Pretreatment platelet 5-HT concentration predicts the short-term response to paroxetine in major depression. Grupo de Trastornos Afectivos.

BACKGROUND: A previous retrospective study revealed that a high pretreatment platelet serotonin (5-HT) concentration was associated with a low response to serotonergic antidepressants in drug-free major depressives. We have examined such a relationship in depressive patients treated with paroxetine. METHODS: Seventy-four drug-free major depressives (DSM-IV) were admitted to the study. Clinical ratings were performed and blood was drawn prior to the initiation of treatment and after 4 weeks of paroxetine (20 mg/day). The concentrations of 5-HT, 5-hydroxyindoleacetic acid, and tryptophan were determined in plasma and blood. RESULTS: Paroxetine treatment reduced platelet 5-HT to 17% of baseline after 4 weeks of treatment. Responder patients had a pretreatment platelet 5-HT concentration 22% lower than nonresponders (p < .035). Admission HAMD scores, plasma paroxetine concentration, or platelet 5-HT concentration at endpoint did not differ between responders and nonresponders. Yet, the response rate was 11% in patients with high pretreatment platelet 5-HT (> 900 ng/10(9) platelets) and 50% in those below that value (p < .004). CONCLUSIONS: These findings support that depressed patients with a high pretreatment platelet 5-HT concentration have a poor therapeutic outcome after treatment with a standard paroxetine dose. These differences may be related to the existence of molecular differences in the 5-HT transporter.     

EEG hemispheric asymmetry as a predictor and correlate of short-term response to clozapine treatment in schizophrenia.

In search of early neuroleptic response predictors in schizophrenia, functional interhemispheric and intrahemispheric asymmetry indices, derived from spectrally analyzed resting electroencephalographic (EEG) activity, were examined in 17 schizophrenic patients prior to open label treatment with the atypical neuroleptic clozapine. Compared to EEG asymmetry indices derived from a normative data bank, patients exhibited significant interhemispheric (left greater than right) and intrahemispheric (anterior greater than posterior) deviations in delta, theta, alpha and beta frequency bands. Intrahemispheric indices were positively correlated with clinical ratings of positive symptoms and global psychopathology. Clozapine-induced improvements in positive and negative symptoms and global psychopathology symptom ratings were related to pretreatment intrahemispheric asymmetry only, with relationships varying with symptom, recording region and frequency band. The results are discussed in relation to the neurobiology of schizophrenia and the utility of EEG as an informative predictor of treatment response.     

Pretreatment anterior cingulate activity predicts antidepressant treatment response in major depressive episodes

Major depressive disorder leads to substantial individual and socioeconomic costs. Despite the ongoing efforts to improve the treatment for this condition, a trial-and-error approach until an individually effective treatment is established still dominates clinical practice. Searching for clinically useful treatment response predictors is one of the most promising strategies to change this quandary therapeutic situation. This study evaluated the predictive value of a biological and a clinical predictor, as well as a combination of both. Pretreatment EEGs of 31 patients with a major depressive episode were analyzed with neuroelectric brain imaging technique to assess cerebral oscillations related to treatment response. Early improvement of symptoms served as a clinical predictor. Treatment response was assessed after 4 weeks of antidepressant treatment. Responders showed more slow-frequency power in the right anterior cingulate cortex compared to non-responders. Slow-frequency power in this region was found to predict response with good sensitivity (82 %) and specificity (100 %), while early improvement showed lower accuracy (73 % sensitivity and 65 % specificity). Combining both parameters did not further improve predictive accuracy. Pretreatment activity within the anterior cingulate cortex is related to antidepressive treatment response. Our results support the search for biological treatment response predictors using electric brain activity. This technique is advantageous due to its low individual and socioeconomic burden. The benefits of combining both, a clinically and a biologically based predictor, should be further evaluated using larger sample sizes.     

Association of short-term response to haloperidol treatment with a polymorphism in the dopamine D(2) receptor gene

OBJECTIVE: Pharmacogenetic influences on therapeutic response to neuroleptic treatment are poorly understood. This study investigates the association of response to short-term haloperidol treatment with a Taq I polymorphism in the DRD2 gene. METHOD: Fifty-seven patients with acute psychosis were treated with haloperidol for up to 28 days. Improvement and response were measured by using the Positive and Negative Syndrome SCALE: Forty-one patients were homozygous for allele 2, and 16 were heterozygous. RESULTS: Heterozygous patients showed a greater improvement in positive, but not in negative, symptoms on all treatment days than patients homozygous for allele 2. Differences in improvement of positive symptoms reached statistical significance on days 14, 21, and 28. On treatment day 14, 10 (62.5%) of 16 heterozygous patients had at least 50% improvement of positive symptoms, compared with 11 (28.9%) of 38 homozygous patients. CONCLUSIONS: These results support the hypothesis that genetic variations in the DRD2 gene may influence the individual response to antipsychotics.     

