Post-zygotic genomic changes in glutamate and dopamine pathway genes may explain discordance of monozygotic twins for schizophrenia.

BACKGROUND: Monozygotic twins are valuable in assessing the genetic vs environmental contribution to diseases. In the era of complete genome sequences, they allow identification of mutational mechanisms and specific genes and pathways that offer predisposition to the development of complex diseases including schizophrenia. METHODS: We sequenced the complete genomes of two pairs of monozygotic twins discordant for schizophrenia (MZD), including one representing a family tetrad. The family specific complete sequences have allowed identification of post zygotic mutations between MZD genomes. It allows identification of affected genes including relevant network and pathways that may account for the diseased state in pair specific patient. RESULTS: We found multiple twin specific sequence differences between co-twins that included small nucleotides [single nucleotide variants (SNV), small indels and block substitutions], copy number variations (CNVs) and structural variations. The genes affected by these changes belonged to a number of canonical pathways, the most prominent ones are implicated in schizophrenia and related disorders. Although these changes were found in both twins, they were more frequent in the affected twin in both pairs. Two specific pathway defects, glutamate receptor signaling and dopamine feedback in cAMP signaling pathways, were uniquely affected in the two patients representing two unrelated families. CONCLUSIONS: We have identified genome-wide post zygotic mutations in two MZD pairs affected with schizophrenia. It has allowed us to use the threshold model and propose the most likely cause of this disease in the two patients studied. The results support the proposition that each schizophrenia patient may be unique and heterogeneous somatic de novo events may contribute to schizophrenia threshold and discordance of the disease in monozygotic twins.

Integration of DNA sequence and DNA methylation changes in monozygotic twin pairs discordant for schizophrenia.

Schizophrenia is a complex mental disorder with high heritability (80%), extensive genetic heterogeneity, environmental contributions and only 50% concordance in discordant monozygotic (MZ) twins. Discordant MZ twins provide an exceptional opportunity to assess patient specific genome-wide genetic and epigenetic changes that may account for the disease phenotype. A combined analysis of genetic and epigenetic changes on the same twin pairs is expected to provide a more effective approach for two reasons. First, it is now possible to generate relatively reliable complete genome sequences as well as promoter methylation states on an individual level and second, the unaffected twin that originated from the same zygote provides a near perfect genetic match for contrast and comparison. This report deals with the combined analysis of DNA sequence data and methylation data on two pairs of discordant MZ twins that have been clinically followed for over 20 years. Results on Family 1 show that 58 genes differ in DNA sequence as well as promoter methylation in a schizophrenia-affected twin as compared to her healthy co-twin. The corresponding number for family 2 was 13. The two lists are over represented by neuronal genes and include a number of known schizophrenia candidate genes and drug targets. The results argue that changes in multiple genes via co-localized genetic and epigenetic alteration contribute to a liability threshold that is necessary for development of schizophrenia. This novel hypothesis, although logical, remains to be validated.

Copy number variation showers in schizophrenia: an emerging hypothesis.

Genetic discoveries on Schizophrenia remain challenging. Traditional approaches have provided clues, but no genes. Novel theories that must account for extensive heterogeneity, including high discordance of monozygotic (MZD) twins, are needed. To this end, the extensive repeats of the human genome may provide the predisposition for DNA replication errors operational at every cell cycle during meiosis and mitosis. These errors will shower the genome with replication errors including copy number variations. Depending on the timing and the genes involved, this will contribute to the mutational load and disease. The evidence for such a mechanism in schizophrenia is emerging.

Is mandatory outpatient treatment effective?

This paper reviews the major studies of mandatory outpatient treatment (MOT) and examines why there has been inconsistency in some of the findings. Attempts to answer the question "is mandatory treatment effective?" must first clarify the type of mandatory treatment being examined, the type of patient being treated, and the outcome by which effectiveness is measured. There is consistent evidence that various forms of MOT increase follow-up with psychiatric services and that court-ordered outpatient committal decreases victimization of patients in the community. It also appears likely that MOT reduces the use of hospitalization; but, due to methodological problems associated with the research, this conclusion remains controversial.

Involvement of gene-diet/drug interaction in DNA methylation and its contribution to complex diseases: from cancer to schizophrenia.

Most biological processes, including diseases, involve genetic and non-genetic factors. Also, the realization of a genetic potential may depend on environmental factors by directly affecting the expression of gene(s). Exactly how different environmental factors affect gene expression is not well understood. One of the mechanisms may involve DNA methylation and thereby gene expression. Diet, chemicals, and metals are known to affect DNA methylation and other epigenetic processes but are just beginning to be elucidated. For example, methylation of cytosine(s) in the promoter region could prevent the binding of transcription factors or create binding sites for complexes that deacetylate neighboring histones that in turn compact the chromatin, encouraging a gene to become silent. This article will discuss DNA methylation as an epigenetic mechanism of gene regulation and examine how factors like diet, chemicals, and metals may affect DNA methylation. The effect of alterations in DNA methylation may include aberrant expression of genes or genomes and chromosomal instability, which in turn may contribute to the etiology of complex multifactorial diseases. A similar mechanism is now recognized in a number of cancers. There is also indirect evidence to suggest that methylation could apply to a number of complex diseases, including schizophrenia.

