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.

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."

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.

Relational ethics: when mothers suffer from psychosis.

OBJECTIVE: The goal of this review is to aid clinicians with ethical issues arising in the treatment of women who suffer from psychosis. METHOD: This paper is a synthesis of the recent literature in adult and child psychiatry, ethics, law, and child welfare pertaining to the topic of maternal psychosis. Topics include: family planning, the care of pregnant women with schizophrenia, postpartum psychosis, child custody, involuntary treatment, confidentiality issues, and service fragmentation. CONCLUSION: Appreciation of the particularized circumstances of issues arising in the treatment of mothers who suffer from psychosis serve the clinician better than the dispassionate application of a principle-driven ethic.

Does nicotine affect D2 receptor upregulation? A case-control study.

OBJECTIVE: Nicotine has a powerful preventive effect on neuroleptic-induced dopamine D2 receptor upregulation in the rat. The aim of this human positron emission tomography (PET) study was to compare upregulation in a smoker and a non-smoker, both of whom had received haloperidol for the same duration of time. METHOD: Two subjects who had been treated for 16 years with a constant dose of haloperidol were scanned after temporary haloperidol withdrawal, using [11C]-raclopride. RESULTS: The non-smoker, who had received a dose of 10 mg/day, showed a D2 upregulation of 98% and developed severe and persistent symptoms of tardive dyskinesia (TD) upon withdrawal. The chronic smoker, who had been treated with 40 mg/day, displayed a D2 upregulation of 71% and did not develop TD. CONCLUSION: These human observations agree with animal data which showed that nicotine can decrease neuroleptic-induced D2 receptor upregulation. This property of nicotine may play a protective role in movement disorders whose pathophysiology involves D2 receptor hypersensitivity.

Antipsychotic drugs, menstrual regularity and osteoporosis risk.

This report summarizes the preliminary results of a study in progress, a survey of 200 women with schizophrenia in long-term treatment with antipsychotic medication. In the context of providing clinical service to these women (Seeman, 1997; Seeman and Cohen, 1998), we have begun to investigate the possibility of an association among related factors: type of antipsychotic drug use, the presence of amenorrhea, hyperprolactinemia and risk for osteoporosis (Biller et al., 1992; Grinspoon et al., 1999; Halbreich and Palter, 1996; More et al., 2001; Peuskens, 1997; Sowers et al., 1995).

An animal model of nicotinic-acid-induced vasodilation: effect of haloperidol, caffeine and nicotine upon nicotinic acid response.

BACKGROUND: The normal vasodilatory response to ingestion of nicotinic acid (NA) is impaired in some patients with schizophrenia. It is unclear whether the impairment is a feature of the disorder itself or to a confounding factor such as neuroleptics, caffeine or nicotine use. METHODS: To address this question in a controlled manner, we have developed an animal (rat) model of NA-induced vasodilation, in which response is monitored by measuring change in skin temperature. RESULTS: We observed that (i) acute administration of acetylsalicylic acid (100mg/kg), caffeine (2.5mg/kg) and haloperidol (0.1 or 0.5mg/kg) and (ii) chronic administration of haloperidol (0.2mg/kg/day) significantly inhibited NA (30 mg/kg) response, whereas neither acute (0.25mg/kg) or chronic (0.5mg/kg/day for 14 days) administration of nicotine, or chronic administration of caffeine (5mg/kg/day for 14 days) had any significant effect upon NA response. CONCLUSIONS: Our data suggest that at least one drug commonly used to treat schizophrenia (haloperidol) can interfere with the vasodilatory response to NA. Studies using non-medicated patients with schizophrenia are required to determine whether reduced vasodilatory response to NA in schizophrenia is a feature of the disorder or a consequence of treatment.

Clinical trials in psychiatry: do results apply to practice?

OBJECTIVE: The purpose of this communication is to alert psychiatrists to the difficulties of translating results of group difference obtained from large, randomized clinical trials to the treatment of individual patients. METHOD: Reported discrepancies between a) clinical trial participants and general psychiatric patients, b) clinical trial investigators and general clinicians, and c) study trial and usual clinic conditions were assessed. RESULTS: The results confirm that important differences exist in all 3 areas. CONCLUSIONS: Recommendations for researchers include more complete assessments of factors that account for individual difference, an appraisal of outcomes more important to patients than symptom scores, and the use of statistical methods that permit the evaluation of individual difference. Recommendations for clinicians include a careful differentiation of results obtained in different phases of clinical trials and a clear appreciation of the different purposes of those trials. Clinicians should also appreciate that short-term effectiveness is not the same as long-term outcome and that aggregate scores may not apply to individual patients.

Adverse reactions to St John's Wort.

