Dynamic time warp analysis of individual symptom trajectories in depressed patients treated with electroconvulsive therapy.

BACKGROUND: Although electroconvulsive therapy (ECT) effectively improves severity scores of depression, its effects on its individual symptoms has scarcely been studied. We aimed to study which depressive symptom trajectories dynamically cluster together in individuals as well as groups of patients during ECT using Dynamic Time Warp (DTW) analysis. METHODS: We analysed the standardized weekly scores on the 25-item abbreviated version of the Comprehensive Psychopathological Rating Scale (CPRS) in depressed patients before and during their first six weeks of ECT treatment. DTW analysis was used to analyse the (dis)similarity of time series of items scores at the patient level (300 'DTW distances' per patient) as well as on the group level. Hierarchical cluster, network, and Distatis analyses yielded symptom dimensions. RESULTS: We included 133 patients, 64.7% female, with an average age of 60.4 years (SD 15.1). Individual DTW distance matrices and networks revealed marked differences in hierarchical and network clusters among patients. Based on cluster analyses of the aggregated matrices, four symptom clusters emerged. In patients who reached remission, the average DTW distance between their symptoms was significantly smaller than non-remitters, reflecting denser symptom networks in remitters than non-remitters (p=0.04). LIMITATIONS: The assessments were done only weekly during the first six weeks of ECT treatment. The use of individual items of the abbreviated CPRS may have led to measurement error as well as floor and ceiling effects. CONCLUSION: DTW offers an efficient new approach to analyse symptom trajectories within individuals as well as groups of patients, aiding personalized medicine of psychopathology.

Testing for response shift in treatment evaluation of change in self-reported psychopathology amongst secondary psychiatric care outpatients.

OBJECTIVES: If patients change their perspective due to treatment, this may alter the way they conceptualize, prioritize, or calibrate questionnaire items. These psychological changes, also called "response shifts," may pose a threat to the measurement of therapeutic change in patients. Therefore, it is important to test the occurrence of response shift in patients across their treatment. METHODS: This study focused on self-reported psychological distress/psychopathology in a naturalistic sample of 206 psychiatric outpatients. Longitudinal measurement invariance tests were computed across treatment in order to detect response shifts. RESULTS: Compared with before treatment, post-treatment psychopathology scores showed an increase in model fit and factor loading, suggesting that symptoms became more coherently interrelated within their psychopathology domains. Reconceptualization (depression/mood) and reprioritization (somatic and cognitive problems) response shift types were found in several items. We found no recalibration response shift. CONCLUSION: This study provides further evidence that response shift can occur in adult psychiatric patients across their mental health treatment. Future research is needed to determine whether response shift implies an unwanted potential bias in treatment evaluation or a desired cognitive change intended by treatment.

Concordance between self-reported and observer-rated anxiety severity in outpatients with anxiety disorders: The Leiden routine outcome monitoring study.

OBJECTIVES: Anxiety severity measures can be self-report or observer-rated. Although mostly these measures concur, they can diverge markedly. We examined concordance between two anxiety scales: the observer-rated Brief Anxiety Scale (BAS) and the self-report Brief Symptom Inventory 12-item version (BSI-12), and described associations between patient characteristics and discordance. DESIGN: The study used an observational design, using prospective data from 2,007 outpatients with DSM-IV-TR panic disorder with or without agoraphobia, agoraphobia without panic, social phobia, and/or generalized anxiety disorder. METHODS: Overall agreement was described using Pearson's product-moment correlation coefficient. Associations between patient characteristics and discordance (defined as |Z-BAS-Z-BSI-12| ≥ 1) were evaluated with univariable and multivariable multinomial logistic regression analyses. RESULTS: Overall correlation between BAS and BSI-12 was positive and strong (r = .59). Discordance occurred in 24.8% of patients ([Z-BAS ≥ Z-BSI-12 + 1] = 12.2%; [Z-BAS ≤ Z-BSI-12 - 1]  = 12.6%). Patients with higher observed than self-reported anxiety severity did not differ from concordant patients. Patients with lower observed than self-reported anxiety severity more often had panic disorder, less often had social phobia, and had higher scores on cluster B and C personality characteristics than concordant patients. Lower observed than self-reported anxiety severity was best predicted by panic disorder, social phobia, and affective lability. CONCLUSIONS: Results demonstrate that the use of a single source of information gives a one-sided view of pathology. A multimethod approach is highly preferable, as this allows for assessment across different domains and through multiple sources of information, and as such, provides clinicians with vital information. PRACTITIONER POINTS: When assessing anxiety severity, the use of self-report measures provides additional information to observer-rated measures. In patients who have strong cluster B and C personality traits, anxiety severity might be overlooked, even by trained observers. The use of a multimethod assessment strategy is preferable in anxiety severity assessment.

Age-related characteristics of outpatients with anxiety disorders: the Leiden routine outcome monitoring study.