Human EEG response to beta-endorphin.

Beta-endorphin, morphine, and saline were given intravenously to a single schizophrenic subject on separate occasions in a double-blind design. EEG spectral analyses performed on data collected before and after drug injection demonstrated that beta-endorphin and morphine produced similar increases in alpha power within 5 to 15 minutes after injection. This effect could be distinguished from two placebo (saline) injections. These data suggest that intravenous beta-endorphin can produce changes in the central nervous system in humans.     

Dissociation predicts symptom-related treatment outcome in short-term inpatient psychotherapy

OBJECTIVE: Previous research has indicated that dissociation might be a negative predictor of treatment outcome in cognitive behavioural therapy for patients with obsessive-compulsive and anxiety disorders. Using a naturalistic design it was hypothesized that higher levels of dissociation predict poorer outcome in inpatients with affective, anxiety and somatoform disorders participating in a brief psychodynamic psychotherapy. METHOD: A total of 133 patients completed the Symptom Check List (SCL-90), the German short version of the Dissociative Experiences Scale and the Inventory of Interpersonal Problems at the beginning and the end of treatment. The Global Severity Index (GSI) of the SCL-90 was chosen as outcome criterion. RESULTS: A total of 62.4% of study participants were classified as treatment responders, that is, they showed a statistically significant change of their GSI scores. Controlling for general psychopathology, the non-responders had significantly higher baseline dissociation scores than the responders. In a logistic regression analysis with non-response as a dependent variable, a comorbid personality disorder, low baseline psychopathology and high dissociation levels emerged as relevant predictors, but interpersonal problems and other comorbid disorders did not. CONCLUSIONS: Dissociation has a negative impact on treatment outcome. It is suggested that dissociative subjects dissociate as a response to negative emotions arising in psychotherapy leading to a less favourable outcome. Additionally, dissociative patients may have an insecure attachment pattern negatively affecting the therapeutic relationship. Thus, dissociation may directly and indirectly influence the treatment process and outcome.     

Effects of haloperidol pretreatment on the smoking-induced EEG/mood activation response profile

This study examined the role of dopamine in modulating the CNS response to cigarette smoking. In a randomized, double-blind, repeated-measures design, quantitative electroencephalographic (EEG) changes and self-reports induced by the smoking of a single cigarette were assessed in 16 smokers following pretreatment with placebo and a dopamine antagonist, haloperidol (2 mg). Following placebo pretreatment, absolute (muV) and relative (%) amplitudes in slow-frequency bands (delta, theta, alpha1) were reduced and absolute and relative amplitudes in fast-frequency bands (alpha2, beta) were increased following cigarette smoking as compared to sham smoking. Haloperidol pretreatment inhibited the smoking-induced increase in absolute beta frequency. Self-ratings indicated that cigarette smoking induced increases in alertness, contentedness and calmness but not euphoria, and reduced cigarette cravings as compared to the sham smoking conditions. Smoking-induced, alpha2 increments were associated with increases in alertness and decreases in euphoria while beta increments were associated with increased calmness. Smoking-related self-ratings of mood and cigarette acceptability were not altered by haloperidol, but subjects were less content overall in the haloperidol condition as compared to placebo. Discussion of these results focuses on transmitter systems and their relationship to neuro-electric and behavioural activities associated with the smoking habit.     

Brain serotonin transporter availability predicts treatment response to selective serotonin reuptake inhibitors.

BACKGROUND: Few studies have investigated the predictive value of central serotonin transporter (SERT) availability for treatment response to serotonin reuptake inhibitors (SSRIs). This study used brain imaging to examine the relationship between pretreatment brain SERT availability and transporter occupancy by SSRIs with treatment response in two independent depressed populations. METHODS: Study 1: Twenty-three patients with major depression underwent a single photon emission computed tomography (SPECT) measurement of brain SERT availability using [123I]beta-CIT ([123I]methyl 3beta-(4-iodophenyl) tropane-2beta-carboxylate. The SERT availability was correlated with treatment response to fluoxetine (20 mg/day) assessed with weekly Hamilton Depression Rating Scale (HDRS) for 6 weeks. Study 2: The second group included 10 depressed patients who received 6 weeks of paroxetine treatment (20 mg/day) and serial SPECT scans (baseline, during, and after the treatment). RESULTS: In Study 1, higher pretreatment diencephalic SERT availability significantly predicted better treatment response 4 weeks later. Similar results were found in Study 2 and supported Study 1 findings. The data showed that greater occupancy of diencephalic transporters by paroxetine correlated with better treatment response. CONCLUSIONS: Higher pretreatment availability and greater occupancy of SERT in diencephalon may predict better treatment course in response to SSRIs.     

Visual P300 latency predicts treatment response to modafinil in patients with narcolepsy.

