Risk factors and peripheral biomarkers for schizophrenia spectrum disorders: an umbrella review of meta-analyses.

OBJECTIVE: This study aimed to systematically appraise the meta-analyses of observational studies on risk factors and peripheral biomarkers for schizophrenia spectrum disorders. METHODS: We conducted an umbrella review to capture all meta-analyses and Mendelian randomization studies that examined associations between non-genetic risk factors and schizophrenia spectrum disorders. For each eligible meta-analysis, we estimated the summary effect size estimate, its 95% confidence and prediction intervals and the I2 metric. Additionally, evidence for small-study effects and excess significance bias was assessed. RESULTS: Overall, we found 41 eligible papers including 98 associations. Sixty-two associations had a nominally significant (P-value <0.05) effect. Seventy-two of the associations exhibited large or very large between-study heterogeneity, while 13 associations had evidence for small-study effects. Excess significance bias was found in 18 associations. Only five factors (childhood adversities, cannabis use, history of obstetric complications, stressful events during adulthood, and serum folate level) showed robust evidence. CONCLUSION: Despite identifying 98 associations, there is only robust evidence to suggest that cannabis use, exposure to stressful events during childhood and adulthood, history of obstetric complications, and low serum folate level confer a higher risk for developing schizophrenia spectrum disorders. The evidence on peripheral biomarkers for schizophrenia spectrum disorders remains limited.

Factors associated with postpartum psychiatric admission in a population-based cohort of women with schizophrenia.

OBJECTIVE: We aimed to identify factors associated with postpartum psychiatric admission in schizophrenia. METHOD: In a population-based cohort study of 1433 mothers with schizophrenia in Ontario, Canada (2003-2011), we compared women with and without psychiatric admission in the 1st year postpartum on demographic, maternal medical/obstetrical, infant and psychiatric factors and identified factors independently associated with admission. RESULTS: Admitted women (n = 275, 19%) were less likely to be adolescents, more likely to be low income and less likely to have received prenatal ultrasound before 20 weeks gestation compared to non-admitted women. They also had higher rates of predelivery psychiatric comorbidity and mental health service use. Factors independently associated with postpartum admission were age (<20 vs. ≥35 years: adjusted risk ratio, aRR, 0.48, 95% CI 0.24-0.96), income (lowest vs. highest income: aRR 1.67, 1.13-2.47) and the following mental health service use factors in pregnancy: admission (≥35 days/year vs. no days, aRR 4.54, 3.65-5.65), outpatient mental health care (no visits vs. ≥2 visits aRR 0.35, 0.27-0.47) and presence of a consistent mental health care provider during pregnancy (aRR 0.69, 0.54-0.89). CONCLUSION: Certain subgroups of women with schizophrenia may benefit from targeted intervention to mitigate risk for postpartum admission.

Maternal and newborn outcomes among women with schizophrenia: a retrospective population-based cohort study.

OBJECTIVE: More women with schizophrenia are becoming pregnant, such that contemporary data are needed about maternal and newborn outcomes in this potentially vulnerable group. We aimed to quantify maternal and newborn health outcomes among women with schizophrenia. DESIGN: Retrospective cohort study. SETTING: Population based in Ontario, Canada, from 2002 to 2011. POPULATION: Ontario women aged 15-49 years who gave birth to a liveborn or stillborn singleton infant. METHODS: Women with schizophrenia (n = 1391) were identified based on either an inpatient diagnosis or two or more outpatient physician service claims for schizophrenia within 5 years prior to conception. The reference group comprised 432 358 women without diagnosed mental illness within the 5 years preceding conception in the index pregnancy. MAIN OUTCOME MEASURES: The primary maternal outcomes were gestational diabetes mellitus, gestational hypertension, pre-eclampsia/eclampsia, and venous thromboembolism. The primary neonatal outcomes were preterm birth, and small and large birthweight for gestational age (SGA and LGA). Secondary outcomes included additional key perinatal health indicators. RESULTS: Schizophrenia was associated with a higher risk of pre-eclampsia (adjusted odds ratio, aOR 1.84; 95% confidence interval, 95% CI 1.28-2.66), venous thromboembolism (aOR 1.72, 95% CI 1.04-2.85), preterm birth (aOR 1.75, 95% CI 1.46-2.08), SGA (aOR 1.49, 95% CI 1.19-1.86), and LGA (aOR 1.53, 95% CI 1.17-1.99). Women with schizophrenia also required more intensive hospital resources, including operative delivery and admission to a maternal intensive care unit, paralleled by higher neonatal morbidity. CONCLUSIONS: Women with schizophrenia are at higher risk of multiple adverse pregnancy outcomes, paralleled by higher neonatal morbidity. Attention should focus on interventions to reduce the identified health disparities.

