Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder.

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10-8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2=0.35; BD II SNP-h2=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.

Latent structure of psychotic experiences in the general population.

OBJECTIVE: There have been increasing pressures to adopt or incorporate dimensional representations in various sections of DSM-5 including the psychotic disorders section. Thus far, findings offered as evidence of a continuous distribution of psychosis are limited given their exclusive focus on the manifest rather than latent structure of psychotic experiences. The current study sought to determine whether or not psychotic experiences possess a taxonic or dimensional latent structure. METHOD: We investigated the latent structure of psychotic experiences in the Collaborative Psychiatric Epidemiological Surveys (CPES) and the National Comorbidity Survey (NCS). We analyzed responses of participants in these surveys with three multivariate taxometric procedures (MAMBAC, MAXEIG, and L-Mode) after summing responses on the surveys into three indicators of positive psychosis. RESULTS: Taxometric results tended to support a dimensional, rather than taxonic structure for psychotic experiences. In the CPES, all taxometric methods produced graphical and numerical support for a dimensional structure. In the NCS, MAMBAC appeared to slightly support a taxonic structure, whereas MAXEIG and L-Mode supported a dimensional structure. CONCLUSION: There appears to be a dimensional distribution of psychotic experiences in the general population. This supports the incorporation of dimensional representations of psychotic symptoms in the current diagnostic system.

Negative symptoms of schizophrenia: a problem that will not go away.

OBJECTIVE: Negative symptoms of schizophrenia are a common, enduring, and debilitating component of the psychopathology of schizophrenia. Although efforts thus far to elucidate a distinct schizophrenia subtype based upon negative symptoms have yielded mixed results, there are nevertheless neurobiological correlates of the negative symptom typology. METHOD: A review of nosology, typology, and assessment tools for determining core negative symptoms in schizophrenia. RESULTS: Negative symptoms can be difficult to evaluate objectively. Current rating scales 'capture' key domains of negative symptoms, in spite of considerable overlap between these domains. However, each objective assessment trades off methodological rigor and detail against brevity of assessment and ease of use. CONCLUSION: The description of new methods for measuring these devastating symptoms, coupled with the ongoing development of novel antipsychotics and agents that augment antipsychotics have fuelled renewed interest in the evaluation of negative symptoms and optimism that better treatments for negative symptoms can be found.

Pharmacological treatment of negative symptoms of schizophrenia: therapeutic opportunity or cul-de-sac?

UNLABELLED: Negative symptoms of schizophrenia are debilitating and they contribute to poor outcome in schizophrenia. Initial enthusiasm that second-generation antipsychotics would prove to be powerful agents to improve negative symptoms has given way to relative pessimism that the effects of current pharmacological treatments are at best modest. METHOD: A review of the current 'state-of-play' of pharmacological treatments for negative symptoms in schizophrenia. RESULTS: Treatment results to date have been largely disappointing. The evidence for efficacy of second-generation antipsychotics is reviewed. CONCLUSION: The measurement and treatment trials methodology for the evaluation of negative symptoms need additional refinement before therapeutic optimism that better treatments for negative symptoms can be realized.

Red blood cell membrane essential fatty acid metabolism in early psychotic patients following antipsychotic drug treatment.

A role of indices of oxidative stress, oxidative injury, and abnormal membrane phospholipid, specifically the phospholipid essential polyunsaturated fatty acids (EPUFAs) metabolism has been suggested based on studies in separate groups of patients with or without medication. The current study investigated the relationship between these biochemical measures in first-episode psychotic patients (N=16) at baseline and after 6 months of antipsychotic treatment (N=5 each with risperidone and olanzapine) and compared them to matched normal subjects. The indices of oxidative stress included: antioxidant enzymes; superoxide dismutase, glutathione peroxidase and catalase; and the oxidative injury as the levels of plasma lipid peroxides. The key membrane EPUFA's been; linolenic acid, arachidonic acid, nervonic acid, docosapentaenoic acid and docosahexaenoic acid. Furthermore, the changes in these biochemical measures were correlated with clinical symptomatology. Data indicated that, at baseline, reduced levels of antioxidant enzymes were associated with increased plasma lipid peroxides and reduced membrane EPUFAs, particularly omega-3 fatty acids. Furthermore, these biochemical measures normalized after 6 months of antipsychotic treatment. Parallel-improved psychopathology indicated that membrane EPUFA status might be partly affected by oxidative damage, which together may contribute to the pathophysiology and thereby, psychopathology of schizophrenia. These data also support the augmentation of antipsychotic treatment by supplementation with a combination of antioxidants and omega-3 fatty acids.

Broad therapeutic uses of atypical antipsychotic medications.