OBJECTIVE: To evaluate the hypothesis that visual P300 latency (VL) predicts treatment response to modafinil (a new wake-promoting agent) in patients with narcolepsy. METHODS: Design: Comparison of responders and non-responders in a double-blind randomized placebo-controlled trial. Setting: Private practice referral sleep disorders center. Patients: Twenty one patients with narcolepsy (ages 17-65 years). Interventions: Auditory and visual P300 testing using 31 evenly spaced scalp electrodes, and baseline polysomnograms and objective and subjective tests of daytime sleepiness, followed by modafinil treatment for 9 weeks. Polysomnograms and tests of sleepiness were then repeated. Main outcome measure: The Maintenance of Wakefulness Test (MWT). Response defined as a final MWT > 7.3min (normative sample mean - 3 SD), plus an increase > 1SD based on normative sample (3.6 min) over baseline MWT. RESULTS: Non-responders had longer age-adjusted 31-electrode mean VL (448.4 ms vs. 410.8 ms, P = 0.024), and larger auditory P300 amplitude, with no topographical P300 differences. Non-responders and responders did not differ on any other baseline clinical variable. Using a cut-off of 0.5 SE from normal regression constant, shorter age-adjusted VL predicted modafinil response, with specificity of 0.71 and sensitivity of 0.86. CONCLUSIONS: VL predicts treatment response to modafinil in patients with narcolepsy.     

Pretreatment episode count and response to lithium treatment in manic-depressive illness

Factors that reliably predict treatment response in bipolar disorder are much needed, particularly since no available treatment routinely affords complete protection from future illness. The number of pretreatment episodes (PTEs) is a proposed predictor, but its value remains uncertain. We therefore reviewed available research on this topic. Based on a computer-assisted search of the literature, we identified 28 reports providing data on response to lithium treatment and on history of past illness. We evaluated their methods and findings to test the hypothesis that greater PTE count predicts inferior clinical response to lithium. Most studies (68%) found no support for the predicted relationship, and those that did or did not find the hypothesized relationship differed nonsignificantly in ratings of overall study quality and individual factors, including study size, previous lithium use, diagnostic criteria, and outcome measures. The concept that PTE count strongly and consistently predicts inferior clinical response to lithium treatment in manic-depressive disorders is not supported by available research, thus adding to emerging uncertainties about the relationship of past history and later course of these often severe, disabling, and life-threatening illnesses.     

Ontogenic changes in cerebral concentration of homovanillic acid in response to haloperidol treatment

Pregnant rabbits of 24–29 days gestation, and young rabbits from birth to 4 weeks of age, were treated with haloperidol (0.2 mg/kg), dopamine-receptor blocking agent. Control animals received glucose. The animals were killed 4 h after haloperidol, and the brains of the young animals (and also of the foetuses, delivered by caesarian section) were analyzed for homovanillic acid (HVA), 5-hyroxyindoleacetic acid (5-HIAA) or dopamine.

The levels of 5-HIAA and dopamine were unchanged after haloperidol, but from the 29th day of gestation the drug induced an increase in the brain levels of HVA. The magnitude of increase, however, was much smaller in the young animals (29 day foetuses and newborn) than in the older animals (3–4 weeks of age.) This change with age was interpreted as an ontogenic development of dopamine receptors, or of a link in the feed-back control of transmitter release, or as an alternative possibility, development of the enzymes involved in the transformation of dopamine to HVA.     

TSH response to TRH and haloperidol response latency in psychoses

Thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) was measured in 19 acutely psychotic (DSM-III schizophrenia, 7; schizophreniform, 2; schizoaffective, 3; affective, mood-incongruent psychosis, 5; manic, mood-congruent psychosis, 2) drug-free patients prior to systematic trials of lithium and/or haloperidol. TSH response was not associated with sex, age, baseline T4, or baseline TSH. A reduced TSH response was associated with affective diagnosis and was a significant predictor of a positive, rapid response to neuroleptic treatment.     

Plasma catecholamine metabolites and early response to haloperidol

Plasma homovanillic acid (HVA) and methoxyhydroxyphenyl glycol (MHPG) as well as serum haloperidol and prolactin were measured in patients admitted to a general hospital psychiatric service for treatment of acute psychosis. At 10 days, good responders compared to poor responders had higher mean plasma HVA values before and during the first week of treatment with 0.2-0.4 mg/kg haloperidol per day. MHPG values showed a similar pattern, although no significant differences were obtained between or within the two groups. Females predominated among good responders; neither DSM-III diagnoses nor steady state haloperidol levels differed significantly between the two groups. Significant correlations within some patients were obtained between prolactin and haloperidol (positive), prolactin and MHPG (negative), and HVA and MHPG (positive). Plasma catecholamine metabolites deserve further study as possible markers of early response to the treatment of acute psychosis with modest doses of neuroleptic drugs.