Clinical interventions for women with schizophrenia: pregnancy.

OBJECTIVE: A comprehensive treatment program for schizophrenia needs to include services to women of childbearing age that address contraception, pregnancy, and postpartum issues, as well as safe and effective parenting. To update knowledge in these areas, a summary of the recent qualitative and quantitative literature was undertaken. METHOD: The search terms 'sexuality,''contraception,''pregnancy,''postpartum,''custody,' and 'parenting' were entered into PubMed, PsycINFO, and SOCINDEX along with the terms 'schizophrenia' and 'antipsychotic.' Publications in English for all years subsequent to 2000 were retrieved and their reference lists further searched in an attempt to arrive at a distillation of useful clinical recommendations. RESULTS: The main recommendations to care providers are as follows: take a sexual history and initiate discussion about intimate relationships and contraception with all women diagnosed with schizophrenia. During pregnancy, adjust antipsychotic dose to clinical status, link the patient with prenatal care services, and help her prepare for childbirth. There are pros and cons to breastfeeding while on medication, and these need thorough discussion. During the postpartum period, mental health home visits should be provided. Parenting support is critical. CONCLUSION: The comprehensive treatment of schizophrenia in women means remembering that all women of childbearing age are potential new mothers.

Menstrual exacerbation of schizophrenia symptoms.

OBJECTIVE: To better understand premenstrual exacerbations of schizophrenia in women and weigh treatment options. METHOD: A PubMed literature search was conducted, using the search terms 'schizophrenia', 'psychosis', 'menstrual exacerbation', 'hormones' and assessing relevance to premenstrual exacerbation of schizophrenia symptoms. RESULTS: Exacerbations are usually distinguishable from periodic or menstrual psychosis, a relatively rare condition. Controversy continues about whether low estrogen periods of the month lead to an increase in schizophrenia symptoms among women of reproductive age or whether some women suffer from both schizophrenia and premenstrual dysphoric disorder (PMDD). No treatment trials of specific interventions have been conducted so that physicians must decide on a case-by-case basis whether to raise antipsychotic doses premenstrually, try estrogens or estrogen/progesterone combinations or selective estrogen receptor modulators, or target PMDD symptoms. CONCLUSION: Clinicians need to be aware of premenstrual symptom aggravation in a large minority of women with schizophrenia. Treatment strategies will depend on the nature of the symptoms that are exacerbated. Optimal treatment needs to be adjusted to the individual woman.

Preventing breast cancer in women with schizophrenia.

OBJECTIVE: To record risk factors for breast cancer in women with schizophrenia and recommend preventive actions. METHOD: A PubMed literature search (from 2005 to 2010) was conducted, using the search terms 'schizophrenia', 'antipsychotics', 'breast cancer' and 'risk factors'. RESULTS: Several risk factors of relevance to schizophrenia were identified: obesity, elevated prolactin levels, low participation in mammography screening, high prevalence of diabetes, comparatively low parity, low incidence of breastfeeding, social disadvantage, high levels of smoking and alcohol consumption, low activity levels. CONCLUSION: Awareness of breast cancer risk should lead to more accurate risk ascertainment, stronger linkage with primary care, regular monitoring and screening, judicious choice and low dose of antipsychotic treatment, concomitant use of adjunctive cognitive and psychosocial therapies, referral to diet and exercise programmes as well as smoking and drinking cessation programmes, avoidance of hormonal treatment and discussion with patient and family about the pros and cons of preventive measures in high-risk women. Psychiatrists are in a position to reverse many of the identified risk factors.

Delusional loving.

Erotomania is reexamined by an in-depth study of eight patients. There appear to be two main varieties: the phantom lover syndrome, or fixed delusion elaborated around a person who does not exist, and erotomania proper, a recurrent tendency to believe that one is loved by a powerful, prominent man.

Schizophrenia and the influence of male gender.

Adolescent boys are the demographic group most likely to receive a diagnosis of schizophrenia. Before adulthood, boys accumulate more potential brain hazards than girls, and this may predispose them to disordered neurodevelopment during adolescence. Hormonal and immune gender differences that emerge at this time likely play an additional and significant role. Very recently, gender differences can be examined even before the onset of full-blown illness, in individuals at "clinically high risk."

Temporal horn enlargement is present in schizophrenia and bipolar disorder.

