Primary structure of the serotonin transporter in unipolar depression and bipolar disorder

Genetic factors have been implicated in the etiology of affective disorders but due to the complex inheritance patterns of these disorders, identification of the responsible gene(s) has so far been unsuccessful. Decreased platelet serotonin (5-HT) transport and reduced binding of imipramine or paroxetine to brain and platelet 5-HT uptake sites/transporters in patients with depression and suicide victims define the 5-HT transporter (5-HTT) as a candidate gene. The primary structure of the 5-HTT was analyzed in 17 patients meeting DSM-III-R diagnostic criteria for major depressive or bipolar disorder and in 4 healthy controls using polymerase chain reaction (PCR-) amplification and sequencing of complementary deoxyribose nucleic acid (cDNA) synthesized from platelet 5-HTT messenger ribose nucleic acid (mRNA). Direct PCR sequencing of the protein coding region failed to reveal changes in the deduced amino acid sequence of the platelet/brain 5-HTT (40,000 base pairs sequence screened), although a conservative single-base substitution representing a silent polymorphism was found. The results provide preliminary evidence that alterations in the primary structure of 5-HTT are not generally involved in the pathogenesis of unipolar depression and manic-depressive illness.     

Isolation of a novel auxin receptor from soluble fractions of rice (Oryza sativa L.) shoots

We report a single stranded conformational polymorphism (SSCP) analysis of the coding region of the dopamine D1 receptor (DRD1) in Tourette's syndrome (n = 50) and control (n = 50) subjects. Tourette's syndrome populations with comorbidity for attention deficit-hyperactivity disorder (AD-HD) (n = 35) and obsessive compulsive disorder (OCD) (n = 30) were also screened. As a related study, we also screened patients diagnosed with alcohol dependence (n = 72). The present study discovered no DRD1 coding region mutations in any of the Tourette's syndrome or alcohol dependent patients. One silent mutation, a C for a T at Ile49, was discovered in one control subject. The non-polymorphic structure of the DRD1 gene among the Tourette's syndrome, Tourette's syndrome comorbid with AD-HD and OCD and the alcohol dependent populations screened by SSCP suggests that coding region mutations of the DRD1 gene are unlikely to contribute to the inheritance of these disorders.     

A highly polymorphic microsatellite marker located within the choroideremia gene

Although serotonergic dysregulation is a leading pathogenetic hypothesis for obsessive-compulsive disorder (OCD), some evidence also suggests a possible dysregulation of the dopaminergic system in this disorder. Therefore, individual differences in deoxyribonucleic acid (DNA) coding for dopamine receptor proteins might contribute to the genetic background of this disorder. Previously we reported a null mutation in exon 1 of the dopamine D4 receptor gene. The variant type is characterized by a 13 bp deletion and is predicted to code for a truncated, non-functional receptor. We assessed the frequency of this polymorphism in 157 OCD patients, 196 schizophrenics, 111 bipolars and 162 healthy controls of Italian descent. Our findings do not implicate a role for this mutation in conferring a susceptibility to OCD and confirm previous negative results regarding its involvement in schizophrenia and bipolar disorder.     

Systematic search for variation in the human norepinephrine transporter gene: identification of five naturally occurring missense mutations and study of association with major psychiatric disorders

The complete coding region of the norepinephrine transporter (NET) gene was systematically screened for genetic variants in 137 unrelated individuals (including 46 probands with bipolar affective disorder and 45 schizophrenic probands, as well as 46 blood donors) using single-strand conformation analysis. We identified 13 DNA sequence variants, among them five missense substitutions. The missense substitutions Val69Ile, Thr99Ile, Val245Ile, Val449Ile, and Gly478Ser are located at putative transmembrane domains (TMD) 1, 2, 4, 9, and 10, respectively. The Thr99Ile substitution is at the 5th position of the putative leucine-zipper in TMD2. In a case-control study distribution of missense substitutions was found to be similar in 103 patients with bipolar affective disorder, in 228 schizophrenia patients and in 187 controls, indicating that presence of these variants is not causally related to major psychiatric diseases. The detection of a highly polymorphic silent 1287G/A polymorphism was utilized to demonstrate biallelic expression of the NET in adult human brain.     

