Personalized medicine begins with the phenotype: identifying antipsychotic response phenotypes in a first-episode psychosis cohort.

AIMS: Here, we present a clustering strategy to identify phenotypes of antipsychotic (AP) response by using longitudinal data from patients presenting first-episode psychosis (FEP). METHOD: One hundred and ninety FEP with complete data were selected from the PEPs project. The efficacy was assessed using total PANSS, and adverse effects using total UKU, during one-year follow-up. We used the Klm3D method to cluster longitudinal data. RESULTS: We identified four clusters: cluster A, drug not toxic and beneficial; cluster B, drug beneficial but toxic; cluster C, drug neither toxic nor beneficial; and cluster D, drug toxic and not beneficial. These groups significantly differ in baseline demographics, clinical, and neuropsychological characteristics (PAS, total PANSS, DUP, insight, pIQ, age of onset, cocaine use and family history of mental illness). CONCLUSIONS: The results presented here allow the identification of phenotypes of AP response that differ in well-known simple and classic clinical variables opening the door to clinical prediction and application of personalized medicine.

Patient characteristics driving clinical utility in psychiatric pharmacogenetics: a reanalysis from the AB-GEN multicentric trial.

Clinical utility of commercial multi-gene pharmacogenetic tests in depression is starting to be studied with some promising results on efficacy and tolerability. Among the next steps is the definition of the patient profile that is most likely to benefit from testing. Here we present a reanalysis of data from the AB-GEN randomized clinical trial showing that clinical utility of pharmacogenetic testing can be markedly influenced by patient characteristics such as age, baseline severity and duration of current depressive episode.Trial registration ClinicalTrials.gov NCT02529462.

Pharmacogenetic study of antipsychotic induced acute extrapyramidal symptoms in a first episode psychosis cohort: role of dopamine, serotonin and glutamate candidate genes.

This study investigated whether the risk of presenting antipsychotic (AP)-induced extrapyramidal symptoms (EPS) could be related to single-nucleotide polymorphisms (SNPs) in a naturalistic cohort of first episode psychosis (FEP) patients. Two hundred and two SNPs in 31 candidate genes (involved in dopamine, serotonin and glutamate pathways) were analyzed in the present study. One hundred and thirteen FEP patients (43 presenting EPS and 70 non-presenting EPS) treated with high-potency AP (amisulpride, paliperidone, risperidone and ziprasidone) were included in the analysis. The statistical analysis was adjusted by age, gender, AP dosage, AP combinations and concomitant treatments as covariates. Four SNPs in different genes (DRD2, SLC18A2, HTR2A and GRIK3) contributed significantly to the risk of EPS after correction for multiple testing (P<1 × 10(-4)). These findings support the involvement of dopamine, serotonin and glutamate pathways in AP-induced EPS.

Occupational disability in bipolar disorder: analysis of predictors of being on severe disablement benefit (PREBIS study data).

OBJECTIVE: Patients diagnosed with bipolar disorder (BD) are reported to have significant work impairment during interepisode intervals. This study was carried out to assess potential predictors of occupational disability in a longitudinal follow-up of euthymic patients. METHOD: We included 327 euthymic patients diagnosed with BD type I or type II, 226 of whom were employed and 101 were receiving a severe disablement benefit (SDB). Sociodemographic data were studied and episode recurrence was assessed along a 1-year follow-up. Logistic regression analysis was applied to determine predictors of receiving SDB. Cox regression was built to study recurrences. RESULTS: Predictors of receiving SDB were: axis II comorbidity [Odds Ratio (OR) = 2.94, CI: 1.26-6.86, P = 0.013], number of manic episodes (OR = 1.21, CI: 1.10-1.34, P < 0.001), being without stable partner (OR = 2.44, CI: 1.34-4.44, P = 0.004) and older age (OR = 1.08, CI: 1.05-1.12, P < 0.001). Bipolar patients receiving SDB presented more episodic recurrences regardless of polarity than employed bipolar patients (P = 0.002). The time until recurrence in 25% of the bipolar patients receiving SDB was 6.08 months (CI: 4.44-11.77) being 13.08 months (CI: 9.60 to -) in the employed group. CONCLUSION: Occupational disability in bipolar patients is associated with axis II comorbidity, more previous manic episodes, not having a stable relationship, older age, and more recurrences at 1-year follow-up.

P300 event-related potential in euthymic patients with bipolar disorder.

Auditory P300 event-related potential (ERP) and performance on Sustained Attention were evaluated in 24 euthymic bipolar patients and 38 healthy volunteers. There were no significant differences between groups, and performance in sustained attention had no significant influence in the P300 responses. P300 response might be driven by the presence of mood symptoms.

