No association of a dodecamer duplication in the human opposite paired (HOPA) gene with mental retardation and schizophrenia in Chinese patients from Taiwan

The human opposite paired-containing (HOPA) gene is believed to be a co-activator of the thyroid hormone receptor and involved in thyroid hormone signal transduction. The gene consists of 45 exons and includes a dodecamer duplication in exon 43, which has been reported to be associated with mental retardation, autism, psychiatric disorders and hypothyroidism. We were interested to know if the 12-bp duplication variant of the HOPA gene is a risk factor for mental retardation and schizophrenia in the Chinese population. We investigated the prevalence of the 12-bp variant in a sample of Chinese mental retardation and schizophrenic patients from Taiwan by PCR-based genotyping. None of the mentally retarded and schizophrenic patients were found to have this dodecamer duplication variant. Our results indicate that the HOPA polymorphism might be very rare in our population and is unlikely to be a major risk factor for mental retardation and schizophrenia in the Chinese population.     

Lithium-induced subclinical hypothyroidism: review of the literature and guidelines for treatment

BACKGROUND: This review addresses the definition, prevalence, etiology, and clinical significance of lithium-associated subclinical hypothyroidism and offers guidelines for evaluation and treatment of this condition. DATA SOURCES: MEDLINE was used to search all articles written in English from 1964-present that included the words lithium and thyroid; lithium and subclinical hypothyroidism; mood and thyroid function; and bipolar illness and thyroid function. STUDY FINDINGS: Lithium interferes with thyroid metabolism and increases the incidence of overt and subclinical hypothyroidism. Subclinical hypothyroidism may be associated with the presence of somatic and neuropsychiatric symptoms and interfere with treatment responsiveness. CONCLUSION: A careful assessment of thyroid function is recommended prior to initiating lithium treatment and during maintenance treatment. Recommendations regarding the threshold for initiation of thyroxine supplementation in patients with lithium-associated subclinical hypothyroidism are discussed in relationship to the degree of detrimental effects potentially associated with thyroid dysfunction.     

Low birth weight and risk of affective disorders and selected medical illness in offspring at high and low risk for depression

Numerous studies have demonstrated that low birth weight (LBW) is associated with the development of medical conditions, such as hypertension and diabetes, and psychiatric disorders, such as depression. One possible mechanism through which LBW might increase risk for both medical and psychiatric disorders is by altering the biologic systems (such as the hypothalamic-pituitary-adrenal [HPA] axis function) that govern emotion regulation and physical reactivity. In this study, we conducted secondary data analyses in a longitudinal study originally designed to understand the intergenerational transmission of major depressive disorder (MDD). We examined the risk for both medical and psychiatric illnesses known to be influenced by HPA axis dysregulation in the context of parental depression. The study had 2 primary objectives: (1) to examine whether LBW increases the risk of selected adult illness that may be influenced by the HPA axis and (2) to examine whether the increased risk of illness varies by parental depression status. We conducted longitudinal assessments of 244 offspring of depressed and nondepressed parents for more than 20 years. Psychopathology and medical illness were assessed by direct interview conducted by clinicians blind to risk status and previous diagnosis. We examined the effect of BW in 3 categories: less than 2.5 kg (LBW), 2.5-3.5 kg, and more than 3.5 kg (reference group). Offspring with LBW had a significantly increased risk of MDD, anxiety disorders, phobia, suicidal ideation, impaired functioning, allergies, and hypertension compared to those with BW exceeding 3.5 kg. The association between LBW and depression was stronger among children of depressed parents than among children of nondepressed parents, with an interaction term (BW and parental depression status) significant for MDD (P = .05), suggesting that parental depression may augment the impact of LBW on offspring depression:     