Issues in the monopharmacotherapy and polypharmacotherapy of obsessive-compulsive disorder

Polypharmacotherapy is again becoming common place in clinical practice. Obsessive-compulsive disorder (OCD) as a single primary diagnosis is responsive exclusively to the serotonin reuptake inhibitors (SRIs) and this fact forms the major evidence supporting a central role for 5-HT (serotonin) in the pathogenesis of the disorder. Presently, the highly potent serotonin reuptake inhibitors clomipramine, fluoxetine, fluvoxamine, and paroxetine are the only agents approved by the Food and Drug Administration (FDA) for OCD, but there is evidence that other SRIs, such as sertraline, are also effective. Because OCD is often treatment refractory and highly comorbid with other psychiatric disorders, the use of polypharmacotherapy can be justified. Other serotonergic medications such as lithium, buspirone, trazodone, or fenfluramine may be useful as adjuvant treatments in treatment-refractory OCD and adjuvant antipsychotics are useful in tic disorders, personality disorders, and psychotic disorders. The usefulness of polypharmacotherapy should be tempered by adverse effects including the serotonin syndrome, withdrawal phenomena, extrapyramidal side effects, and drug-drug interactions.     

The human serotonin 7 (5-HT7) receptor gene: genomic organization and systematic mutation screening in schizophrenia and bipolar affective disorder

In the present study, we evaluated the possible contribution of genetic variation of the serotonin 5-HT7 receptor to the development of schizophrenia and bipolar affective disorder. Cloning and characterization of exon-flanking intronic sequences enabled us to investigate the whole coding region and the exon-intron boundaries of the human 5-HT7 receptor gene. Using single-strand conformational analysis, we screened for presence of DNA sequence variation in a sample of 137 unrelated individuals including 45 schizophrenic and 46 bipolar affective patients, as well as 46 healthy controls. We detected two rare naturally occurring receptor variants (Pro-279-Leu, Thr-92-Lys) and a silent nucleotide substitution (A-->G) at position +1233. The occurrence of the Pro-279-Leu and Thr-92-Lys substitutions was studied in an extended sample of patients (n = 462) and controls (n = 335). The Leu-279 variant was found in similar frequency in all groups, indicating that presence of this variant is not causally related to the development of schizophrenia or bipolar affective disorder. The Lys-92 variant was found in a single individual who suffered from bipolar affective disorder. Investigation of the patient's family revealed independent segregation between the Lys-92 variant and psychiatric illness. Our data suggests that genetic variation of the 5-HT7 receptor does not play a major role in the development of bipolar affective disorder and schizophrenia.     

Serotonergic systems

Since its identification in neurons of the central nervous systems (CNS), serotonin (5-HT) has been implicated in the pathophysiology of psychiatric disorders, such as schizophrenia, depression, generalized anxiety disorder (GAD), panic disorder (PD), and obsessive-compulsive disorder (OCD). These findings have stimulated research on brain 5-HT pathways, especially during the last two decades as more selective drugs have been introduced into medical practice. This article reviews selected topics relevant for psychiatry.     

Association analysis of the 5-HT2C receptor and 5-HT transporter genes in bipolar disorder

We selected 42 patients with bipolar disorder type I (BPI) and 40 healthy controls for genetic analysis of DNA polymorphisms in the serotonin receptor 2c (5-HTR2c) and serotonin transporter (5-HTT) genes. No significant associations were found in the total patient sample. However, when the individuals were divided according to gender, trends for association with both polymorphisms (P = 0.051 for 5-HTR2c and P = 0.049 for 5-HTT) in female patients were observed. These results suggest that variations in these genes may be responsible for a minor increase in susceptibility for bipolar disorder in women.     

