Belén Arranz

Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first-episode psychosis.

Objectives Weight gain, leading to further morbidity and poor treatment adherence, is a common consequence of treatment with antipsychotic drugs. Two recent studies in the same cohort of Chinese Han subjects have shown that polymorphisms of the promoter regions of both the serotonin 5-hydroxytryptamine 2C (5-HT2C) receptor and the leptin genes, are associated with antipsychotic-induced weight gain over 10 weeks. We have investigated whether these effects remain true in a Caucasian population and following longer term treatment. Methods Seventy-three Spanish caucasian patients with a first-episode psychosis and initially drug-naive were genotyped for the 5-HT2C receptor −759C/T and leptin −2548A/G polymorphisms. Body mass index and plasma leptin levels were monitored after 6 weeks, 3 months and 9 months of antipsychotic treatment. Results Patients with the −759T variant allele showed significantly less weight gain than those without this allele. This effect held true in the smaller group of patients receiving olanzapine. The −2548 leptin polymorphism was not associated with short-term (6 week and 3 month) weight increases but did show significant association with 9-month antipsychotic-induced weight gain. The 5-HT2C −759 genotype was significantly associated with pre-treatment plasma leptin levels. Conclusions These findings confirm the importance of two genetic factors associated with long-term antipsychotic-induced weight increases in schizophrenia, and implicate a role for leptin in the 5-HT receptor-mediated weight regulation.

Brain 5-HT1A, 5-HT1D, and 5-HT2 Receptors in suicide victims

We report on 5-HT1A, 5-HT1D, and 5-HT2 binding sites in 23 control subjects and 18 suicide victims subdivided according to the method of death and the previous existence of depressive symptoms. No difference in maximum binding (Bmax) or binding affinity (Kd) was found between the control and overall suicide groups for the binding sites studied. The drug overdose subgroup showed, however, a significant decrease in the 5-HT1A binding affinity, probably explained by the higher sensitivity of this binding site to the acute administration of tricyclic antidepressants. A significant decrease in 5-HT1D binding affinity was also found in the depressed suicides, together with a significant decrease in the number of 5-HT1D binding sites in the nondepressed suicides. Further studies should be carried out on the 5-HT1D binding site as it might represent a new tool in the understanding of the depressive illness.

Altered 5-HT2A binding sites and second messenger inositol trisphosphate (IP3) levels in hippocampus but not in frontal cortex from depressed suicide victims

The binding parameters of 5-HT(2A) and levels of its second messenger, 1,4,5-trisphosphate (IP(3)), were simultaneously studied in frontal cortex and hippocampus from the brains of 18 control subjects and 18 depressed suicide victims. All suicides met DSM-III-R criteria for depressive symptoms, suffered a violent death and had not taken any antidepressant drugs for at least 6 months prior to death. A significant decrease in the number of 5-HT(2A) binding sites (154+/-22 vs. 254+/-36 fmol/mg), together with a significantly lower apparent affinity constant (1.02+/- 0.08 vs. 1. 36+/-0.09 nM), was detected in hippocampus but not in frontal cortex from the depressed suicides compared to the control subjects. Furthermore, IP(3) concentrations were significantly increased in hippocampus (3.2+/-0.3 vs. 2.1+/-0.3 pmol/g) but not in frontal cortex (1.3+/-0.3 vs. 2.7+/-0.5 pmol/g) from the suicide victims. The reported results may indicate a significant hypersensitivity of the 5-HT(2A) postsynaptic receptor located in the hippocampus from depressed suicide victims, giving rise to an enhancement of its intracellular signaling system with higher IP(3) production.

Altered 5-HT2A and 5-HT4 Postsynaptic Receptors and Their Intracellular Signalling Systems IP3 and cAMP in Brains from Depressed Violent Suicide Victims

Serotonin 5-HT2A and 5-HT4 binding parameters and their second messengers 1,4,5-inositol triphosphate (IP3) and cyclic adenosyl monophosphate (cAMP) were studied in the frontal cortex, hippocampus, caudate nucleus and amygdala of 19 control subjects and 19 antidepressant-free, violent suicide victims. A significantly higher number of 5-HT4 receptors and higher second messenger cAMP concentrations were found in the frontal cortex and caudate nucleus of the depressed suicide victims as compared with the control group. Furthermore, significantly increased 5-HT2A binding sites and IP3 concentrations were noted in the caudate nucleus of the suicide victims, together with a significantly reduced number of 5-HT2A binding sites, higher binding affinity and increased IP3 concentrations in the hippocampus. No significant alterations in 5-HT4 and cAMP or in 5-HT2A and IP3 concentrations were observed in the amygdala. The caudate nucleus of depressed suicide victims seems to be the brain region with the highest alteration of the serotonergic system, and hence with the most diagnostic sensitivity. Further studies on suicidality and depression should focus on the functionality of the caudate nucleus.