BACKGROUND: Ventricular enlargement and temporal lobe volume deficits have been demonstrated in patients with affective disorder as well as those with schizophrenia. This study compares quantitative measures of temporal lobe, hemispheric, and ventricular volumes in a group of patients with chronic schizophrenia and bipolar disorder and seeks to determine if the groups can be differentiated on the basis of measured brain abnormalities. METHODS: A series of coronal magnetic resonance imaging sections were acquired and analyzed for each of 22 patients with chronic schizophrenia, 14 patients with bipolar disorder, and 15 community volunteers. Eleven regions of interest for each brain were defined, which included temporal lobe, superior temporal gyrus, hemisphere, lateral ventricle, third ventricle, and temporal horn measures. Tissue measures were obtained by tracing, and cerebrospinal fluid measures were obtained by fluid-tissue thresholding using specialized computer software. RESULTS: Both patient groups had significantly larger temporal horn volumes in comparison with the control group both before and after correction for intracranial volume. The two patient groups did not differ from each other or controls on any other tissue or fluid measure. CONCLUSIONS: This study confirms the findings of increased temporal horn volume in patients with schizophrenia and suggests that this structural abnormality does not differentiate the structural neuropathology of schizophrenia from that of bipolar disorder.

Psychopathology in women and men: focus on female hormones.

OBJECTIVE: The goal of this overview is to examine male/female differences in psychopathology in light of the known effects of gonadal steroids, especially estradiol, on neural function. METHOD: The epidemiology of specific psychopathological syndromes is highlighted with respect to male/female differences and discussed against the backdrop of recent neuroendocrine findings. RESULTS: A number of differences between the sexes in rates of illness and course of illness are documented, with Alzheimer's disease, schizophrenia, alcoholism, and mood and anxiety disorders each illustrating slightly different hormone-mediated risks and buffers. CONCLUSIONS: Estrogens are neuroprotective with respect to neuronal degeneration, growth, and susceptibility to toxins. The cyclic fluctuations of estrogens and progesterone enhance the response to stress, which confers susceptibility to depression and anxiety.

Neuroleptic-free intervals in the treatment of schizophrenia.

During a period of 1-2 1/2 years the neuroleptic regimen of 14 schizophrenic outpatients was interrupted every 6 months by drug holidays of 6 weeks' duration. As a result, 10 patients achieved a substantially reduced maintenance dose. The authors were unable to predict for whom the drug holidays would be safe.

Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. The International Late-Onset Schizophrenia Group.

OBJECTIVE: Although schizophrenia is generally regarded as an illness with onset in late adolescence or early adult life, a sizeable minority of patients first become ill in middle or old age. Inconsistencies in diagnostic systems and nomenclature, coupled with a tendency among most schizophrenia researchers to ascribe late-onset psychoses to organic factors, have led to such cases occupying an ambiguous position in relation to schizophrenia. Through systematic review of the literature and publication of a consensus statement from an international group of experts in the field, this article aims to clarify the positions of late-onset schizophrenia and very-late-onset schizophrenia-like psychosis. METHOD: The authors conducted a MEDLINE literature review and developed a consensus statement summarizing the findings from 2 days of debate and discussion by members of the International Late-Onset Schizophrenia Group. RESULTS: The group achieved consensus on diagnosis, nomenclature, treatment guidelines, and future research directions. CONCLUSIONS: In terms of epidemiology, symptom profile, and identified pathophysiologies, the diagnoses of late-onset schizophrenia (illness onset after 40 years of age) and very-late-onset schizophrenia-like psychosis (onset after 60 years) have face validity and clinical utility. General adoption of these categories will foster systematic investigation of such patients.

Earlier puberty as a predictor of later onset of schizophrenia in women.

OBJECTIVE: The aim of this study was to determine whether puberty plays a mediating role in onset of schizophrenia. The hypothesis was that there is an inverse relation between age at puberty (menarche) and age at onset in women. METHOD: Competent and consenting individuals with DSM-IV-defined schizophrenia or schizoaffective disorder and their mothers underwent a 45-minute interview to ascertain age at first odd behavior, age at first psychotic symptoms, age at first hospitalization, and ages at various indices of puberty. Information about substance use, head injury, perinatal trauma, and first-degree family history of schizophrenia was also obtained. RESULTS: In the women (N = 35), the earlier the age at menarche, the later the ages at both the first psychotic symptoms and the first hospitalization. There was no significant association between puberty and onset in the men (N = 45). Other than gender, none of the examined variables played a role in the interaction of puberty and onset of illness. CONCLUSIONS: In women, early puberty (whether through hormonal or social influence) was associated with later onset of schizophrenia. This effect was not found in men; in fact, the trend was in the opposite direction.

Schizophrenia: normal sequence in the dopamine D2 receptor region that couples to G-proteins. DNA polymorphisms in D2.