Occurrence of free D-aspartate and aspartate racemase in the blood shell Scapharca broughtonii

In spite of the high prevalence of tuberculosis worldwide, there are few studies on its psychiatric complications. The mental state of 53 patients with pulmonary tuberculosis seen in a Nigerian chest clinic was examined using the 30-item General Health Questionnaire (GHQ-30), the Present State Examination (PSE), and a clinical evaluation based on the International Classification of Disease, tenth edition (ICD-10). Results were compared with two comparison groups: (1) a group of 20 long-stay orthopedic patients with lower limb fractures; and (2) a group of 20 apparently healthy controls. The sociodemographic characteristics of the groups were also compared. A significantly higher prevalence of psychiatric disorders was found in the tuberculosis group (30.2%) than in the orthopedic group (15%) and the apparently healthy controls (5%). The types of psychiatric disorders encountered included mild depressive episode, generalized anxiety disorder, and adjustment disorder (ICD-10). Psychiatric morbidity was higher in tuberculosis patients with low educational attainment, and did not show a statistically significant relationship with other sociodemographic parameters. Ways of improving the mental health of tuberculosis patients are discussed.     

A computer-administered version of the Yale-Brown Obsessive-Compulsive Scale.

The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) was converted to an interactive computer-administered format. To examine its utility, the computer version of the Y-BOCS was administered in a design counterbalanced with the clinician-administered version to a sample of patients with obsessive-compulsive disorder (OCD), patients with other anxiety disorders, and nonpatient controls. The computer-administered version of the Y-BOCS correlated highly with the clinician-administered version, especially in the OCD sample, and showed equal ability to distinguish OCD patients from Ss in the other 2 groups. It was also well understood and liked by Ss, who showed no preference for the clinician interview over the computer interview. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acceptance by Swedish users of a multimedia program for primary and secondary prevention of malignant melanoma

A case control study was conducted among cases with schizophrenia (DSM IV criteria) and screened adult controls from three cohorts. Bi-allelic polymorphisms in the promoter region of the serotonin transporter gene (5-HTT) were examined in conjunction with those of the serotonin 5-HT2a receptor (HTR2). No significant association with 5-HTT was detected among US Caucasians (n = 207), African-Americans (n = 84) or Caucasians from Sweden (n = 221). However, survival analysis suggested an association with the age at onset among the Swedish cases. The association should be considered tentative as it was not evident in the smaller US samples. The following exploratory analyses among the US samples were also not significant: associations with subgroups of patients based on familiality or response to medications, or altered risk due to the joint effects of 5-HTT and HTR2 genotypes.     

Serotonin transporter (5-HTT) gene variants associated with autism?

An association study was performed to elucidate the role of the serotonin transporter (5-HTT) gene as a susceptibility factor for autism as treatment of patients with antidepressant drugs which selectively target 5-HTT reduced autistic or concomitant symptoms, such as repetitive behavior and aggression, and ameliorate language use. Using the transmission/disequilibrium test (TDT) an analysis was done for a common polymorphism in the upstream regulatory region (5-HTTLPR), a VNTR in intron 2 of the gene and a haplotype of both loci in 52 trios fulfilling stringent criteria for autism and an extended group of 65 trios including patients showing no language delay in their first 3 years of life. A higher frequency and preferential transmission of the long allele of the 5-HTTLPR was observed, but the TDT gave a statistically significant value ( P = 0. 032) only for the extended patient group. This result is in contrast to a recent study by a US group presenting preliminary evidence for preferential transmission of the short allele of 5-HTTLPR in 86 trios. Both studies failed to reveal significant linkage disequilibrium between the VNTR in intron 2 of the gene and autism. In our study haplotype analysis of the 5-HTTLPR and the VNTR in intron 2 supplied evidence for an association of 5-HTT and autism in the stringent ( P = 0.069) and extended patient group ( P = 0.049). Overall, we were not able to replicate the findings of the first study on 5-HTT and autism and instead observed a tendency for association of the opposite genetic variant of the gene with the disorder. The implications for genetic variants of the serotonin transporter in the etiology of autism and possible subgroups of patients, therefore, needs clarification in further studies with other and larger patient samples.     