Severity of personality disorders and suicide attempt.

OBJECTIVE: Severity of personality disorders (PDs) may be more useful in estimating suicide risk than the diagnosis of specific PDs. We hypothesized that suicide attempters with severe PD would present more attempts and attempts of greater severity/lethality. METHOD: Four hundred and forty-six suicide attempters were assessed. PD diagnosis was made using the International Personality Disorder Questionnaire--Screening Questionnaire. PDs were classified using Tyrer and Johnson's classification of severity (no PD, simple PD, diffuse PD). Severity/lethality of attempts was measured with the Suicide Intent Scale, Risk-Rescue Rating Scale and Lethality Rating Scale. RESULTS: Attempters with severe (diffuse) PD had more attempts than the other groups. After controlling for age and gender, this difference remained significant only for the younger age group and women. There was no relationship between severity of PDs and severity/lethality of attempts. CONCLUSION: Younger female attempters with severe PD are prone to repeated attempts. However, the severity of PD was not related to the severity/lethality of suicide attempts.

A bibliometric study of the use of the classification and diagnostic systems in psychiatry over the last 25 years.

BACKGROUND: Our purpose was to examine the use of classification and diagnostic systems in the field of psychiatry (CDSP) from a bibliometric perspective, over the period 1980-2005. METHODS: We selected (in EMBASE and MEDLINE databases) documents that contained, in any of their sections, the descriptors 'psychiatr*', 'DSM*', 'ICD*', or 'diagnostic criteria',as well as other more specific descriptors. As a bibliometric indicator of production we applied Price's law. We also calculated the national participation index (PI) and correlated it with overall PI in biomedical and health sciences, and with PI in the discipline of psychiatry. RESULTS: We obtained 20,564 original documents; 15,743 referred to the Diagnostic and Statistical Manual of Mental Disorders (DSM) and 3,106 to the International Classification of Diseases (ICD). Our results indicate non-fulfilment of Price's law, since scientific production on CDSP does not undergo exponential growth (correlation coefficient r = 0.9651, vs. r = 0.9927 after linear adjustment). Of the 10 journals with the highest impact factor in the field of psychiatry, the Journal of Clinical Psychiatry has the highest PI in the DSM subgroup (PI = 14.77), and the British Journal of Psychiatry in the ICD subgroup (PI = 1.54). The principal producer country is the United States (PI = 37.9), though in proportion to its production in the psychiatric field the ranking is headed by Finland. Only 10 countries, of the 20 major producers in health sciences, surpass their own PI in the field of psychiatry (Brazil, Italy, Japan, Austria, Spain, Germany, France, India, Switzerland, and China). CONCLUSIONS: Over recent years, the use of CDSP (basically the DSM or ICD) in the scientific literature has increased. Nevertheless, the abstracts to these studies, included in the principal databases, should always specify the diagnostic criteria employed, with a view to increasing information levels and reliability for the reader.

Genetic association study between pathological gambling and a functional DNA polymorphism at the D4 receptor gene.

A Spanish sample consisting of 68 Caucasian pathological gambling patients (47 males and 21 females) and 68 unaffected controls were screened by the molecular analysis of a functional DNA polymorphism in the locus for the D4 dopamine receptor gene. Our results are consistent with the existence of a significant association between genetic variants at a DRD4 gene polymorphism and pathological gambling (chi 2 = 11.82; P = 0.037). This association seems to be sex-influenced, since there was no significant association when only males were considered (chi 2 = 9.45; P = 0.09), but there was a more significant association if we only considered female subjects (chi 2 = 8.73; P = 0.033). Individuals with the longest allele (D7) were the most frequent in affected females (chi 2 = 4.50; P = 0.033). This work provides a new evidence of the implication of the dopaminergic reward pathways, now through the involvement of DRD4, in the aetiology of this impulsive disorder.

Pathological gambling and platelet MAO activity: a psychobiological study.

OBJECTIVE: The authors studied platelet monoamine oxidase (MAO) activity and psychological characteristics of male pathological gamblers. METHOD: Twenty-seven male pathological gamblers were compared with a group of healthy individuals who were matched by age, sex, and tobacco consumption. Measures included platelet MAO activity and scores on the MMPI and Zuckerman's Sensation Seeking Scale. RESULTS: Platelet MAO activity and scores on several MMPI scales for the two groups were significantly different, but measures of sensation seeking were not. No correlations of biological significance were found between platelet MAO activity and psychological ratings. CONCLUSIONS: Low platelet MAO activity may be a biological predisposition for impulsivity in pathological gamblers. Although no psychological pattern is characteristic of pathological gamblers, they differ from healthy individuals in some personality traits. No significant relationship could be established between platelet MAO activity and psychological measures.