Reproductive factors affecting the course of affective illness in women

Women are at higher risk than men to develop depressive episodes during the reproductive years. Furthermore, women are vulnerable to depressions associated with oral contraceptives, abortion, the premenstrual period, the puerperium, and menopause. The phenomenology and the biologic mechanisms involved in these illnesses perhaps should be viewed in the context of other manifestations of the link between depression and female reproductive functions. For example, women are especially vulnerable to a rapid cycling form of affective illness and to hypothyroidism, an associated factor for this form of affective disorder. The postpartum period is also associated with impaired thyroid function, and there are reports of the induction of rapid cycles of mood following the termination of pregnancy. Thus, alterations in thyroid hormones may be a feature of both postpartum and rapid cycling forms of affective disorder in women. A previous history of a postpartum depression places a woman at a high risk for the development of a subsequent puerperal episode. Also, difficulties during pregnancy may predispose a woman to the development of other reproductive-related depressions. The role reproductive hormones play in this possible sensitization phenomenon needs to be examined in order to understand the relationship of depression to the female reproductive cycle.     

A perspective on the thyroid and depression

There is extensive literature documenting an association between abnormalities of the hypothalamic-pituitary-thyroid axis and disorders of mood. However, the specific abnormality in thyroid functioning associated with primary affective disorder remains poorly understood. Various aspects of the relationship between thyroid functioning and affective illness are reviewed. Particular attention is paid to psychiatric symptoms and clinical thyroid disorders as well as abnormalities of basal thyroid hormone levels in depression and the use of thyroid hormones in the treatment of depressive illness. Current hypotheses regarding the association between altered thyroid functioning and depressive illness are critically reviewed.     

Physical and psychiatric comorbidities among patients with severe mental illness as seen in Uganda

While psychiatric and physical comorbidities in severe mental illness (SMI) have been associated with increased mortality and poor clinical outcomes, problem has received little attention in low- and middle-income countries (LMICs). This study established the prevalence of psychiatric (schizophrenia, bipolar affective disorder, and recurrent major depressive disorder) and physical (HIV/AIDS, syphilis, hypertension and obesity) comorbidities and associated factors among 1201 out-patients with SMI (schizophrenia, depression and bipolar affective disorder) attending care at two hospitals in Uganda. Participants completed an assessment battery including structured, standardised and locally translated instruments. SMIs were established using the MINI International Neuropsychiatric Interview version 7.2. We used logistic regression to determine the association between physical and psychiatric comorbidities and potential risk factors. Bipolar affective disorder was the most prevalent (66.4%) psychiatric diagnoses followed by schizophrenia (26.6%) and recurrent major depressive disorder (7.0%). Prevalence of psychiatric comorbidity was 9.1%, while physical disorder comorbidity was 42.6%. Specific comorbid physical disorders were hypertension (27.1%), obesity (13.8%), HIV/AIDS (8.2%) and syphilis (4.8%). Potentially modifiable factors independently significantly associated with psychiatric and physical comorbidities were: use of alcohol for both syphilis and hypertension comorbidities; and use of a mood stabilisers and khat in comorbidity with obesity. Only psychiatric comorbidity was positively associated with the negative outcomes of suicidality and risky sexual behaviour. The healthcare models for psychiatric care in LMICs such as Uganda should be optimised to address the high burden of psychiatric and physical comorbidities.

     

History of major depression is associated with neuropsychiatric symptoms but not systemic inflammation in a cross-sectional study in obese patients

Obesity is a major public health burden associated with neuropsychiatric comorbidities leading to social and occupational impairment. Given the growing prevalence of both obesity and mental disorders worldwide, understanding the risk factors of obesity-related neuropsychiatric comorbidities is crucial to develop preventive strategies and individualized treatments. Recent findings suggest that adiposity-driven inflammation contributes to neuropsychiatric comorbidities in obesity. However, not all obese subjects afflicted with chronic inflammation develop neuropsychiatric symptoms, suggesting additional risk factors. The aim of this study was to investigate the impact of personal history of major depressive disorder (MDD) on obesity-related inflammation and neuropsychiatric symptoms, and their relationship.A case-control study was conducted comparing 66 obese patients (body mass index > 35 kg/m²) and 22 healthy non-obese participants, free of any current neuropsychiatric diseases including MDD. Neuropsychiatric symptoms were assessed using the Neurotoxicity Rating Scale (NRS). Sociodemographic and clinical variables were gathered and blood was collected for the measurement of serum levels of high-sensitivity C-reactive protein (hs-CRP). Multiple regression analyses were performed to assess the contribution of obesity and personal history of MDD to clinical outcomes and inflammatory status in study participants.Hs-CRP levels as well as NRS scores were significantly increased in the obese group. Overall, personal history of depression accounted for increased NRS scores but no significant association was found with inflammatory status. In addition, history of depression did not significantly modulate the relationship of obesity-related inflammation with NRS scores. Interestingly, obese individuals with history of recurrent MDD (n = 13) exhibited higher scores in the cognitive and sickness symptoms dimensions of the NRS compared to obese subjects with history of one depressive episode only.Findings indicate that history of depression contributes to neuropsychiatric symptoms, but not to systemic inflammation, in obese subjects free of current depressive episode. These results provide relevant information on the risk factors that may help identify obese subjects with increased risk of neuropsychiatric comorbidity.     