Course of psychiatric and substance abuse syndromes co-occurring with bipolar disorder after a first psychiatric hospitalization

BACKGROUND: Patients with bipolar disorder frequently meet criteria for other psychiatric and substance abuse diagnoses. To clarify relationships among these disorders, the authors examined the course of syndromes co-occurring with bipolar disorder for 12 months after a first hospitalization. METHOD: Seventy-seven patients were recruited from consecutive inpatient admissions who met DSM-III-R criteria for bipolar disorder, manic or mixed with psychosis. The 12-month syndromal course of co-occurring DSM-III-R alcohol and drug abuse disorders, posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and other anxiety disorders were longitudinally recorded. RESULTS: The rates of all syndromes, except other anxiety disorders, were elevated. OCD demonstrated an interval course that frequently mirrored the course of the bipolar disorder. The courses of PTSD and substance abuse syndromes were separate from that of the bipolar disorder in many of those with both syndromes. Alcohol and drug abuse syndromes were strongly correlated. CONCLUSION: The obsessive-compulsive syndrome may represent an alternative expression of bipolar disorder in some patients. In contrast, PTSD appears to represent a truly separate disorder, which is possibly more prevalent in bipolar patients due to a shared risk factor. Substance abuse does not appear to simply result from attempts at self-medication or from the impulsivity of mania. These results suggest that future studies examining the course of syndromes co-occurring with bipolar disorder are warranted.     

Axis I psychopathology in individuals with traumatic brain injury

OBJECTIVES: To assess the incidence, comorbidity, and patterns of resolution of DSM-IV mood, anxiety, and substance use disorders in individuals with traumatic brain injury (TBI). DESIGN: The Structured Clinical Interview for DSM-IV Diagnoses (SCID) was utilized. Diagnoses were determined for three onset points relative to TBI onset: pre-TBI, post-TBI, and current diagnosis. Contrasts of prevalence rates with community-based samples, as well as chi-square analysis and analysis of variance were used. Demographics considered in analyses included gender, marital status, severity of injury, and years since TBI onset. SETTING: Urban, suburban, and rural New York state. PARTICIPANTS: 100 adults with TBI who were between the ages of 18 and 65 years and who were, on average, 8 years post onset at time of interview. MAIN OUTCOME MEASURES: SCID Axis I mood diagnoses of major depression, dysthymia, and bipolar disorder; anxiety diagnoses of panic disorder, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), and phobia; and substance use disorders. RESULTS: Prior to TBI, a significant percentage of individuals presented with substance use disorders. After TBI, the most frequent Axis I diagnoses were major depression and select anxiety disorders (ie, PTSD, OCD, and panic disorder). Comorbidity was high, with 44% of individuals presenting with two or more Axis I diagnoses post TBI. Individuals without a pre-TBI Axis I disorder were more likely to develop post-TBI major depression and substance use disorders. Rates of resolution were similar for individuals regardless of previous psychiatric histories. Major depression and substance use disorders were more likely than were anxiety disorders to remit. CONCLUSION: TBI is a risk factor for subsequent psychiatric disabilities. The need for proactive psychiatric assessment and timely interventions in individuals post TBI is indicated.     

Decision making and set shifting impairments are associated with distinct symptom dimensions in obsessive-compulsive disorder.

Obsessive- compulsive disorder (OCD) is clinically heterogeneous. The authors examined how specific OCD symptom dimensions were related to neuropsychological functions using multiple regression analyses. A total of 39 OCD patients and 40 controls completed the Iowa Gambling Task (IGT; A. Bechara, A. R. Damasio, H. Damasio, & S. W. Anderson, 1994), which is a test of decision making, and the Wisconsin Card Sorting Test (R. K. Heaton, 1981), which is a test of set shifting. OCD patients and controls showed comparable decision making. However, patients with prominent hoarding symptoms showed impaired decision making on the IGT as well as reduced skin conductance responses. OCD patients had poorer set shifting abilities than controls, and symmetry/ordering symptoms were negatively associated with set shifting. These results help explain previous inconsistent findings in neuropsychological research in OCD and support recent neuroimaging data showing dissociable neural mechanisms involved in mediating the different OCD symptom dimensions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Structure-activity studies of analogues of neurokinin A mediating contraction of rat uterus