Psychiatric comorbidity in pathological gamblers seeking treatment.

OBJECTIVE: The authors' goal was to determine the frequency of psychiatric comorbidity among treatment-seeking pathological gamblers, compare the severity of gambling and psychological problems in gamblers with and without comorbid disorders, and investigate differences between gamblers with and without comorbid disorders in the dopamine D(2) receptor gene (DRD(2)). METHOD: Sixty-nine pathological gamblers who consecutively applied to a specialized outpatient treatment program were evaluated with structured interviews, self-report questionnaires, and psychological scales and were genotyped for a DRD(2) polymorphism. RESULTS: A comorbid psychiatric disorder was present in 43 (62.3%) of the gamblers. The most frequent diagnoses were personality disorders (N=29 [42.0%]), alcohol abuse or dependence (N=23 [33.3%]), and adjustment disorders (N=12 [17.4%]). Gamblers with comorbid psychiatric disorders had gambling scores and psychological scale scores indicating greater severity of gambling and psychopathology. Significant differences in DRD(2) allele distribution were found in gamblers with and without comorbid disorders. CONCLUSIONS: Psychiatric comorbidity is common among pathological gamblers and is associated with greater severity of clinical problems. The DRD(2) gene could be a liability genetic factor for psychiatric comorbidity in pathological gambling.

Lack of association between manic-depressive illness and a highly polymorphic marker from GABRA3 gene.

We have carried out an association study between a dinucleotide repeat polymorphism in GABRA3 gene and manic-depressive illness in a Spanish population. This may be an important candidate gene for bipolar affective disorders since it is located in the Xq28 region, previously implicated in linkage studies. In addition, severe GABergic alterations have been reported in patients. We have not found significant differences between controls and patients in allele frequencies or genotypes.

A prospective study of the paradoxical relationship between impulsivity and lethality of suicide attempts.

BACKGROUND: Biological studies suggest that lower serotonergic activity is associated with both greater suicide lethality and impulsive personality traits. These results may lead to the conclusion that impulsivity in the attempt should be associated with greater lethality. However, Klerman's review of epidemiologic suicide studies suggests an inverse relationship between impulsivity and lethality. This seemingly paradoxical relationship between impulsivity and lethality has not been explored in large representative clinical samples of suicide attempts. METHOD: During 1996 to 1998, 478 individuals who attempted suicide were studied in a general hospital in Madrid, Spain. Impulsivity was measured as described in the literature by combining 2 items of Beck's Suicidal Intent Scale (active preparation for attempt and degree of premeditation). Lethality of the attempt was assigned 1 of 4 levels according to the need for medical and/or psychiatric treatment. RESULTS: More than half of the attempts were impulsive (55%; 95% confidence interval [CI], 51% to 59%), approximately one fourth of the attempts had an intermediate level of impulsivity (28%; 95% CI, 24% to 32%), and approximately one sixth of the attempts were not impulsive (17%, 95% CI, 13% to 21%). There was an inverse association between the impulsivity and lethality of the suicide attempt (chi2 = 62.639, df = 6, p < .0001). The most impulsive attempts tended to result in less morbidity, while the less impulsive attempts tended to be more lethal. CONCLUSION: If the inverse relationship between impulsivity and lethality is replicated in other large and representative samples, new studies will be needed to clarify the complex interactions between the clinical dimensions (lethality, impulsivity as a state, and impulsivity as a personality trait) and the biological correlates (particularly serotonergic function) of suicidal behavior.

No association between particular DRD3 and DAT gene polymorphisms and manic-depressive illness in a Spanish sample.

We have carried out an association study of a polymorphism in the 3'UTR of the dopamine transporter gene (DAT) and a polymorphism in the coding region of the D3 receptor gene (DRD3) in Spanish patients with manic depression and in controls. No significant differences in allelic and genotypic frequencies of either of these polymorphisms was found in patients compared with controls.

The value of cytidine-5-diphosphate-choline in the prevention of impairment of memory function after electric convulsive therapy. A double-blind study.

1. A double-blind study of the effect of CDP-choline on memory impairment following bilateral ECT was performed on 22 inpatients suffering from endogenous depression. 2. Memory scores were checked after 2 and 4 ECT sessions, and the length of the post-ECT confusional state was also measured. 3. The results show no statistically significant differences between the reduced memory scores obtained by both groups. Our findings do not support the hypothesis that CDP-choline affords protection against ECT-induced memory dysfunction in depression cases.

Plasmatic somatostatin as a marker of positive symptoms of schizophrenia.

