Towards a muscarinic hypothesis of schizophrenia

Although the neurotransmitter dopamine plays a prominent role in the pathogenesis and treatment of schizophrenia, the dopamine hypothesis of schizophrenia fails to explain all aspects of this disorder. It is increasingly evident that the pathology of schizophrenia also involves other neurotransmitter systems. Data from many streams of research including pre-clinical and clinical pharmacology, treatment studies, post-mortem studies and neuroimaging suggest an important role for the muscarinic cholinergic system in the pathophysiology of schizophrenia. This review will focus on evidence that supports the hypothesis that the muscarinic system is involved in the pathogenesis of schizophrenia and that muscarinic receptors may represent promising novel targets for the treatment of this disorder.     

The prevention of schizophrenia

Preventive strategies can be divided into universal, selective and indicated prevention and early intervention. Universal interventions are directed to the general population. Selective approaches are targeted at people who have risk factors for an illness, but who do not show any current signs. Indicated approaches target high risk individuals with minimal signs or symptoms foreshadowing mental disorder, but who do not meet diagnostic levels at the current time. Early intervention involves treating those with already diagnosable disorder in a timely and optimal manner aiming to decrease the severity of the illness, and reduce secondary morbidity. Although universal and selective interventions are not yet viable strategies, indicated prevention and early intervention are now realistic possibilities in schizophrenia. Development of methods to identify those at risk of psychosis continues to evolve. Promising results in the prevention and delay of transition to psychotic disorder from high risk state have been found. Early intervention in schizophrenia, including promotion of early help-seeking, has been shown to reduce the duration of untreated psychosis, which is known to be associated with poor outcome in schizophrenia. Early intervention programmes which optimise the care of the first episode have been shown to produce better outcomes than routine management.     

The prevention of schizophrenia

Preventive strategies can be divided into universal, selective and indicated prevention and early intervention. Universal interventions are directed to the general population. Selective approaches are targeted at people who have risk factors for an illness, but who do not show any current signs. Indicated approaches target high risk individuals with minimal signs or symptoms foreshadowing mental disorder, but who do not meet diagnostic levels at the current time. Early intervention involves treating those with already diagnosable disorder in a timely and optimal manner aiming to decrease the severity of the illness, and reduce secondary morbidity. Although universal and selective interventions are not yet viable strategies, indicated prevention and early intervention are now realistic possibilities in schizophrenia. Development of methods to identify those at risk of psychosis continues to evolve. Promising results in the prevention and delay of transition to psychotic disorder from high risk state have been found. Early intervention in schizophrenia, including promotion of early help-seeking, has been shown to reduce the duration of untreated psychosis, which is known to be associated with poor outcome in schizophrenia. Early intervention programmes which optimise the care of the first episode have been shown to produce better outcomes than routine management.     

Toward a new prevention of suicide in schizophrenia.

Suicide is the primary cause of death among schizophrenic patients; follow-up studies suggested that 10-13% of schizophrenic patients die by suicide. Preventive measures based on early recognition of risk factors and the establishment of drug treatment protocols are no doubt of great help but have not resulted in a significant reduction of the number of suicides among these patients. Schizophrenia is a chronic disorder affecting all aspects of the individual's life. Prevention should therefore be addressed to various areas. This paper overviews studies dealing with major fields of interest in the prevention of suicide among patients with schizophrenia. The authors focus on the role of pharmacological treatment, psychosocial interventions and psychotherapy, the struggle against stigmatization and the role of GPs. Prevention of suicide among inpatients with schizophrenia is also analysed. It is concluded that those integrated strategies already in use and the implementation of less known interventions should constitute a more effective prevention of self-inflicted deaths among these patients.     

Relapse prevention in schizophrenia: attitudes of neurologists-psychiatrists.

