment in verbal memory may associate more with bipolar disorder than to vulnerability to other psychotic disorders, and be more related to fully developed disease; impairments in verbal learning and memory were found only in patients, and they were not found to be highly heritable. Finally, the most potential endophenotype, i.e. processing speed, seemed to contribute to a range of other cognitive dysfunctions seen in bipolar disorder patients. Processing speed, in particular, has also been shown to be a valid endophenotype in subsequent association analyses in psychiatric genetics in Finland and internationally. Information concerning cognitive impairments and their association with the psychosocial consequences of bipolar disorder is important in planning treatment. It is also important to understand and acknowledge that patients may have cognitive impairments that affect their everyday life. Psychosocial interventions and neuropsychological rehabilitation may supplement other conventional treatments for bipolar patients.

Importance of COMT in the regulation of prefrontal dopamine

The prefrontal cortex (PFC), located in the anterior region of the frontal lobe, is considered to have several key roles in higher cognitive and executive functions. In general, the PFC can be seen as a coordinator of thought and action allowing subjects to behave in a goal-directed manner. Due to its anatomical connections with a variety of cortical and subcortical structures, several neurotransmitters, including dopamine, are involved in the regulation of PFC activity. In general, the majority of released dopamine is cleared by the dopamine transporter (DAT). In the PFC however, the number of presynaptic DAT is diminished, emphasizing the relative importance of catechol-O-methyltransferase (COMT) in dopamine metabolism. As a result, the role of COMT in the etiology of psychotic disorders is under constant debate. The present study investigated the role of COMT in prefrontal cortical dopamine metabolism by different neurochemical methods in COMT knockout (COMT-KO) mice. Pharmacological tools to inhibit other dopamine clearing mechanisms were also used for a more comprehensive and collective picture. In addition, this study investigated how a lack of the soluble (S-) COMT isoform affects the total COMT activity as well as the pharmacokinetics of orally administered L-dopa using mutant mice expressing only the membrane-bound (MB-) COMT isoform. Also the role of COMT in striatal and accumbal dopamine turnover during Δ9-tetrahydrocannabinol (THC) challenge was studied. We found markedly increased basal dopamine concentrations in the PFC, but not the striatum or nucleus accumbens (NAcc), of mice lacking COMT. Pharmacological inhibition of the noradrenaline transporter (NET) and monoamine oxidase (MAO) elevated prefrontal cortical dopamine levels several-fold, whereas inhibition of DAT did not. The lack of COMT doubled the dopamine raising effects of NET and MAO inhibition. No compensatory expression of either DAT or NET was found in the COMT-KO mice. The lack of S-COMT decreased the total COMT activity by 50-70 % and modified dopamine transmission and the pharmacokinetics of exogenous Ldopa in a sex and tissue specific manner. Finally, we found that subsequent tolcapone and THC increased dopamine levels in the NAcc, but not in the striatum. Conclusively, this study presents neurochemical evidence for the important role of COMT in the PFC and shows that COMT is responsible for about half of prefrontal cortical dopamine metabolism. This study also highlights the previously underestimated proportional role of MB-COMT and supports the clinical evidence of a gene x environment interaction between COMT and cannabis.

Patterns of neurocognitive impairment in first-episode bipolar disorder and schizophrenia.

BACKGROUND:
Researching psychotic disorders in unison rather than as separate diagnostic groups is widely advocated, but the viability of such an approach requires careful consideration from a neurocognitive perspective.
AIMS:
To describe cognition in people with bipolar disorder and schizophrenia and to examine how known causes of variability in individual's performance contribute to any observed diagnostic differences.
METHOD:
Neurocognitive functioning in people with bipolar disorder (n = 32), schizophrenia (n = 46) and healthy controls (n = 67) was compared using analysis of covariance on data from the Northern Ireland First Episode Psychosis Study.
RESULTS:
The bipolar disorder and schizophrenia groups were most impaired on tests of memory, executive functioning and language. The bipolar group performed significantly better on tests of response inhibition, verbal fluency and callosal functioning. Between-group differences could be explained by the greater proclivity of individuals with schizophrenia to experience global cognitive impairment and negative symptoms.
CONCLUSIONS:
Particular impairments are common to people with psychosis and may prove useful as endophenotypic markers. Considering the degree of individuals' global cognitive impairment is critical when attempting to understand patterns of selective impairment both within and between these diagnostic groups.