Petros Malitas

Further evidence for a possible association between serotonin transporter gene and lithium prophylaxis in mood disorders.

We previously reported an association between the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (SERTPR) and the prophylactic efficacy of lithium in a sample of 201 Italian subjects affected by Mood disorders. The aim of the present study was to replicate analyses on an independent sample. In total, 83 subjects affected by Bipolar disorder were recruited in the Mood Disorders Clinic of the Eginition Hospital of the Athens University, Medical School Department of Psychiatry. All patients were administered with lithium as prophylactic therapy and they were prospectively observed for at least 3 years. Subjects were typed for their SERTPR variant using polymerase chain reaction techniques. SERTPR variants were associated with lithium outcome among those subjects who had few manic episodes before lithium treatment and, as a trend, among subjects who received a high daily dose of lithium (⩾1200 mg/die). In both cases, subjects with the l/l variant showed a higher probability to develop an illness episode within 3 years of prophylactic treatment with lithium. The present study confirmed our previous observation of a better response of SERTPR*l/s carriers, but could not confirm a poor efficacy in subjects with the SERTPR*s/s genotype. Notwithstanding the conflicting results, SERTPR variants are a possible liability factor for lithium long-term efficacy in mood disorders. Further studies on independent and large samples are required to determine the reliability and direction of the possible association between SERTPR variants and lithium outcome.

APOE epsilon‐4 allele and cytokine production in Alzheimer's disease

The APOE epsilon‐4 allele has consistently emerged as a susceptibility factor for Alzheimers disease (AD). Pro‐inflammatory cytokines are detectable at abnormal levels in AD, and are thought to play a pathophysiological role. Animal studies have shown dose‐dependent correlations between the number of APOE epsilon‐4 alleles and the levels of pro‐inflammatory cytokines. The aims of this study were to investigate the influence of APOE genotypes on TNF‐α, IL‐6, and IL‐1β secreted by peripheral blood mononuclear cells (PBMC) from human patients with AD and to analyze the correlation between cytokine production and AD clinical features.

Vitamin B12 Levels in Alzheimer's Disease: Association with Clinical Features and Cytokine Production

Alzheimers disease (AD) has been associated with up-regulation of pro-inflammatory cytokines (e.g., specific gene variants for TNF-alpha; IL-6; IFN-gamma) and low plasma levels of cyanocobalamin (vitamin B12). Our goal was to relate B12 levels to AD symptoms and to expression of pro-inflammatory cytokines. Clinical manifestations were investigated for a case series of fifty-five outpatients using the MMSE, Neuropsychiatric Inventory (NPI) and Cornell Scale for Depression in Dementia (CDDS). Plasma B12 levels were measured by radioligand binding assay. Basal and PMA-stimulated levels of IFN-gamma, TNF-alpha, and IL-6 were measured by ELISPOT (PBMC culture supernatant). 47 patients were genotyped for APOE. Ten patients (18%) had their B12 levels below < 250 pg/ml. They did not statistically differ from those 45 who had normal levels in most demographic and clinical features; their MMSE scores were lower (14.7 vs 19.6 p=0.03) but not after adjustment for disease duration. A greater basal production of IL-6 was reported in patients who had low B12 levels compared to normal B12 subjects (1333 pg/ml vs 976 p< 0.01); this association was confirmed after controlling for age of onset and APOE genotype. In conclusion, low B12 level is associated with greater production of IL-6 in peripheral blood mononuclear cells. Further research is warranted to elucidate whether this neuroinflammatory effect of cobalamin is implicated in the pathophysiology of AD.