Preliminary study of the relationship between thyroid status and cognitive and neuropsychiatric functioning in euthyroid patients with Alzheimer dementia.

OBJECTIVE: To investigate whether variations within normal ranges of thyroid functioning are related to cognitive and neuropsychiatric functioning in Alzheimer disease (AD). BACKGROUND: Mild alterations of thyroid hormone levels, even in the normal range, are associated with changes in mood and cognitive functioning in older, nondemented adults, and lower concentrations of thyroid hormones have been shown to be associated with an increased risk for cognitive decline. Less is known about the relationship between thyroid hormone levels and cognitive and neuropsychiatric dysfunction in AD. METHOD: Twenty-eight euthyroid patients with AD on donepezil underwent evaluation of thyroid status, including measures of thyroid-stimulating hormone (TSH) and free thyroxine (FT4), and cognitive and neuropsychiatric assessment with the Alzheimer's Disease Assessment Scale, Neuropsychiatric Inventory, and Visual Analog Mood Scales. RESULTS: Correlational analyses indicated statistically significant associations between FT4 concentrations and self-reported feelings of fear and fatigue. Fear and fatigue were negatively correlated with FT4. There were no significant relationships between thyroid hormones and cognition and other depressive and anxiety symptoms. CONCLUSIONS: Results of this preliminary study support a relationship between thyroid status and neuropsychiatric symptoms in euthyroid individuals with AD, with lower concentrations of FT4 associated with fear and fatigue.     

Evidence for a biological hypothesis of obsessive-compulsive disorder

There is scant but provocative evidence to support the concept of a biological etiology in obsessive-compulsive disorder (OCD). This evidence includes the phenomenologic similarities and associations with other major psychiatric disorders for which there is evidence of biologic etiologies; the genetic studies that show an increased familial occurrence of psychiatric illness including OCD and concordance for this disorder in monozygotic twins; biologic evidence and the historical association of OCD and CNS damage; the treatment response of OCD to antidepressant medication and possibly those medications that selectively modify serotonin neuronal activity and to selective anterior limbic leukotomy. This evidence and the evidence linking OCD to depressive illness are specifically reviewed and discussed.     

History of depression and other psychiatric illness as risk factors for Alzheimer disease in a twin sample

Although case-control studies have found elevated risk for Alzheimer disease (AD) associated with a prior psychiatric history, most of the previous research had inadequate controls for familial risk factors. Putative psychiatric risk factors were evaluated for a registry-based sample of 65 twin pairs discordant for AD. Risk ratios were calculated for psychiatric illness at any time and for episodes more than 10 years before dementia onset. Prior psychiatric illness was significantly associated with elevated risk. Most of these cases represented depressive episodes. When analyses were restricted to individuals whose mental illness commenced more than 10 years before dementia onset, the magnitude of the odds ratio decreased markedly. These findings suggest that a history of psychiatric illness, especially depression, may be associated with an elevated risk for AD. In particular, these results are consistent with an interpretation that symptoms of depression and similar complaints represent prodromal phases of dementia.     