The atypical antipsychotics have a low incidence of extrapyramidal side effects (EPS), have improved tardive dyskinesia profiles, and have a broad range of therapeutic efficacy. These agents offer important therapeutic advantages that extend beyond their initial regulatory approval in several conditions and patient groups. The use of atypical antipsychotics is most relevant in the treatment of mood disorders, where these medications are being used increasingly for acute mood stabilization and in patients who are resistant to other treatments. Similar circumstances and clinical advantages pertain to the use of atypical antipsychotics in the treatment of behavioral disturbances in patients with dementia and in the management of personality disorders-both circumstances where conventional antipsychotics were initially poorly tolerated because of EPS. The low incidence of EPS associated with atypical antipsychotics is highly beneficial in several neuropsychiatric conditions. The extent to which endocrine and metabolic dysregulations associated with atypical antipsychotics will influence antipsychotics' role remains to be determined. As therapeutic opportunities evolve and diversify, atypical antipsychotics, because of favorable adverse-effect profiles, will have enhanced patient tolerability and use in nonpsychiatric conditions.

Treatment-refractory schizophrenia.

Treatment-refractory schizophrenia is common. Refinements in pharmacologic and psychosocial treatments of schizophrenia offer the expectation of superior outcomes for this disadvantaged patient group. This article critically reviews those articles that were published during the year 2000 that address this treatment-refractory population.

Insight and schizophrenia.

Few clinical attributes, if any, have such a profound impact on the management of schizophrenia as that associated with lack of insight. Yet, despite its importance, the clinical correlates of lack of insight are poorly understood. In one present study of long-stay patients at a state facility, lack of insight showed modest associations with positive and negative symptoms and with diminished executive function on cognitive testing. Insight did not differ between patients receiving typical and atypical antipsychotic medications.

Schizophrenia today: what do we know-and how sure are we?

The growth of our understanding of the biology and treatment of schizophrenia is still very much a work in progress. In this article, which introduces a series of papers presented at a conference entitled "Schizophrenia: Doing the Right Thing Well," held at Northcoast Behavioral Healthcare System (Cleveland, May 2000), the authors provide a short overview of what is known about schizophrenia today. He briefly reviews findings concerning epidemiology, phenomenology and course, neurobiology, and treatment, and highlights some of the most significant findings to date as well as areas needing further research. Early evaluation and treatment, in advance of the florid presentation of the illness, offer much hope, but only if our knowledge of the diagnostic specificity of prodromal and neurodevelopmental precursors can be enhanced. Significant advances in medication treatment have been made, and the newer antipsychotic medications overall have a more benign adverse-effect profile than the older agents, although the specter of endocrine/metabolic complications looms as a significant long-term concern. The authors conclude that, although many advances in our understanding of the etiology and treatment of schizophrenia have been made, much remains to be learned.

Schizophrenia research: a progress report, summarizing proceedings of the 1999 International Congress on Schizophrenia Research.

The Seventh International Congress on Schizophrenia Research was held in Santa Fe, New Mexico, in April 1999. This was the largest Congress meeting to date, with almost 1,000 presentations that covered all aspects of schizophrenia research. This article provides an account of the Congress proceedings. Several research areas received extensive coverage, including early detection of illness through the use of cognitive and behavioral precursors of schizophrenia and the etiology and treatment of childhood-onset and first episode schizophrenia. The etiopathophysiological hypothesis of schizophrenia as a disorder of neural dysconnectivity was promoted across cognitive, neurochemical, neuroimaging, and postmortem domains. The importance of cognition as a major outcome measure and the impact of new antipsychotics on the treatment and conceptualization of schizophrenia were also major topics. Overall, the conference was noteworthy for the convergence of findings across research domains.

A content analysis of state hospital policies on sex between inpatients.

Eighty-one state psychiatric hospitals in 16 states were surveyed about whether they had policies on sex between inpatients. Thirty-one hospitals responded by sending a copy of their policies, which were analyzed for explicit definitions and distinctions between various sexual behaviors; for the presence and content of statements about patients' rights and personal autonomy, duty to protect, competency to consent, and staff guidance and education; and for instructions on the management of sexual incidents. Fourteen of the 31 policies explicitly forbade inpatient sex; 12 stressed patient autonomy. Only five specified that staff should receive special training. The results indicate that hospitals vary widely in their attention and management approach to inpatients' sexual behavior.

Ziprasidone: pharmacology, clinical progress and therapeutic promise.