Depression and Social Phobia Secondary to Alcohol Dependence

Background: According to the self-medication hypothesis, individuals with depression and anxiety disorders use alcohol to control their symptoms and subsequently become dependent. Conversely, alcohol dependence disorder (ADD) can cause or exacerbate psychiatric disorders. This study analyzed the characteristics of depression and social phobia secondary to ADD. (1) What is their functional impact? (2) Are they independent or associated conditions? (3) Do they completely remit in abstinent individuals? (4) Is the remission of one disorder associated with the remission of the other disorder? Methods: Sixty-four inpatients with ADD were evaluated with depression and anxiety disorder scales upon admission to hospital and after 5 weeks of detoxification. Results: Baseline comparisons differentiated patients with a Hamilton Rating Scale for Depression (HDRS) score >35 (n = 50; 78%) from those with an HDRS score ≤35 by higher levels of generalized anxiety and lower global functioning. Patients with generalized social phobia [Leibowitz Social Anxiety Scale (LSAS) score >60: n = 20; 31.2%] were not distinguishable from those with an LSAS score ≤60 by depressive and anxiety disorder symptoms. In postdetoxification assessment, patients who remitted from depression (HDRS score <7: n = 35; 54.6%) had a lower generalized anxiety and marginally higher levels of hypochondriasis compared to nonremitter subjects (HDRS score ≧7). Patients who remitted from social phobia (LSAS score <30: n = 32; 50%) did not significantly differ from nonremitter subjects in depressive and anxiety disorder symptoms. Generalized anxiety (Hamilton Rating Scale for Anxiety) and hypochondriasis (Whiteley Index) were the significant predictors of global functioning (Global Assessment Scale). Conclusions: Depression and social phobia secondary to ADD are independent conditions that do not completely remit after cessation of drinking. Specific treatments are needed to reduce residual depressive and anxiety symptoms in abstinent alcoholics.

Interleukin-1 alpha and beta, TNF-alpha and HTTLPR gene variants study on alcohol toxicity and detoxification outcome.

Genetic factors may influence the liability to treatment outcome and medical complications in alcoholism. In the present study we investigated the IL-1A rs1800587, IL-1B rs3087258, TNF-alpha rs1799724 and the HTTLPR variants in a sample of 64 alcohol dependents and 47 relatives versus a set of clinical parameters and outcome measures. Alcohol dependents had a less favorable clinical profile compared to relatives (higher cholesterol, triglycerides, glucose, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, gamma-glutamyltransferase). After detoxification, all clinical indexes improved and hepatic enzyme levels were similar in alcohol dependents and relatives, except for the GGT that remained significantly higher in alcohol dependents. Alcoholic depressive and anxiety scores were significantly reduced after detoxification. IL-1A, IL-1B, TNF-alpha and HTTLPR variants were not associated with any baseline clinical index or change after detoxification. In our sample IL-1A, IL-1B, TNF-alpha and HTTLPR do not appear as liability factors for alcohol toxicity or detoxification outcome, however the small sample size may influence the observed results.

TPH2 gene variants and anxiety during alcohol detoxification outcome

Clinical outcome of alcoholism may be partly under genetic control. The serotonergic system is involved in alcohol intake, and it has been widely investigated in alcohol dependence. Recently, attention has been focused on the neuronal tryptophan hydroxylase 2 gene (TPH2). TPH2 variants have been consistently associated with anxiety-related traits; since anxiety is critical for alcohol dependence treatment, in the present paper we investigated 9 SNPs within the THP2 gene in anxiety symptoms during the detoxification procedure. The sample comprised 68 alcohol-dependent patients who where evaluated with the Hamilton Rating Scale for Anxiety, before and after the detoxification procedure. Other psychopathological indicators of outcome, such as depression and anxiety sub-features were also investigated. We did not observe a role for TPH2 variants in the efficacy of treatment in relieving anxiety and other psychopathological symptoms. However, a haplotype that included the promoter rs4570625 polymorphism (associated with anxiety-related traits in previous studies) showed an association with the severity of anxiety symptoms on admission. This preliminary finding, although obtained on a small sample, may provide further support for a role of the TPH2 gene in emotional behaviors. Furthermore, the present study suggests the possible functional significance of the promoter rs4570625 polymorphism. The present preliminary results are of interest in alcoholism, given that comorbidity with anxiety represents a critical problem in treatment settings and response to detoxification.

Epistasis between IL1A, IL1B, TNF, HTR2A, 5-HTTLPR and TPH2 variations does not impact alcohol dependence disorder features.