The diagnostic dilemma of myxedema and madness, axis I and axis II: a longitudinal case report

A patient with presumed chronic paranoid schizophrenia had chronic thyroiditis and Grade I hypothyroidism. Psychosis cleared following treatment with thyroid replacement. The probable presence of two axis II disorders may have contributed to the missed medical diagnosis and the patient's eventual suicide. The personality disorders were a major problem in the patient's medical and psychiatric care. The differential diagnosis among hypothyroidism and primary axis I psychotic and depressive psychopathology has always been problematic. When axis II pathology is also present, the diagnostic dilemma is increased.     

Perinatal factors in the expression of Tourette's syndrome: an exploratory study

The search for nongenetic factors that mediate the expression of a genetic vulnerability to Tourette's syndrome (TS) is an important undertaking that may provide valuable clues concerning the pathophysiology of this disorder as well as potential treatment approaches. In a direct interview study, the perinatal experiences of 31 TS patients were compiled in an effort to identify risk factors associated with tic severity. Severity of maternal life stress during pregnancy, gender of the child, and severe nausea and/or vomiting during the first trimester were found to be significantly associated with current tic severity. Future longitudinal studies of "at-risk" children are needed to confirm these findings. Set in the context of a known chromosomal site for the TS diathesis, such studies will permit the identification and quantification of risk and protective factors in the expression of TS and further develop TS as a model neuropsychiatric disorder for the study of gene-environment interactions.     

Low testosterone levels predict incident depressive illness in older men: effects of age and medical morbidity

OBJECTIVE: Prior studies found that chronic low testosterone levels are associated with an increased risk of depression. We investigated whether low testosterone levels in older men predict depressive illness over 2 years, while controlling for age and medical morbidity. METHOD: Participants were 748 men, aged 50 years or older, without prior ICD-9-diagnosed depressive illness, with a testosterone level obtained between 1995 and 1997. Measures were age, mean total testosterone levels (low: < or = 2.5 ng/mL), medical morbidity, and incidence and time to depressive illness. RESULTS: Men with low testosterone levels had a greater 2-year incidence of depressive illness (18.5% vs. 10.4%, df = 1, p = .006) and a shorter time to onset of depressive illness (log-rank chi(2) = 8.1, df = 1, p = .004). The unadjusted hazard ratio (HR) for depressive illness in men with low testosterone levels was 1.9 (95% confidence interval [CI] = 1.2 to 3.0, p = .005). After adjustment for age and medical morbidity, men with low testosterone levels continued to have a shorter time to depressive illness (adjusted HR = 2.1; 95% CI = 1.3 to 3.2, p = .002). Due to a significant interaction between age and medical morbidity, we conducted stratified Cox regression analyses and found that low testosterone levels and high medical morbidity or an age of 50 to 65 years were associated with increased depressive illness (p = .002). CONCLUSION: Low testosterone levels are associated with an earlier onset and greater incidence of depressive illness. Men with low testosterone levels who had high medical morbidity or were aged 50 to 65 years had an increased risk for depressive illness. Further prospective studies are needed to examine the role of testosterone in depressive illness in older men.     

Neuropsychiatric manifestations of HIV infection and AIDS

As the life expectancy of people living with HIV infection has increased (through recent advances in antiretroviral therapy), clinicians have been more likely to encounter neuropsychiatric manifestations of the disease. Some patients present with cognitive deficits due to an HIV-triggered neurotoxic cascade in the central nervous system. However, more patients present with a depressive spectrum disorder during the course of their illness, the underlying pathogenesis of which is not as well understood. This category of psychiatric disorders presents diagnostic challenges because of the many neurovegetative confounding factors that are present in association with HIV illness. As quality of life becomes a more central consideration in the management of this chronic illness, better awareness of these neuropsychiatric manifestations is paramount. This article reviews these clinical issues and the available psychopharmacologic treatment options.     