Choosing among the atypical antipsychotics currently available for the treatment of schizophrenia requires the clinician to evaluate the relative merits of each agent. Ziprasidone is another atypical antipsychotic, currently under consideration for approval to use in clinical practice, whose role is at present unclear. Based upon the information reviewed here, ziprasidone is an agent which possesses the preclinical and clinical attributes which characterize an "atypical" antipsychotic and is an effective antipsychotic medication for the treatment of psychosis. Ziprasidone appears to discriminate from other atypical antipsychotics by its low propensity for weight gain and by the availability of a short-acting intramuscular formulation. Its role in clinical practice will be determined by clinician experience and by additional phase IV clinical trials.

Comprehensive disease management for schizophrenia.

This is a period of rapid development in the pharmacotherapy of schizophrenia. New generation antipsychotic medications appear overall to be more efficacious and better tolerated than the older, conventional antipsychotics. Moreover, these atypical antipsychotics appear to have a broader profile of efficacy which likely includes cognitive effects, possibly antiaggressive effects and the potential to reduce comorbid substance abuse in schizophrenia. Future research efforts are aimed at clarifying the relative profile and potentially broader efficacy of each of these drugs. Future clinical and administrative efforts should focus on availability and access to new treatments, the promulgation of "best practices" and the articulation and implementation of comprehensive care for persons with schizophrenia.

Implementing effectiveness research and improving care for schizophrenia in real-world settings.

OBJECTIVE: To review recent advances in medication practices and standards of care in the treatment of schizophrenia and examine the disparity between the knowledge base and clinical practice. DATA SOURCES: Key literature on medication practices, novel pharmacotherapies, and the evolution of practice guidelines for schizophrenia were reviewed. DISCUSSION: Emerging data demonstrate a lack of consistent application of current knowledge and best practices, in part due to major structural inconsistencies in the public mental health system. Implementation of results from effectiveness research as well as the incorporation of practice guidelines may help bridge this gap. CONCLUSION: As standards of care for schizophrenia are developed, the following issues will need particular attention: coordination with the criminal justice system, comprehensive treatment of comorbid illnesses, outcomes based on symptoms in all domains, and continuous and integrated collection of data to produce rational cost justification.

The role of typical and atypical antipsychotic medications in the management of agitation and aggression.

The management of agitation and aggression in psychiatric inpatients is a significant clinical dilemma. Establishing a clear diagnosis and distinguishing whether aggression is an acute manifestation or a long-standing or repetitive problem are fundamental antecedents of medication treatment. For acute aggression, either benzodiazepines or antipsychotic medications (typical and atypical) are recommended choices. Currently, on the basis of efficacy, ease of use, and availability in multiple (tablet, liquid, intramuscular) preparations, typical antipsychotics such as loxapine should be considered as first choice for acute aggression (in psychosis). On the other hand, atypical antipsychotics, particularly clozapine, should be considered when aggression in psychosis persists and/or is repetitive. Typical antipsychotics are indicated for persistent aggression in psychosis when medication noncompliance is the obstacle to effective treatment.

Novel antipsychotic agents and their implications for forensic psychiatry.

Recent developments in psychopharmacology have lead to the introduction of several novel antipsychotic agents into clinical practice. As these agents become more commonly encountered, it is essential that forensic psychiatrists have a working knowledge of their efficacy as well as the advantages of their use. This article reviews current literature regarding the clinical efficacy and mechanisms of action of clozapine, risperidone, olanzapine, quetiapine, sertindole, and ziprasidone, with a discussion of their use in forensic psychiatry. Specifically, studies show certain advantages of the novel agents in the treatment of violent patients. Use of these medications may also reduce the risk of civil litigation. The novel antipsychotic agents offer the potential of improved patient care within forensic settings by both expediting judicial processing while providing long-term cost savings. Forensic patients represent an underserved population but must have equal access to new medications as they become available. Familiarity with these issues and the medications themselves will facilitate their use in forensic settings.

New antipsychotic agents: emerging clinical profiles.

The past 5 years have witnessed an intense period of change in the pharmacotherapy of schizophrenia. Several new antipsychotic agents have become available for clinical use, and more are likely to appear over the next few years. The new agents require that clinicians treating patients with schizophrenia adopt new ways of thinking regarding the pharmacotherapy of this illness. Longer drug trials than have traditionally been used may be required to determine response to the newer agents, and response should be measured across negative symptoms, cognitive symptoms, and broader rehabilitative dimensions. Clozapine has an established role in treatment-resistant schizophrenia. Other new antipsychotics are being used with broader clinical indications. The relative efficacy of these agents, particularly in treatment-refractory patients, remains to be determined. The availability of the newer agents may represent an opportunity to reduce the incidence of tardive dyskinesia and to gain better management of comorbid substance abuse and aggression among schizophrenic patients. Significant cost savings could accrue from more effective disease management.