The overall high relapse rates observed in schizophrenia are attributed to several causes. One important factor influencing satisfactory prevention of relapse is the lack of consistent treatment strategies among medical doctors, especially neurologists-psychiatrists. Nearly one-third of the members of the Hellenic Society of Neurology and Psychiatry were asked to fill in anonymously a structured questionnaire on their treatment attitudes and prescribing tactics regarding schizophrenic patients both after the first schizophrenic episode and after multiple episodes. The majority of Greek neurologists-psychiatrists seem to adopt prescribing habits that approximate the current international standards for prevention of schizophrenic relapse. Their attitudes regarding the treatment and prevention of relapse for the first schizophrenic episode and first relapse are determined from multiple factors. These are: the expected relapse rates after the first episode, the expected prevalence of extrapyramidal side effects following a long-term neuroleptic treatment, the patient's expected treatment compliance after the first episode, the doctor's experience with treating schizophrenics, and lastly the knowledge of current literature on the topic. These results point to the need for continuing education, especially of the younger mental health professionals and those working in the private sector, addressing the issue of the actual risk of developing side effects from the treatment. In due course, benefits could result for everyday psychiatric practice and the patients' compliance with treatment.     

Towards a neurodevelopmental hypothesis in schizophrenia]

Since the first designation by E. Bleuler, various etiopathogenic theories have been proposed in schizophrenia. The dopaminergic hyperactivity hypothesis remains the more valid one. Recently, a neurodevelopmental hypothesis has been suggested in schizophrenia. This hypothesis postulates an early disturbance in the development of central nervous system, mainly in the temporo-limbic areas. This disturbance is not secondary to a degenerative process. It may take place during the end of the second trimester of the pregnancy and be complete at the time of puberty. Genetic and environmental factors co-occur to explain these brains developmental disturbances. This hypothesis has been formulated according to a tremendous amount of various data obtained with different methodologies. Neuropathological techniques observed a reduction in the number of cells and cyto-architectural anomalies in different brain areas such as hippocampus and para-hippocampus gyrus. The lack of associated gliosis suggests an early phenomenon developing before birth. Structural brain abnormalities have been demonstrated using various neuroimaging techniques. Computed tomographic scanning and magnetic resonance imaging reveal structural anomalies such as ventricular dilatation, and positron emission tomography functional ones such as frontal hypometabolism. These results appear to be unrelated to the severity, the duration and the treatment of the disease. More informations are needed to eventually confirm this hypothesis. Clinical, cognitive and neuropsychological data have to be completed. Longitudinal studies are urgently needed using clinical, epidemiological, genetic and neuroimaging techniques.     

Language and schizophrenia: Towards a synthesis

This paper proposes a primary deficit that may be a common principal factor in the development of the “schizophrenias.” The way in which this deficit might interact over time with social/developmental variables to produce the classic symptoms of schizophrenic psychosis is discussed as well as the range of behaviors associated with the broader concepts of schizophrenia. The deficit offers a link with a number of etiologic factors.Work is in progress delineating the treatment, rehabilitation and research implications of this hypothesis.     

Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia

Epidemiological studies have indicated an association between maternal bacterial and viral infections during pregnancy and the higher incidence of schizophrenia in the resultant offspring post-puberty. One hypothesis asserts that the reported epidemiological link is mediated by prenatal activation of the foetal immune system in response to the elevation of maternal cytokine level due to infection. Here, we report that pregnant mouse dams receiving a single exposure to the cytokine-releasing agent, polyriboinosinic-polyribocytidilic acid (PolyI:C; at 2.5, 5.0, or 10.0 mg/kg) on gestation day 9 produced offspring that subsequently exhibited multiple schizophrenia-related behavioural deficits in adulthood, in comparison to offspring from vehicle injected or non-injected control dams. The efficacy of the PolyI:C challenge to induce cytokine responses in na?ve non-pregnant adult female mice and in foetal brain tissue when injected to pregnant mice were further ascertained in separate subjects: (i) a dose-dependent elevation of interleukin-10 was detected in the adult female mice at 1 and 6h post-injection, (ii) 12 h following prenatal PolyI:C challenge, the foetal levels of interleukin-1beta were elevated. The spectrum of abnormalities included impairments in exploratory behaviour, prepulse inhibition, latent inhibition, the US-pre-exposure effect, spatial working memory; and enhancement in the locomotor response to systemic amphetamine (2.5 mg/kg, i.p.) as well as in discrimination reversal learning. The neuropsychological parallels between prenatal PolyI:C treatment in mice and psychosis in humans, demonstrated here, leads us to conclude that prenatal PolyI:C treatment represents one of the most powerful environmental-developmental models of schizophrenia to date. The uniqueness of this model lies in its epidemiological and immunological relevance. It is, sui generis, ideally suited for the investigation of the neuropsychoimmunological mechanisms implicated in the developmental aetiology and disease processes of schizophrenia.     