OBJECTIVE: To report 2 cases of adverse reactions to St John's wort, a popular herbal treatment for depression. METHOD: We present 2 case histories and review the existing literature regarding St John's wort. RESULTS: St John's wort may cause serotonin syndrome in sensitive patients. In addition, St John's wort may be associated with hair loss. CONCLUSIONS: For clinical reasons, it is important to recognize and report adverse reactions to herbal remedies and to document that these treatments have side effects commensurate with their potent action on brain neurochemistry.

Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study.

RATIONALE: Dopamine D2 receptor upregulation in the striatum is regularly seen in response to the administration of traditional antipsychotics in animal experiments. This is associated with hyperactivity and, for this reason, D2 receptor upregulation has long been postulated as central to tardive dyskinesia (TD). OBJECTIVE: Using positron emission tomography (PET), the present study attempted to determine whether antipsychotic-induced D2 receptor up-regulation also occurs in humans. METHODS: The long-term effects of traditional and novel antipsychotics on dopamine D2 receptors were investigated in nine subjects meeting DSM-IV criteria for schizophrenia who were deemed eligible for temporary treatment washout. Subjects had been treated with traditional antipsychotics (haloperidol n=3, perphenazine n=1) and novel antipsychotics (risperidone n=3, olanzapine n=2) in the moderate to high dosage range. Fourteen days after treatment withdrawal, the binding potentials (BPs) of dopamine D2 receptors were measured using 11[C] raclopride. The obtained BPs were compared to the BPs from antipsychotic-naive control subjects with schizophrenia. RESULTS: There was a significant increase in the D2 BP in both groups combined that reached 34%. The increases in the D2 BPs in the groups treated with conventional and novel antipsychotics were 37% and 31%, respectively. Significantly, the patients showing the highest degree of D2 receptor upregulation (98%) developed severe and persistent TD shortly after being started on a new antipsychotic with low affinity for D2 receptors. CONCLUSION: This study demonstrates for the first time, using in vivo neuroreceptor imaging, that dopamine D2 receptor binding is increased after long-term treatment with antipsychotics in humans. The data suggest that both traditional and novel antipsychotics with high affinity for dopamine D2 receptors are associated with a substantial increase in D2 receptor binding. The present data in humans agree well with animal data that implicate D2 receptor-mediated mechanisms in motor hyperactivity.

Duration of pretreatment phases in schizophrenia: women and men.

OBJECTIVE: To determine the relative duration of the prepsychotic prodrome and the period of untreated psychosis in women and men with schizophrenia. METHOD: From a larger study population, we selected 27 women and 34 men treated at 1 facility. To determine the time of first behavioural change and the time of first psychotic symptoms, we administered the Interview for the Retrospective Assessment of the Onset of Schizophrenia (IRAOS). Subjects' mothers were interviewed using the same instrument. Time of first treatment was determined by hospital record. RESULTS: The first sign of behavioural disturbance occurred at approximately the same age in women and men. The prepsychotic prodrome was almost twice as long for women as for men. The duration of untreated psychosis did not differ between the 2 sexes. Substance abuse did not influence the observed difference between men and women in the duration of the prepsychotic phase. The interval between first behavioural sign and first treatment was, on average, 6 years for men and 9 years for women. CONCLUSION: As-yet-unknown factors speed up the progression from nonspecific symptoms to psychosis in men or delay it in women.

Women and schizophrenia.

Several important questions emerge from the study of gender differences in schizophrenia: Why does schizophrenia begin later in women? Why is outcome superior in women, at least in the first 15 years after onset? What causes sex differences in symptoms? What can gender differences teach us about the etiology of schizophrenia? Do men and women require substantially different treatments? What interventions during pregnancy and after childbirth ensure optimal health for the children of mothers with schizophrenia? Although complete answers may not yet be forthcoming, it is important to define the questions and keep them in mind when delivering services to women suffering from this severe, persistent mental illness.

Estrogen receptor activation and tardive dyskinesia.

OBJECTIVE: To undertake a selective review of the epidemiology, etiology, and treatment of tardive dyskinesia (TD), with emphasis on the potential influence of estrogen in its expression. METHOD: Both Medline and Psycinfo databases were used to search for articles with the following key words: tardive dyskinesia, humans, animals, dopamine, estrogen, estrogen replacement therapy, antioxidants and oxidative stress. RESULTS: The studies reviewed here suggest that estrogen modulates dopamine-mediated behaviours and that it protects against oxidative stress-induced cell damage caused by long-term exposure to antipsychotic medication. CONCLUSIONS: Estrogen's multimodal role in the central nervous system may prove useful for the amelioration or prevention of TD. All the evidence suggests that a placebo-controlled, randomized trial with safer forms of estrogen should be conducted in postmenopausal women with TD.