In various studies of psychiatric patients, alterations in adrenergic receptor (AR) expression or function have been suggested. Herein, the alpha2A AR gene was screened in 206 patients with schizophrenia, attention deficit hyperactivity disorder (ADHD), autism, alcohol dependence, or cocaine dependence. The entire coding region was examined for single base pair changes, using restriction endonuclease fingerprinting (REF), a screening method that can detect virtually 100% of mutations in 2-kb DNA segments. In the approximately 600 kb of screened sequence, six novel nucleotide changes were identified. The changes resulted in four missense changes (A25G, N251K, R368L, and K370N), and a sequence in the 3' untranslated region. In addition, a silent change (G363G) was found at high frequency in Asians and Native Americans. Of the four missense changes, two found in patients with alcohol/drug dependence occur in highly conserved amino acids, suggesting that these are of likely functional significance. As the alpha2A ARs are widely distributed both pre- and postsynaptically, and as many pharmacological agents with multiple effects target these receptors, the novel missense changes described herein may be candidates for involvement in alcohol/drug dependence, in other clinical disorders or traits, or in differential response to pharmacotherapy.     

Psychiatric comorbidity in women with binge eating disorder: Prevalence rates from a non-treatment-seeking sample.

This study provides estimates of comorbid psychiatric disorders in women with binge eating disorder (BED). Sixty-one BED and 60 control participants, who were recruited from the community, completed the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-III-Revised (DSM-III-R) Axis I and Axis II disorders and self-report measures of eating and general psychiatric symptomatology. Regarding psychiatric diagnoses, women with BED had higher lifetime prevalence rates for major depression. any Axis I disorder, and any Axis II disorder relative to controls. BED women also evidenced greater eating and psychiatric symptomatology than did controls. Results suggest that the prevalence of comorbid psychiatric disorders in BED may be lower than previously indicated by clinical studies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of myelin basic protein and proteolipid protein genes in multiple sclerosis: single strand conformation polymorphism analysis of the human sequences

Susceptibility to multiple sclerosis (MS) is widely held to have a strong genetic component. While the identities of genes conferring susceptibility are currently unknown, possible candidates include those genes coding for proteins which function in central nervous system (CNS) myelin. Two such genes are the human myelin basic protein (MBP) and proteolipid protein (PLP) genes, whose products make up approximately 80% of the total protein in CNS myelin. The association of a variable number tandem repeat (VNTR) 5' to the human MBP gene with MS has been the subject of conflicting reports. Here we test the hypothesis that mutations in the human MBP and PLP genes might be associated with MS by examining the entire expressed sequence of both genes by single strand conformation polymorphism (SSCP) analysis, using a panel of 71 MS patients and 71 controls. We have also re-examined the VNTR region in patients and controls. Three base changes were found in the human PLP gene and nine base changes in the human MBP gene; these were essentially equally distributed between patients and controls. No preferential distribution of various alleles of the VNTR between patients and controls was found. Although intronic and regulatory regions have not been examined, it would appear unlikely that mutations in these genes coding for the two major CNS myelin proteins contribute significantly to genetic susceptibility to MS.     

Obsessive compulsive disorder. Clinical and epidemiologic studies

Until recently, Obsessive-Compulsive Disorder (OCD) was considered rare trouble with rather poor outcome. Currently progress in behavioral psychology, psychopharmacology and methodology of epidemiologic studies multiplying by 50 the traditional prevalence rates, give an impetus to the interest in this pathology. Recent clinical and epidemiologic data in OCD are reported in this paper. Multiple questions are evoked such as the issue of OCD homogeneity, the meaning of comorbidity with other psychological disorders: depression, panic attacks, schizophrenia, Gilles de la Tourette syndrome, the reality of OCD prevalence rate in general and psychiatric populations, the usefulness of classical demarcation between psychosis/neurosis in the treatment of OCD, and finally the search for a genetic diathesis and risk factors implicated in predisposition to OCD. A close relationship between clinical, epidemiologic and genetic approaches seems to be required in order to answer these questions and constitutes a first step prior to carrying on basic and applied research.