Because dopamine (DA) D2 receptors are a target in neuroleptic therapy and have been found to be elevated in schizophrenia, the human DA D2 receptor gene was examined for possible abnormalities in schizophrenia. Moreover, since D2 receptors in psychosis have a reduced coupling to D1 receptors, the cytoplasmic third loop of D2 was chosen for deoxyribonucleic acid (DNA) sequencing, since this region is essential for coupling to G-proteins. This region also contains exon 5, which is expressed in the long form of D2, but not in the short form of D2. In eight schizophrenia cases, this region had normal exon sequences (exons 4, 5 and 6), and normal sequences at its intron-exon junctions. However, exon 6 contained three DNA polymorphic base changes, and introns 4 and 5 revealed three missing bases and two polymorphic base changes, none of which would be expected to alter the D2 receptor protein in schizophrenia.

Clinic versus private treatment of psychosis.

Thirty patients with a hospital diagnosis of schizophrenia were randomly assigned upon discharge to either 1) a specialized aftercare clinic of 2) to private psychiatrists. At the end of six months, the clinic patients had spent significantly less time as hospital readmissions and were significantly more occupied (i.e. employed or in school) than the private patients. It seems possible that attendance at clinic provides group pressure to maintain drug compliance and may thus work to reduce rehospitalization. It is also likely that the network of clinic paramedical and volunteer staff, by its flexibility and availability, aids the patient's transition into employment.

Marital therapy with borderline patients: is it beneficial?

Marital therapy has developed techniques which do not, for the most part, rely on the individual psychiatric diagnosis of the 2 partners. When both spouses suffer from Borderline personality disorders, the standard techniques do not seem to apply, are difficult to put into effect and the results of therapy are poor. The authors illustrate their experience with the description of a 3 month trial of marital therapy involving a borderline couple. The outcome suggests the need for careful individual and interactional diagnosis prior to marital therapy. Specific psychotherapeutic techniques should be tested for use with Borderline marriage partners.

Hormonal side effects in women: typical versus atypical antipsychotic treatment.

Neuroleptic-induced hyperprolactinemia can cause menstrual disorders, impaired fertility, galactorrhea, and sexual dysfunction, as well as hypoestrogenism secondary to disruption of the hypothalamic-pituitary-ovarian axis. The development of the prolactin-sparing atypical antipsychotic drugs offers prevention and resolution of these adverse reactions. Thus far, this property of the new medications has received insufficient clinical attention. The authors use case vignettes to discuss assessment and management of clinical situations that arise as a result of antipsychotic-induced endocrine changes.

Tardive dyskinesia with Tourette-like syndrome.

This is a single case study of a 22 year old Japanese-Canadian woman who developed schizophrenia, was treated with ECT and several successive neuroleptics and subsequently, three years later, developed a tardive dyskinesia syndrome in association with a behavioral change resembling Gilles de la Tourette disease. This combined syndrome lasted seven months. After neuroleptics were withdrawn, the syndrome diminished in severity and disappeared after four months. Since both tardive dyskinesia and Tourette's disease are thought to be caused by relative overactivity or supersensitivity of the dopamine system, their reversible appearance after long term dopamine receptor blockade by neuroleptics can be expected in susceptible individuals.

Tardive dyskinesia in schizophrenic outpatients: prevalence and significant variables.

All the patients (N = 94) of an outpatient clinic for schizophrenia were evaluated for the presence and severity of neuroleptic induced tardive dyskinesia. Fourty-four percent of the patients showed some degree of tardive dyskinesia. The proportion of patients with tardive dyskinesia increased directly with age and with number of years of neuroleptic treatment. Recent dose reduction exacerbated the syndrome. There were no gender differences in the clinic as a whole. Severity of dyskinesia correlated with anticholinergic drug use, with the piperazine/butyrophenone group of neuroleptics and with the use of depot-administered drugs. The depot correlation was highly significant in the under-30 age group.

A human serotonin-7 receptor pseudogene.

Although the serotonin-7 receptor was cloned several years ago, its localization in brain tissues remains confusing because of the existence of a related expressed pseudogene, the sequence of which has not hitherto been reported. During the course of searching for related receptor genes, we also searched for this pseudogene to determine its sequence. Human genomic DNA was screened for dopamine and serotonin receptor-like genes, using the polymerase chain reaction method and degenerate oligonucleotide primers based on the similar sequences in the transmembrane-6 and -7 regions of the serotonin-5A, the serotonin-7, and the dopamine D2, D3 and D4 receptors. This resulted in one of the clones having a 115 bp fragment, of which 89% of the bases were identical to the transmembrane-6 and -7 regions of the serotonin-7 receptor sequence. The fragment was radiolabelled and used to screen a human fetal brain cDNA library. A novel cDNA clone of 1326 bp was isolated. Based on the nucleotide sequence, 88% of the bases in this sequence of the pseudogene are identical to the human serotonin-7 receptor coding sequence. However, compared to the serotonin-7 receptor DNA sequence, the pseudogene sequence has nucleotide deletions and insertions, resulting in frame-shifts and stop codons. It was concluded that this sequence represented a pseudogene related to the serotonin-7 receptor gene.