Client satisfaction in a feasibility study comparing face-to-face interviews with telepsychiatry.

We carried out a pilot study comparing satisfaction levels between psychiatric patients seen face to face (FTF) and those seen via videoconference. Patients who consented were randomly assigned to one of two groups. One group received services in person (FTF from the visiting psychiatrist) while the other was seen using videoconferencing at 128 kbit/s. One psychiatrist provided all the FTF and videoconferencing assessment and follow-up visits. A total of 24 subjects were recruited. Three of the subjects (13%) did not attend their appointments and two subjects in each group were lost to follow-up. Thus there were nine in the FTF group and eight in the videoconferencing group. The two groups were similar in most respects. Patient satisfaction with the services was assessed using the Client Satisfaction Questionnaire (CSQ-8), completed four months after the initial consultation. The mean scores were 25.3 in the FTF group and 21.6 in the videoconferencing group. Although there was a trend in favour of the FTF service, the difference was not significant. Patient satisfaction is only one component of evaluation. The efficacy of telepsychiatry must also be measured relative to that of conventional, FTF care before policy makers can decide how extensively telepsychiatry should be implemented.

Clinically significant differences among Canadian mental health acts.

OBJECTIVES: First, to highlight the major differences among mental health acts in different Canadian jurisdictions as they relate to involuntary admission criteria, treatment authorization, review and appeal procedures, and conditional leave and community treatment orders. Second, to analyze the impact of these differences on the care that individuals with mental illness receive. METHOD: We examined the mental health act provisions of all Canadian jurisdictions to determine how the clinical management of a typical case would differ among jurisdictions. We used a statement of principles for mental health legislation endorsed by the Canadian Psychiatric Association to guide the analysis. We confirmed interpretation of each act and its implementation through key informant contact in each province and territory. RESULTS: We found clinically significant differences among the provinces and territories on all major components of their mental health acts. CONCLUSION: Provisions that prevent patients receiving appropriate clinical care can be found in some Canadian mental health acts. Alternate provisions that support appropriate clinical care, that respect the human rights and personal dignity of patients, and that are consistent with the Canadian Charter of Rights and Freedoms can be found in the legislation of other jurisdictions.

A survey of the use of community treatment orders by psychiatrists in Saskatchewan.

OBJECTIVE: To determine the pattern of use and satisfaction with community treatment orders (CTOs) by psychiatrists in Saskatchewan. METHOD: All psychiatrists who were licensed to practise by the College of Physicians and Surgeons of Saskatchewan were surveyed by mail in July 1998. RESULTS: The response rate was 72%. The responding psychiatrists were treating 14 patients on CTOs at the time of the survey. Psychiatrists were generally satisfied with the operation of CTOs, though many felt that commitment of only of 3 months before mandatory renewal was too short a period. Almost one-half expected their use of treatment orders to increase. CONCLUSION: While CTOs are used for only a small number of patients in Saskatchewan, they are a clinically useful tool for dealing with a group of otherwise difficult-to-treat patients.

Molecular characterization of a MSRV-like sequence identified by RDA from monozygotic twin pairs discordant for schizophrenia.

Retroviral-related amplicons were used in modified RDA to identify four sequences from affected members of three pairs of monozygotic twins discordant for schizophrenia. One sequence (schizophrenia associated retrovirus, SZRV-1, GenBank Accession No. AF135487) is characterized here. It is similar to two known sequences of retroviral origin: multiple sclerosis-associated retrovirus, MSRV (GenBank Accession No. AF009668), and ERV-9 (GenBank Accession No. S77575). It is present in multiple copies in the human genome and has been localized to six different chromosomal sites. A zooblot shows that this multicopy sequence is predominant in the primate lineage and present in rhesus monkeys and humans. SZRV-1 is expressed as a 9-kb RNA band in the placenta. This could offer support to the hypothesis that retroviral sequences transposing during fetal growth may alter neurodevelopmental genes and cause diseases, although its direct involvement in the causation of schizophrenia remains to be established.

Review board outcomes for involuntary patients in provincial psychiatric hospitals.

OBJECTIVE: To identify long-term trends and compare different psychiatric hospitals with regard to outcomes of involuntary certification. METHOD: Data on outcomes of involuntary certification were obtained from the London and St Thomas Psychiatric Hospitals for 1987 to 1997, from the Psychiatric Patient Advocate Office pertaining to 10 psychiatric hospitals for 1987 to 1993, and from published data from the North Bay Psychiatric Hospital for 1992 to 1994. Data were compared regarding outcome variables. RESULTS: There are variable rates and proportions among the psychiatric hospitals for outcomes of involuntary certification, including patients choosing to withdraw their applications to Review Boards, physicians cancelling involuntary certificates by completing Form 5s, and Review Boards rescinding certificates. Overall, few certificates were rescinded by the Boards, a trend that was even more pronounced in recent years. CONCLUSIONS: Patients who are in psychiatric hospitals on an involuntary basis are infrequently released from hospital as a result of a Review Board rescinding their certificate.