We assessed a set of biological (HDL, LDL, SGOT, SGPT, GGT, HTc, Hb and T levels) and psychometric variables (investigated through HAM-D, HAM-A, GAS, Liebowitz Social Anxiety Scale, Mark & Mathews Scale, Leyton scale, and Pilowski scale) in a sample of 64 alcohol dependent patients, at baseline and after a detoxification treatment. Moreover, we recruited 47 non-consanguineous relatives who did not suffer alcohol related disorders and underwent the same tests. In both groups we genotyped 11 genetic variations (rs1800587; rs3087258; rs1799724; 5-HTTLPR; rs1386493; rs1386494; rs1487275; rs1843809; rs4570625; rs2129575; rs6313) located in genes whose impact on alcohol related behaviors and disorders has been hypothesized (IL1A, IL1B, TNF, 5-HTTLPR, TPH2 and HTR2A). We analyzed the epistasis of these genetic variations upon the biological and psychological dimensions in the cases and their relatives. Further on, we analyzed the effects of the combined genetic variations on the short – term detoxification treatment efficacy. Finally, being the only not yet investigated variation within this sample, we analyzed the impact of the rs6313 alone on baseline assessment and treatment efficacy. We detected the following results: the couple rs6313 + rs2129575 affected the Leyton -Trait at admission (p = 0.01) (obsessive-compulsive trait), whilst rs1800587 + 5-HTTLPR impacted the Pilowski test at admission (p = 0.01) (hypochondriac symptoms). These results did not survive Bonferroni correction (p ≤ 0.004). This lack of association may depend on the incomplete gene coverage or on the small sample size which limited the power of the study. On the other hand, it may reflect a substantial absence of relevance of the genotype variants toward the alcohol related investigated dimensions. Nonetheless, the marginal significance we detected could witness an informative correlation worth investigating in larger samples.

No association between genetic markers in BDNF gene and lithium prophylaxis in a Greek sample

Abstract Lithium efficacy is, at least partially, under genetic control. We investigated the association between markers in BDNF and lithium prophylactic efficacy. A set of 10 SNPs within BDNF were genotyped in a sample of 83 bipolar patients. Response to lithium was assessed by presence or absence of any illness phases during a period of 3 years of longitudinal observation. No significant association was detected between the genetic variants tested in BDNF and lithium prophylaxis. Despite the negative association, limitations including small sample size suggest that larger scale genetic associations studies of these genes and lithium prophylaxis are nonetheless indicated.

A zolpidem and cocaine abuse case report.

A case is presented of a 30-year-old man, prescribed zolpidem for insomnia arising from cocaine abuse, who sought to use this hypnotic to reduce his craving for cocaine. However, after taking cocaine and up to 300 mg/day zolpidem, he became euphoric and hyperactive. It is suggested that at high doses, zolpidem, like cocaine, has a stimulatory effect on the brain dopaminergic reward pathway. (Int J Psych Clin Pract 2002; 6: 217-219 )

Correlation of liver dysfunction biological markers to the mood status of alcohol-dependent individuals

Objective: Alcohol intake is a major cause of liver cirrhosis as well as chronic liver disease, and commonly coexists with mood disorders such as depression and anxiety. The aim of the present study was to investigate the possible correlation between liver dysfunction related to alcohol intake with anxiety and depressive-like symptomatology prior to and after the detoxification period. Methods: One hundred alcohol abusing/dependent subjects (81 males and 19 females) were treated on an inpatient basis according to a standard detoxification protocol and measurements of serum levels of hepatic enzymes (ASAT, ALAT, γGT), and measures of anxiety (HARS), depression (HDRS) and global functioning (GAS) were also obtained at baseline and at weekly intervals over a period of 4 weeks. Results: Increased levels of hepatic enzymes were observed upon admission that were significantly reduced (P<0.001) following completion of the detoxification treatment. In addition, the psychopathological profile was improved at the end of the detoxification period and a significant correlation was obtained between the levels of hepatic enzymes and the global functioning of alcohol-dependent individuals. Conclusion: This observation further supports a relationship between the depressogenic action of alcohol and the disordered liver function observed in alcohol-dependent individuals, with possible implications in the diagnosis and treatment of mood disorders associated to alcohol abuse.