Turner syndrome and schizophrenia: A further hint for the role of the X-chromosome in the pathogenesis of schizophrenic disorders

Abnormalities of sex chromosomes are associated with various forms of neuropsychiatric disorders, such as schizophrenia. Turner syndrome occurs approximately threefold more frequently in female schizophrenics compared to the general female population. A single case is reported. We report on a case of a 41-year-old woman with Turner syndrome, schizophrenia, mental retardation, and hypothyroidism. A polymorphism of the HOPA gene within Xq13 termed HOPA^12bp is associated with schizophrenia, mental retardation, and hypothyroidism. Interestingly, Xq13 is the X-chromosome region that contains the X-inactivation center and a gene escaping X-inactivation whose gene product may be involved in the X-inactivation process as well as in the pathogenesis of sex chromosome anomalies such as Turner syndrome. These genes that escape X-inactivation may produce their gene products in excess, influencing normal brain growth and differentiation. Our case gives a further hint for an involvement of the X-chromosome in the pathogenesis of schizophrenia.     

Psychiatric outcomes associated with chronic illness in adolescence: A systematic review

Recent years have seen an increased focus on the high rates of psychiatric comorbidities in adults with chronic illness. This systematic review explored whether chronic illness in adolescents was similarly associated with poor psychiatric outcomes. The literature search identified 129 articles, only 5 of which were indicated to be at a low risk of methodological bias. Four of these articles found a strong relationship between asthma in adolescence and an increase in the prevalence of anxiety and depressive disorders, while the remaining article, which focused on diabetes mellitus, indicated similarly increased rates of psychiatric illness. Trends among the remaining studies suggested that many illnesses were not associated with poor adolescent mental health. Please note that chronic conditions with a neurological aetiology were excluded from the main review due to indications of qualitative differences in comorbidities. Findings highlight that the well-being of adolescents with chronic illness warrants a specific research focus.     

No evidence for allelic association of serotonin 2A receptor and transporter gene polymorphisms with depression in Alzheimer disease

Patients with Alzheimer disease (AD) often exhibit psychiatric symptoms associated with cognitive impairment. The serotoninergic system may be involved in the development of depressive symptoms in AD patients, as suggested by the evidence that antidepressant drugs having the serotonin transporter as their target are effectively used to treat depressive AD patients. The aim of this study was to investigate the role of serotonin in depression, searching for association of two serotoninergic polymorphisms (T102C of serotonin receptor 5-HT2A and serotonin transporter linked polymorphic region -5-HTTLPR- of SLC6A4 gene) with depressive symptoms and considering their possible interactions with Apolipoprotein E (ApoE) and between themselves, in a sample of 208 sporadic AD patients and 116 normal controls from Italy. 5-HTTLPR and T102C are not associated with AD when separately analysed. However, we found out an interaction between the two polymorphisms in L/L and C/C genotype carriers increasing the risk for the disease (p=0.015, OR=8.048; 95% CI: 1.497-43.262). No association of the polymorphisms was detected with depression linked to AD. No interaction between 5-HTTLPR and T102C was detected in depressive AD subjects, even after stratification according to the presence of ApoE4 allele. These results suggest that the serotoninergic system may be not involved in the pathogenesis of depressive symptoms in AD patients, and it may be involved in other aspects of disease pathophysiology like cognitive symptoms and psychosis.     

Effect of lithium maintenance therapy on thyroid and parathyroid function.

OBJECTIVES: To assess changes induced by lithium maintenance therapy on the incidence of thyroid, parathyroid and ion alterations. These were evaluated with respect to the duration of lithium therapy, age, sex, and family history (whether or not the patient had a first-degree relative with thyroid disease). DESIGN: Prospective study. SETTING: Affective Disorders Clinic at St. Mary's Hospital, Montreal. PATIENTS: One hundred and one patients (28 men and 73 women) with bipolar disorder receiving lithium maintenance therapy ranging from 1 year's to 32 years' duration. The control group consisted of 82 patients with no psychiatric or endocrinological diagnoses from the hospital's out-patient clinics. OUTCOME MEASURES: Laboratory analyses of calcium, magnesium and thyroid-stimulating hormone levels performed before beginning lithium therapy and at biannual follow-up. RESULTS: Hypothyroidism developed in 40 patients, excluding 8 patients who were hypothyroid at baseline. All patients having first-degree relatives affected by thyroid illness had accelerated onset of hypothyroidism (3.7 years after onset of lithium therapy) compared with patients without a family history (8.6 years after onset of lithium therapy). Women over 60 years of age were more often affected by hypothyroidism than women under 60 years of age (34.6% versus 31.9%). Magnesium levels in patients on lithium treatment were unchanged from baseline levels. After lithium treatment, calcium levels were higher than either baseline levels or control levels. Thus, lithium treatment counteracted the decrease in plasma calcium levels associated with aging. CONCLUSIONS: Familial thyroid illness is a risk factor for hypothyroidism and hypercalcemia during lithium therapy.     

