María Paz García-Portilla

Depressive disorders and the menopause transition

AIM Depressive disorders and symptoms are common among middle-aged women. The effects of hormones on depression remain unclear. This review aims to clarify the nature of depressive disorders during the menopause transition as well as their links with climacteric syndrome, sexuality, cardiovascular risk and cognitive function. MATERIAL AND METHODS The recent literature on depressive disorders and menopause is reviewed. RESULTS AND CONCLUSIONS Women are more vulnerable than men to depressive disorders. Endocrine influences have been postulated but differences in, for example, coping style and response to stress may also contribute to the gender difference in the prevalence of depressive disorders. Gender differences in socialization may lead to higher rates of depression in women. There are data top suggest that menopause and depression are associated, although there is not a common clear causative factor. Women with climacteric symptoms (hot flushes, night sweats, vaginal dryness and dyspareunia) are more likely to report anxiety and/or depressive symptoms. Bothersome vasomotor symptoms could be associated with sleep disturbances, which in turn can increase reports of anxiety and depressive symptoms. Biopsychosocial and partner factors have a significant influence on middle-aged womens sexuality and depressive disorders, and most antidepressants can have a negative effect on sexual response. Lastly, studies have consistently shown that women with high levels of depressive symptoms are at greater cardiovascular risk and have poorer cognitive function than non-depressed women. At present, a direct relationship between psychiatric symptoms and hormonal changes such as estrogen decrease has not been clearly found. Stress, educational level, ethnicity, socioeconomic factors and partner status may influence the prevalence and clinical course of both menopause symptoms and depressive disorders. Since in many cases depression is a lifelong condition, and is associated with severe comorbid conditions, further studies are needed to improve the early diagnosis of depression; it may be advisable to monitor a womans mental health during the menopause transition to prevent a depressive disorder having long-term negative consequences.

Cardiovascular risk in patients with bipolar disorder.

BACKGROUND To date, little is known about cardiovascular risk (CVR) in terms of coronary heart disease (CHD) and cardiovascular mortality risk (CMR) in patients with bipolar disorder. This study provides data on the overall risk of any fatal or non-fatal coronary heart disease (CHD) and on the cardiovascular mortality risk (CMR) within 10 years in these patients. METHODS Naturalistic, cross-sectional, multicenter study conducted in Spain. Patients were evaluated for cardiovascular risk using the Framinghan function (CHD) and the Systematic COronary Risk Evaluation (SCORE) function (CMR). RESULTS The mean age was 46.6 years and 49% were male. Forty-six percent were in remission. Ten-year CHD risk was 7.6% (males 10.2% versus females 4.7%, p<0.001) and 10-year CMR was 1.8% (males 2.2% versus females 1.3%, p 0.161). Fifty-one percent smoked and 34% was obese. Metabolic syndrome was present in 22.4% of the sample (35.6% according to AHA and NHLBI criteria). Cardiovascular risk significantly increases with age, body mass index and presence of metabolic syndrome. LIMITATIONS The cross-sectional design of the study. CONCLUSIONS Cardiovascular risk is high in patients with bipolar disorder. It is associated with age, body mass index and metabolic syndrome. Psychiatrists should be aware of this issue and carefully monitor these patients for cardiovascular risk factors, including cigarette smoking, as part of the standard of care when treating them.

Association study between obsessive-compulsive disorder and serotonergic candidate genes.

BACKGROUND To date, research examining the relationship between serotonergic genes and obsessive-compulsive disorder (OCD) has yielded conflicting results. The purpose of this study is to investigate the association between four serotonergic polymorphisms (STin2 VNTR and 5-HTTLPR of the SLC6A4 gene, and A-1438G (rs6311) and T102C (rs6313) of the HTR2A gene) and OCD. METHODS 99 OCD patients, 456 non-OCD psychiatric patients, and 420 healthy controls from a homogeneous Spanish Caucasian population were genotyped using standard methods. RESULTS All groups showed Hardy-Weinberg equilibrium for the analyzed genetic variability. A-1438G and T102C polymorphisms were in complete linkage disequilibrium. OCD patients showed an excess of STin2.12 carriers (12/12, 12/10, and 12/9 genotypes) compared with healthy controls (chi(2) (1)=7.21, corrected p=0.021; OR=3.38, 95% CI=1.32-8.62) and non-OCD psychiatric patients (chi(2) (1)=6.70, corrected p=0.030; OR=3.24, 95% CI=1.27-8.26). However, no differences were found between non-OCD patients and healthy controls (chi(2) (1)=0.05, corrected p>1; OR=1.04, 95% CI=0.72-1.51). No significant differences were found with respect to A-1438G and 5-HTTLPR polymorphisms. CONCLUSIONS Our data provide supporting evidence of an association between the STin2 VNTR polymorphism of the SLC6A4 gene and OCD.