Why are patients discharged by review boards?

OBJECTIVE: To identify why Review Boards revoked certificates for involuntary hospitalization. METHOD: The outcome of all applications for a Review Board hearing at 2 psychiatric hospitals in Ontario were recorded from the beginning of 1987 to the end of 1996. All cases where a certificate of involuntary hospitalization was revoked were identified. For each of these cases, the clinical record, including the Review Board's written reasons for its decision, was reviewed. RESULTS: During the study period, 2644 patients applied for a review of their involuntary hospitalization. Only 42% of applications reached a hearing. Of these, 9% were revoked. Several recurring reasons for overturning certificates were identified. These included the physician relying too much on hearsay evidence, relatives supporting discharge at the hearings, and the patient clearly having recovered by the time the hearing took place. CONCLUSIONS: Relatives or staff who observe dangerous behaviour should be encouraged to give evidence at hearings. The treatment team should take careful note of the views of patients' families and friends and review the patients' progress before hearings.

Search for retroviral related DNA polymorphisms using RAPD PCR in schizophrenia.

Random amplification of polymorphic DNA (RAPD) is widely used to detect polymorphisms in many organisms. Individual (or strain) specific amplified bands are generated with single or pairs of primers in PCR reactions and can serve as genetic markers. We have used this method to generate a large number of reproducible bands with single primers, random and retroviral related, on 92 human DNA samples. Theoretically, RAPD PCR presents a logical approach for assessing variability among individuals. We used ten retroviral related primers (12, 20 and 22 bp) and eight random primers (10 bp) to assess individual differences in the context of testing the retroviral hypothesis for schizophrenia. Three pairs of discordant monozygotic twins, four pairs of discordant full sibs and 53 schizophrenic individuals with 25 of their unrelated matched controls were analyzed. Ten of these primers resulted in a total of approx. 850 amplified bands (65-110 bands per primer). Almost all of these bands were identical among each individual analyzed. However, the results are inconclusive with respect to the retroviral hypothesis for schizophrenia. The general lack of RAPD polymorphism in this study may argue for mechanisms other than rearrangements such as inversions, associated with the evolution of the human genome.

The relationship of catatonia symptoms to symptoms of schizophrenia.

OBJECTIVE: To evaluate the relationships of symptoms of catatonic schizophrenia to 77 symptoms relevant for diagnosing schizophrenia and to socioanamnestic variables. METHOD: Data from a sample of 112 Canadian patients diagnosed with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) were evaluated via phi correlation coefficients. RESULTS: Forty-five (40.2%) of our 112 patients had catatonic symptoms, either at the time of this study or in the past. However, only weak correlations (phi < 0.31) to other symptoms relevant for diagnosing schizophrenia were found, and no significant correlations to socioanamnestic variables were found. CONCLUSION: Symptoms of catatonia appear to be independent of the key symptoms of schizophrenia.

A single-primer PCR-based retroviral-related DNA polymorphism shared by two distinct human populations.

Almost 10% of the human genome consists of DNA sequences that share homology with retroviruses. These sequences, which represent a stable component of the human genome (although some may retain the ability to transpose), remain poorly understood. We used degenerate primers specific to the two conserved regions (boxes 4 and 5) of the retroviral pol gene, common to all retroviruses, and PCR-amplified related sequences from individuals representing two distinct populations: Caucasians and Dogrib Indians. The large number of sequences that are reproducibly amplified represent numerous sites of retroviral integration in the human genome. In both populations studied, one of the two primers yielded a polymorphic band, present in approximately 30% of the samples, that has probably been present in the human genome since before the divergence of the two populations approximately 10,000 years ago. It was established that this polymorphism was due to priming-site differences and not to deletions. Further, this priming site is duplicated at two genomic sites (representing 341- and 343-bp fragments) with at least two alleles each. Such novel polymorphisms should provide useful markers and permit assessment of evolutionary mechanisms associated with retroviral-related genomic evolution.

Mental health legislation and the right to appropriate treatment.

OBJECTIVE: To demonstrate how mental health legislation and its implementation can detract from a patient's "right to health." METHOD: The author surveyed colleagues working at the London and St Thomas Psychiatric Hospitals about cases where the structure or implementation of the Mental Health Act in Ontario impeded the provision of good psychiatric care. RESULTS: Four clinical vignettes illustrate specific problems; possible solutions to these difficulties are suggested. CONCLUSION: Physicians must remain vigilant in their role as advocates for patients' right to appropriate treatment.

Sensation Seeking Scales and consumer satisfaction with a substance abuse treatment program.

Satisfaction of 119 addicts with an addiction treatment program was measured by an 11 item satisfaction scale. The scale's internal consistency was acceptable (Cronbach's alpha = .75). The total satisfaction score was weakly but significantly correlated with Zuckerman's Sensation Seeking scales: Those with higher scores on the Boredom Susceptibility scale (i.e., those easily bored) reported less satisfaction, whereas those with higher scores on Thrill and Adventure Seeking scale (i.e., risk, adventure, and thrill seekers) reported higher levels of treatment satisfaction. Older patients were more satisfied with the feedback they received from their psychological tests and also with staff's respect for their rights.