Understanding predisposition to schizophrenia: toward intervention and prevention.

OBJECTIVE: Early intervention to prevent schizophrenia is one of the most important goals of schizophrenia research. However, the field is not yet ready to initiate trials to prevent prodromal or psychotic symptoms in people who are at risk for developing the disorder. In this paper, we consider some of the major obstacles that must be studied before prevention strategies become feasible. METHOD AND RESULTS: One of the most important hurdles is the identification of a syndrome or set of traits that reflects a predisposition to schizophrenia and that might provide potential targets for intervention. In a recent reformulation of Paul Meehl's concept of schizotaxia, we integrate research findings obtained over the last 4 decades to propose a syndrome with meaningful clinical manifestations. We review the conceptualization of this syndrome and consider its multidimensional clinical expression. We then describe preliminary research diagnostic criteria for use in adult, nonpsychotic, first-degree relatives of patients diagnosed with schizophrenia, based on negative symptoms and neuropsychological deficits. We follow this with evidence supporting the validity of the proposed syndrome, which mainly includes social dysfunction and response to a low dosage of one of the newer antipsychotic medications. CONCLUSIONS: Continued progress toward the eventual initiation of prevention strategies for schizophrenia will include sustained efforts to validate the traits reflecting a predisposition to develop the disorder (for example, schizotaxia), follow-up studies to confirm initial findings, and the identification of potentially useful preventive interventions.     

Towards the development of a systematic approach to suicide prevention: the Alberta model.

The author outlines a model recently adopted by the Province of Alberta to provide suicide prevention, intervention and postvention services. Based on the proposals of a Provincial Task Force, the model features interrelated programs of outreach, education and training, research, and fund-raising. It is designed to make use of community resources in an efficient and coordinated manner, attacking the problem on several fronts.     

Targeting synapses and myelin in the prevention of schizophrenia

Many of the functions that are mediated by the prefrontal cortex (PFC) are severely impaired in schizophrenia. The maturation of these functions takes place during late adolescence and early adulthood, which coincides with the period of time when overt symptomatology of schizophrenia most commonly emerges. Two developmental processes occurring during the periadolescence period appear to mediate the functional maturation of the PFC: pruning of exuberant synapses and myelination of axons. It has long been speculated in the literature that disturbances of these processes may result in dysfunction of the PFC and thereby trigger the emergence of symptoms and deficits of schizophrenia. Alternatively, but not mutually exclusively, it has also been suggested that these late developmental processes may not be aberrant but they "unmask" preexisting deficits in the PFC, resulting in the onset of symptoms. The important implication of both of these scenarios is that in either case the emergence of PFC functional disturbances and the onset of symptoms and deficits of schizophrenia would in theory be preventable by pharmacologic manipulation of the synaptic pruning and/or axonal myelination processes. Thus, better understanding of the cellular and molecular mechanisms that mediate these processes will provide truly novel insight into the therapeutics and prevention of schizophrenia.     

Relapse prevention in patients with schizophrenia

Remission is a realistic goal for patients with schizophrenia, and, if sustained remission can be achieved, then patients may eventually attain functional recovery. The chance of relapse is decreased if patients are adherent to their pharmacotherapeutic treatment regimen. This case explores how to prevent relapse for a patient with schizophrenia and comorbid substance use disorder who is nonadherent to an oral atypical antipsychotic. To help the patient achieve treatment goals, intervention strategies such as switching medications and implementing psychosocial therapies are considered.     

Seven keys to relapse prevention in schizophrenia

Relapse prevention is a primary goal in the treatment of schizophrenia. Relapse can cause significant personal distress, interfere with rehabilitation efforts, and result in psychiatric hospitalization. The emergence of psychotic symptoms and disruptive behaviors can also lead to arrest and incarceration, particularly among patients who are not engaged in treatment. This article focuses on the process of relapse in schizophrenia and theoretical foundations of relapse prevention. The Program for Relapse Prevention is presented, along with the results of a recently completed controlled prospective evaluation. Based upon this study and the current literature, the author presents a series of seven clinical strategies for optimal relapse prevention.