Cross-cultural adaptation and validation of the Spanish version of the Calgary Depression Scale for Schizophrenia

BACKGROUND The Calgary Depression Scale for Schizophrenia (CDSS) is a valid tool to assess depression in schizophrenics and has been translated, adapted, and validated to be used in different non-English languages. Therefore, it may be predicted that a Spanish version of this scale will be also a valid instrument to assess symptoms of depression in patients with schizophrenia. OBJECTIVE We determined the validity of the Spanish version of the Calgary scale (CDSS-S). METHODS Outpatients and inpatients (n=93) diagnosed as having schizophrenia by DSM-IV criteria confirmed by SCID-IV interview were included. The Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale (HDRS-17 and HDRS-21 items), Montgomery-Asberg Depression Rating Scale (MADRS), Extrapyramidal Symptoms Rating Scale (ESRS), and Barnes Acathisia Rating Scale were administered by a first rater, whereas the CDSS-S was assessed by a second independent rater. RESULTS The internal consistency (Cronbachs alpha 0.83) and the interrater reliability (>0.73 intraclass correlation coefficient [ICC] for single items and 0.92 for total score) were good. The test-retest reliability was high (ICC of 0.89). The scale showed a good construct validity with statistically significant correlations with HDRS-17, HDRS-21, MADRS, and G6 item (depression) of PANSS. The CDSS showed no correlation with the positive subscale of PANSS and a weak correlation with the negative subscale, general psychopathology subscale, and total score of PANSS. A cut point of five showed 94.7% sensitivity, 86.5% specificity, and 70% and 98% positive and negative predictive values, respectively. CONCLUSIONS The Spanish version of CDSS is a valid instrument to assess depressive episodes for stabilized and acute patients with schizophrenia.

Altered [3H]imipramine and 5-HT2 but not [3H]paroxetine binding sites in platelets from depressed patients

BACKGROUND Serotonergic system alterations were studied in 51 depressed patients classified according to DSM-III-R criteria for major depression with melancholia compared to 31 healthy controls. METHOD [3H]Imipramine and [3H]paroxetine binding sites and the 5HT2 receptor were simultaneously determined in blood platelet membranes. RESULTS A significantly lower maximum binding in [3H]imipramine binding was observed in depressed patients compared to controls (1134+/-74 vs. 1712+/-106 fmol/mg protein, P<0.0001) without changes in the equilibrium dissociation constant (1.10+0.05 vs. 1.25-/+0.09 nM). [3H]Paroxetine binding did not differ between the two groups (Bmax, 1441+/-55 vs. 1280+/-81 fmol/mg protein; Kd, 0.060+/-0.002 vs. 0.062+/-0.002 nM). The K(d) value of 5HT2 binding was lower in depressed patients than controls (0.95+/-0.04 vs. 1.15+/-0.09 nM, P<0.039) without changes in maximum binding (140+/-11 vs. 127+/-14 fmol/mg protein). CONCLUSIONS Taken together, these results suggest that [3H]imipramine and 5HT2 receptors may be good biological markers for serotonergic dysfunction in depressive disorders.

Antipsychotic Drug Treatment of Schizophrenic Patients with Substance Abuse Disorders

Background/Aim: In recent years, there has been a growing interest in developing adequate treatments for patients with a diagnosis of schizophrenia and a comorbid substance use disorder (SUD). In the present paper we aim to critically review published reports on the use of conventional and second-generation antipsychotics in the treatment of patients with schizophrenia and comorbid SUD, to provide clinicians with a clearer view of the pharmacological treatment of this highly prevalent dual diagnosis based upon the evidence arising from the scientific literature. Methods: A search of the relevant literature from Medline, PsycLIT and EMBASE databases, included in the Science Citation Index, and available up to November 2006 was conducted using the terms: ‘schizophrenia’, ‘substance use disorder’ and ‘antipsychotics’. Results: While research on the use of conventional antipsychotics has remained limited, the majority of studies suggest the effectiveness of second-generation antipsychotics, particularly clozapine, for patients with schizophrenia and a comorbid substance use disorder. Conclusion: In the absence of randomized controlled trials that could provide more reliable information, clinical decisions may need to rely on indirect data provided by the increasing number of case reports, open trials and retrospective studies showing a decrease in cigarette smoking, alcohol, cocaine or cannabis use and an improvement of overall psychiatric symptoms.