Differential role of serotonergic polymorphisms in alcohol and heroin dependence

BACKGROUND Twin studies suggest that genetic factors account for 40-60% of the variance in alcohol dependence. It has been stated that different drug dependencies may have unique genetic influences. Alterations in serotonin availability and function can affect drinking behaviour. This study aimed to investigate whether three serotonergic polymorphisms (HTR2A A-1438G (rs6311), and SCL6A4 5-HTTLPR and STin2 VNTR) were associated with alcohol dependence, and, whether the serotonergic polymorphisms played a similar role in conferring vulnerability in alcohol and heroin dependence. METHODS 165 alcohol dependent patients, 113 heroin dependent patients, and 420 healthy controls from a homogeneous Spanish Caucasian population were genotyped using standard methods. RESULTS Genotypic frequencies of the A-1438G, 5-HTTLPR, and STin2 VNTR polymorphisms did not differ significantly across the three groups. None of the three polymorphisms contributed to distinguishing alcoholic patients from healthy controls. There was an excess of -1438G and 5-HTTLPR L carriers in alcoholic patients in comparison to the heroin dependent group (OR (95% CI)=1.98 (1.13-3.45) and 1.92 (1.07-3.44), respectively). The A-1438G and 5-HTTLPR polymorphisms also interacted in distinguishing alcohol from heroin dependent patients (Wald (df)=10.21 (4), p=0.037). The association of -1438A/G with alcohol dependence was especially pronounced in the presence of 5-HTTLPR S/S, less evident with 5-HTTLPR L/S and not present with 5-HTTLPR L/L. SCL6A4 polymorphism haplotypes were similarly distributed in all three groups. CONCLUSIONS Our data do not support a role of serotonergic polymorphisms in alcohol dependence but suggest a differential genetic background to alcohol and heroin dependence.

Rare Genotype Combination of the Serotonin Transporter Gene Associated With Treatment Response in Severe Personality Disorder

The insertion deletion (ins/del) polymorphism of the serotonin transporter gene (5‐HTTLPR) has been associated with several psychiatric phenotypes and antidepressants response. We investigated, in a large cohort of 5,608 controls and subjects suffering from various psychiatric disorders, the frequency of haplotypes and corresponding genotypes combining the 5‐HTTLPR and the other serotonin transporter promoter functional variant (rs25531). We showed that rs25531 lies 18 bp 5′ to the site where the 43 bp (and not 44 bp as previously described) ins/del defines the 14‐ and 16‐repeat alleles. These polymorphisms should therefore be considered as four alleles instead of a triallelic unique locus. The very rare G‐14/G‐16 genotype was carried on by only three subjects. These are women with a history of suicide attempt with a psychiatric history strongly suggesting a borderline personality disorder. Two of them have shown a non‐response to serotoninergic antidepressant. Interestingly, in one of them was observed a spectacular response after the introduction of bupropion. The genotyping droved our therapeutic approach, by preferring a dopaminergic over a serotoninergic agent. This study highlights the usefulness of studying very rare clinical cases as well as rare variants, in order to deal with the biological heterogeneity of spectral disorders.

Impact of substance use on the physical health of patients with bipolar disorder

Garcia‐Portilla MP, Saiz PA, Benabarre A, Florez G, Bascaran MT, Díaz EM, Bousoño M, Bobes J. Impact of substance use on the physical health of patients with bipolar disorder.

Genetic variability at IMPA2, INPP1 and GSK3β increases the risk of suicidal behavior in bipolar patients

Bipolar patients (BP) are at high risk of suicide. Causal factors underlying suicidal behavior are still unclear. However, it has been shown that lithium has antisuicidal properties. Genes involved in its putative mechanism of action such as the phosphoinositol and the Wnt/β-catenine pathways could be considered candidates for suicidal behavior (SB). Our aim was to investigate the association of the IMPA1 and 2, INPP1, GSK3α and β genes with suicidal behavior in BP. 199 BP were recruited. Polymorphisms at the IMPA1 (rs915, rs1058401 and rs2268432) and IMPA2 (rs66938, rs1020294, rs1250171 and rs630110), INPP1 (rs3791809, rs4853694 and 909270), GSK3α (rs3745233) and GSK3β (rs334558, rs1732170 and rs11921360) genes were genotyped. All patients were grouped and compared according to the presence or not of history of SB (defined as the presence of at least one previous suicidal attempt). Single SNP analyses showed that suicide attempters had higher frequencies of AA genotype of the rs669838-IMPA2 and GG genotype of the rs4853694-INPP1gene compared to non-attempters. Results also revealed that T-allele carriers of the rs1732170-GSK3β gene and A-allele carriers of the rs11921360-GSK3β gene had a higher risk for attempting suicide. Haplotype analysis showed that attempters had lower frequencies of A:A haplotype (rs4853694:rs909270) at the INPP1 gene. Higher frequencies of the C:A haplotype and lower frequencies of the A:C haplotype at the GSK-3β gene (rs1732170:rs11921360) were also found to be associated to SB in BP. Therefore, our results suggest that genetic variability at IMPA2, INPP1 and GSK3β genes is associated with the emergence of SB in BP.