1. Somatostatin displays a regulatory function on several aminergic neurotransmitters, including dopamine. In addition, decreased CSF levels of the peptide has been found in Schizophrenia and other neuropsychiatric disorders. 2. In the present work, we have investigated levels of plasmatic somatostatin in a sample of 50 schizophrenic patients compared with a normal control group. 3. Somatostatin was increased in the patient group (p less than 0.01) as a whole but statistical analysis revealed that the increase was associated with the presence of positive symptoms (Factorial Analysis) with a significant correlation, specially with delusion and hallucination scores in the Andreasen rating scales.

Neuroleptic-induced catatonia: neuroleptic malignant syndrome?

1. The authors describe a case report of catatonia syndrome after administration of depot neuroleptics. 2. Differential diagnosis was made between neuroleptic malignant syndrome or catatonic syndrome complicated by infection. The signs and symptoms observed throughout the patient's course are detailed. 3. A critical review is made of bibliography on the topic, with emphasis on the lack of clear clinical description and poor conceptual definition.

Tianeptine therapy for depression in the elderly.

1. Depression is frequent in the elderly but difficult both to diagnose and treat due to a number of distinctive features. 2. Tianeptine is a novel antidepressant with a reverse mode of action to that of the selective serotonin reuptake inhibitors yet with proven efficacy and safety. 3. 63 elderly patients (mean age:68.8 years; range:65-80 years) with depressive symptoms (major depression:55.6%; dysthymia:44.4%) were included in a 3-month open multicenter study with tianeptine (25 mg daily). 4. 43 patients (68.2%) completed the study. There were no drop-outs due to side-effects. Total Montgomery and Asberg Depression Rating Scale scores were significantly decreased (p < 0.01) on day 14, with a response rate of 76.7%. 5. Improvements were also observed in anxiety and cognitive performance. Side-effects were seen in only 11.7% of patients, with no changes in laboratory or ancillary safety parameters. Tianeptine is thus effective and well tolerated in this category of patient.

Decreased platelet monoamine oxidase activity in female bulimia nervosa.

UNLABELLED: The involvement of brain serotonin systems in the pathophysiology of eating disorders has been repeatedly demonstrated in recent studies. Platelet MAO activity is an index of brain serotonin activity and lowered platelet MAO levels have been found in association with impulsive behaviors. In addition, some preliminary reports indicate that platelet MAO could be lowered in eating disorder patients. METHODS: 47 patients with DSM-IV eating disorders were studied, including 30 with bulimia nervosa and 17 with anorexia nervosa binge eating-purging type. Platelet MAO activity was measured by isotopic methods using C-14 benzylamine and compared with a control group of 30 healthy subjects. Impulsive personality features were studied with specific rating scales. RESULTS: Platelet MAO activity was significantly lower (4.4+/-2.4 nmol/h/10(8) platelets) in the bulimic patients than in the control group (6.9+/-2.5) (p<0.001). No significant differences were found between pure bulimics and binge eating-purging anorectics. Platelet MAO was inversely and significantly correlated with scores on impulsivity scales and with borderline personality disorder characteristics. CONCLUSIONS: Platelet MAO activity is lowered in patients with bulimia, which may reflect dysfunction in impulse control mechanisms. Since platelet MAO has a predominant genetic component, there is need for studies on the association of low platelet MAO and higher risk for developing eating disorders.

Sertraline in the treatment of mixed anxiety and depression disorder.

BACKGROUND: Mixed anxiety and depression disorder (MAD) has been recognized in ICD-10 as a diagnostic group including those anxious and depressed patients which do not fit sufficient criteria for any major axis I disorders. MAD is usually treated as a combination of anxiety and depression, although there are data indicating that selective serotonin reuptake inhibitors (SSRIs) might be active on both anxiety and depression. METHOD: 38 patients diagnosed of MAD according to ICD-10 criteria were treated with flexible doses of sertraline for 8 weeks. Benzodiazepines were not allowed during the trial. Efficacy was evaluated with the Clinical Global Impression (CGI) improvement scale and with Hamilton's depression and anxiety Scales. Personality scales, including the Cloninger's TCI and Eysenck's EPQ, were used to test the predictive value of personality traits in the response to treatment. RESULTS: Anxiety was reduced by 55% and depression by 60% in Hamilton scales. At week 8, 29 patients were considered responders (CGI 1 ó 2). Two patients discontinued the trial, only one of them due to adverse events. The mean dose of sertraline was 83.4 mg/day. CONCLUSION: Sertraline showed an excellent tolerability in patients with mixed anxiety-depression disorder despite high levels of baseline anxiety. The response level was high and similar to that reported for patients with major depression. These results warrant further controlled trials to assess the efficacy of SSRIs in MAD.