Genetics of the serotonergic system in suicidal behavior

Genetic factors contribute to the risk of psychopathology in many psychiatric conditions, but the specific genes are yet to be identified. Neurotransmitter alterations are implicated in the etiology of psychopathology based, in part, on studies of neurotransmitter receptors and their biosynthetic or degradative enzymes in postmortem tissue. Identification of the altered receptors and enzymes serves to identify candidate genes of potential etiological significance. Polymorphisms in these genes can contribute to alterations in protein function in vivo that are part of the neurochemical underpinnings of psychopathologies such as major depressive disorder, psychoses, alcoholism, personality disorders, aggressive-impulsive traits, or suicidal behavior. Altered serotonergic function is implicated in the etiology and pathogenesis of several major psychiatric conditions. In particular, there is much evidence for an association of lower serotonergic function and suicidal behavior. Thus genes related to the serotonergic system are candidate genes worthy of study as part of the genetic diathesis for suicidal behavior. This review examines the following polymorphisms in the serotonin biosynthetic enzyme tryptophan hydroxylase (TPH; A779C substitution), the serotonin transporter (5-HTT, 5-HTTLPR allele), the 5-HT(1B) receptor (G861C, C129T substitution) and the 5-HT(2A) receptor (T102C) for their relationship to suicidal behavior. For the TPH gene, we found the less common U or A allele variant of the A779C polymorphism was associated with suicide attempt. Other studies have found the U allele to be associated with aggression and lower serotonergic function in vivo. A 44 base pair insertion/deletion in the 5' flanking promoter region of the 5-HTT gene may result in less 5-HTT expression and 5-HTT binding. We examined 220 cases postmortem and found no association between the promoter genotype and 5-HTT binding. We also found no association with major depressive disorder (MDD), suicide or pathological aggression, despite finding significantly fewer 5-HTT sites in the prefrontal cortex of depressed and/or suicide cases. In genomic DNA samples from 178 unrelated subjects, we detected two polymorphisms for the 5-HT(1B) receptor at nucleotides 861 and 129. However, no association between either polymorphism and depression, suicide, aggression, or alcoholism was observed. There are two common polymorphisms for the 5-HT(2A) receptor gene in humans. The results of studies of 5-HT(2A) receptor gene polymorphisms do not indicate significant major associations with suicidal behavior. In contrast, the 5-HT(2A) receptor itself is reported to be increased in suicide. Functional polymorphisms involving the promoter region that affect gene expression may explain this finding. Studies of candidate genes related to serotonergic function in brain are increasingly used to establish genetic alterations contributing to psychiatric illness. The most meaningful studies combine the study of candidate genes with direct measures of related proteins as well as psychopathology.     

Course and outcome of child and adolescent major depressive disorder

Major depressive disorder (MDD) is a familial recurrent illness that significantly interferes with the child's normal development and is associated with increased risk for suicidal behaviors and psychiatric and psychosocial morbidity. Although most children and adolescents recover from their first depressive episode, 30-70%, in particular those with familial history of MDD, comorbid psychiatric disorders, dysthymia, subsyndromal symptoms of depression, anxiety, negative cognitive style, and exposure to negative life events (e.g., family conflicts and abuse) will experience one or more depressive recurrences during their childhood, adolescence, and adulthood. Depressed youth who present with psychosis, psychomotor retardation, pharmacological induced hypomania/mania, and/or family history of bipolar disorder are at high risk to develop bipolar disorder.