Sexual function assessment in postmenopausal women with the 14-item changes in sexual functioning questionnaire.

INTRODUCTION Sexual function assessment is relevant to improve female health care. AIM Assess sexual function in postmenopausal women and determine predictors related to sociodemographic, lifestyle, and health-related female/partner data and tool measures. METHODS Cross-sectional study in which 117 sexually active postmenopausal women filled out the 14-item Changes in Sexual Functioning Questionnaire (CSFQ-14), the 10-item Center for Epidemiologic Studies Short Depression Scale (CESD-10), the Menopause Rating Scale (MRS), and a general questionnaire containing female/partner data. Correlations between tool measurements and female/partner data were analyzed. MAIN OUTCOME MEASURES Primary end point was sexual function predictors. RESULTS Median age was 57 years, 8.5% had low income, 3.4% had surgical menopause, 17.1% had hypertension, and 66.7% increased body mass index. In addition, 21.4% were current hormone therapy users and 28.2% engaged in regular exercise. According to the MRS, muscle/joint problems (86.3%) and physical/mental exhaustion (81.2%) were the top encountered menopausal symptoms. Also, 48.7% displayed depressed mood (CESD-10 total scores ≥ 10) and 64.1% displayed total CSFQ-14 scores ≤41, suggesting sexual dysfunction. Internal consistency (Cronbachs alpha) was high for all tools: total CSFQ-14 scale (0.87), total MRS (0.80), and the CESD-10 (0.85). CSFQ-14 total scores inversely correlated with MRS scores (total, psychological, and urogenital, P < 0.05). Arousal scale scores inversely correlated with MRS total and urogenital scores whereas orgasm scores only with the total MRS. CESD-10 scores inversely correlated with all CSFQ-14 scores and positively with all MRS scores. Multiple linear regression was used to obtain a reduced best-fit model predicting total CSFQ-14 scores (sexual function). Total CSFQ-14 scores were positively correlated to female education, and education and regular exercising in the partner and inversely correlated to CESD-10 total scores. CONCLUSION Assessed with the CSFQ-14 tool, sexual function of this postmenopausal sample correlated to female/partner educational, lifestyle, and health factors. More research is warranted in this regard.

Psychometric evaluation of the negative syndrome of schizophrenia

In this paper, we reviewed the available instruments for assessing the negative syndrome of schizophrenia, describing their strengths and weaknesses. Current instruments were classified into two categories according to their content validity and assessment approach as first- or second-generation instruments. The BPRS, SANS, the SENS and the PANSS belong to the first generation, while the BNSS, the CAINS and the MAP-SR belong to the second generation. The NSA can be considered a transitional instrument between the two. First-generation instruments have more content validity problems than second-generation instruments do, as they do not accurately reflect the currently accepted negative syndrome (they do not include all negative symptoms and signs or they include symptoms from other dimensions). They also have more problems relative to the use of behavioural referents instead of internal experiences of deficits when assessing symptoms, which may lead to measuring functioning instead of negative symptoms. Further research needs to be done in this area in order to ensure the evaluation of primary negative symptoms and internal experiences involved in negative symptoms rather than external behaviours.

Long term outcomes of pharmacological treatments for opioid dependence: does methadone still lead the pack?

The aim of this review was to update and summarize the scientific knowledge on the long term outcomes of the different pharmacological treatment options for opioid dependence currently available and to provide a critical discussion on the different treatment options based on these results. We performed a literature search using the PubMed databases and the reference lists of the identified articles. Data from research show that the three pharmacological options reviewed are effective treatments for opioid dependence with positive long term outcomes. However, each one has its specific target population and setting. While methadone and buprenorphine are first line options, heroin‐assisted treatment is a second line option for those patients refractory to treatment with methadone with concomitant severe physical, mental, social and/or functional problems. Buprenorphine seems to be the best option for use in primary care offices. The field of opioid dependence treatment is poised to undergo a process of reinforcement and transformation. Further efforts from researchers, clinicians and authorities should be made to turn new pharmacological options into clinical reality and to overcome the structural and functional obstacles that maintenance programmes face in combatting opioid dependence.