Serotonergic, noradrenergic, and dopaminergic measures in suicide brains

Concentrations of the three main monoamines (5-HT, NA, and DA), their metabolites (5-HIAA, DOPAC, and HVA), and the serotonin precursor 5-hydroxy-L-tryptophan were simultaneously measured in frontal cortex, gyrus cinguli, and hypothalamus from 23 controls and 18 suicide victims. Overall suicides did not show significant differences with respect to the control group in any of the measured compounds. Significant increases in noradrenaline and dopamine concentrations were noted in the carbon monoxide poisoning suicides, together with a significant increased hypothalamic dopamine in the drug overdose suicides. It is suggested that the suicidal behavior is not related to substantial changes in cortical and hypothalamic monoaminergic function; however, the reported results could be secondary to the rapid effect of hypoxia and of the acute self-administration of certain drugs in specific metabolic pathways.

Variations in [3H]imipramine and 5-HT2A but not [3H]paroxetine binding sites in suicide brains

Both the [3H]imipramine and [3H]paroxetine binding sites and the 5-HT2A receptor were simultaneously determined in frontal cortex, cingulate cortex, hippocampus and amygdala from 17 control subjects and 17 depressed suicide victims. A significant decrease in the maximum binding (Bmax) of [3H]imipramine was observed in the hippocampus of suicide victims as compared to control subjects (160 +/- 25 vs. 328 +/- 52 fmol/mg protein; P = 0.007) without changes in the apparent affinity constant (Kd). Furthermore, a significant decrease in the number of 5-HT2A binding sites, together with a significantly lower Kd, was also observed in the hippocampus of suicides as compared to control subjects (129 +/- 18 vs. 225 +/- 32 fmol/mg protein; P = 0.02 and 0.91 +/- 0.07 vs. 1.38 +/- 0.08 nM, respectively; P = 0.006). [3H]Paroxetine binding did not display modifications between the two groups in either Bmax or Kd from any of the brain regions studied. When all four brain regions were taken together, a down-regulation was noted between presynaptic [3H]imipramine binding and the postsynaptic 5-HT2A receptor (r = -0.40; P = 0.0013) in the control group. This correlation did not appear in the suicide group. No correlation was observed between [3H]paroxetine binding and the 5-HT2A receptor in either control subjects or suicides. Taken together, these results suggest that the 5-HT uptake site measured with [3H]imipramine and the 5-HT2A receptors are reliable markers of serotonergic dysfunction.

One-year, randomized, open trial comparing olanzapine, quetiapine, risperidone and ziprasidone effectiveness in antipsychotic-naive patients with a first-episode psychosis

The aim of this study was to compare the 12-month effectiveness of several second-generation antipsychotic drugs, with that of haloperidol in never-treated patients with first-episode psychosis. In total, 114 patients without life time exposure to any psychotropic medication were randomized to haloperidol, olanzapine, risperidone, quetiapine or ziprasidone. Primary outcome was time to all-cause discontinuation. Secondary outcomes included discontinuation rates and symptom change as measured by the Positive and Negative Syndrome Scale (PANSS). The overall discontinuation rate 64%. At 12 months, the proportion of patients discontinuing treatment was 40.0% for olanzapine, 56.5% for quetiapine, 64.0% for risperidone, 80.0% for ziprasidone and 85.7% for haloperidol. Mean time to antipsychotic discontinuation was higher in patients randomized to second-generation antipsychotics than in those taking haloperidol. Significantly lower discontinuation was noted in patients on olanzapine than on haloperidol, or ziprasidone. Our results suggest that olanzapine might lead to longer treatment continuation in treatment naïve FEP patients than haloperidol and, possibly ziprasidone. Global psychopathology was significantly less reduced by haloperidol than with each individual SGA in this earliest phase of treatment.