OBJECTIVE: It has been hypothesised that clinically important age-related differences between adults with anxiety disorders exist; this study aims to elucidate these differences. METHODS: We analysed data from 1950 outpatients diagnosed with DSM-IV-TR anxiety disorders treated at a Dutch hospital or affiliated mental healthcare centres. Three age-groups (young- (18-25; n = 435), mid- (26-40; n = 788) and older adult (41-65; n = 727)) were compared with regard to social demographic characteristics, diagnostic characteristics, anxiety symptom profile, general psychiatric symptom profile and generic health status, in addition, linear analyses were carried out with age as a continuous variable. RESULTS: Average age was 36.48 years (SD 11.71), 62.8% were female. Significant associations with age emerged for gender, employment, education level, living situation, observed depression, agoraphobia (AP), social phobia, aches and pains, inner tension, sleep, interpersonal sensitivity, observed hostility, physical functioning, role limitations due to physical problems, vitality and bodily pain in categorical and continuous analyses. Self reported hostility was only significant in group-wise comparisons; role limitations due to emotional problems were only significant in linear analyses (all at p < .001). CONCLUSIONS: This study identified clinically relevant differences between younger and older adult outpatients with anxiety disorders. Clinicians should take these findings into account, as they may support treatment.

Treatment consumption and treatment re-enrollment in GHB-dependent patients in The Netherlands.

BACKGROUND: The objective of this study was to assess treatment consumption and re-enrollment in treatment in patients with gamma-hydroxybutyrate (GHB)-dependence in Dutch Addiction Treatment Centers (ATCs) in comparison with other addictions. METHODS: A cohort-study using nationwide administrative data from regular Dutch ATCs associated with the Dutch National Alcohol and Drugs Information System (LADIS), covering an estimated 95% of ATCs. We selected in- and out-patients with alcohol, drug and/or behavioral addictions with a first treatment episode in 2008-2011 and consecutive treatments until 2013 (n=71,679). Patients still in treatment at that date (n=3686; 5.1%), forensic patients (n=1949; 2.7%) and deceased patients (n=570; 0.8%) were excluded, leaving 65,474 patients (91.3%). Of those, 596 (0.9%) patients had GHB dependence. We analyzed number of treatment contacts, treatment duration, admissions and admission duration of the first treatment episode, and re-enrollment (defined as having started a second treatment episode in the study period). RESULTS: GHB-dependent patients showed the highest number of treatment contacts, duration of treatment and chance of being admitted. Re-enrollment rates were 2-5 times higher in GHB-dependent patients than other patients with adjusted HR of other addictions ranging from 0.18 (95% confidence interval [CI]: 0.15-0.21) to 0.53 (95% CI: 0.47-0.61). CONCLUSIONS: This study demonstrates high levels of treatment consumption and high rates of treatment re-enrollment in GHB-dependent patients. These findings highlight the urgency of developing effective relapse prevention interventions for GHB-dependent patients.

The effect of atomoxetine on random and directed exploration in humans.

The adaptive regulation of the trade-off between pursuing a known reward (exploitation) and sampling lesser-known options in search of something better (exploration) is critical for optimal performance. Theory and recent empirical work suggest that humans use at least two strategies for solving this dilemma: a directed strategy in which choices are explicitly biased toward information seeking, and a random strategy in which decision noise leads to exploration by chance. Here we examined the hypothesis that random exploration is governed by the neuromodulatory locus coeruleus-norepinephrine system. We administered atomoxetine, a norepinephrine transporter blocker that increases extracellular levels of norepinephrine throughout the cortex, to 22 healthy human participants in a double-blind crossover design. We examined the effect of treatment on performance in a gambling task designed to produce distinct measures of directed exploration and random exploration. In line with our hypothesis we found an effect of atomoxetine on random, but not directed exploration. However, contrary to expectation, atomoxetine reduced rather than increased random exploration. We offer three potential explanations of our findings, involving the non-linear relationship between tonic NE and cognitive performance, the interaction of atomoxetine with other neuromodulators, and the possibility that atomoxetine affected phasic norepinephrine activity more so than tonic norepinephrine activity.

Evaluating the Responsiveness to Therapeutic Change with Routine Outcome Monitoring: A Comparison of the Symptom Questionnaire-48 (SQ-48) with the Brief Symptom Inventory (BSI) and the Outcome Questionnaire-45 (OQ-45).

Assessment of psychological distress is important, because it may help to monitor treatment effects and predict treatment outcomes. We previously developed the 48-item Symptom Questionnaire (SQ-48) as a public domain self-report psychological distress instrument and showed good internal consistency as well as good convergent and divergent validity among clinical and non-clinical samples. The present study, conducted among psychiatric outpatients in a routine clinical setting, describes additional psychometric properties of the SQ-48. The primary focus is on responsiveness to therapeutic change, which to date has been rarely examined within psychiatry or clinical psychology. Since a questionnaire should also be stable when no clinically important change occurs, we also examined test-retest reliability within a test-retest design before treatment (n = 43). A pre-treatment/post-treatment design was used for responsiveness to therapeutic change, comparing the SQ-48 with two internationally widely used instruments: the Brief Symptom Inventory (n = 97) and the Outcome Questionnaire-45 (n = 109). The results showed that the SQ-48 has excellent test-retest reliability and good responsiveness to therapeutic change, without significant differences between the questionnaires in terms of responsiveness. In sum, the SQ-48 is a psychometrically sound public domain self-report instrument that can be used for routine outcome monitoring, as a benchmark tool or for research purposes. Copyright © 2015 John Wiley & Sons, Ltd. Key Practitioner Message The SQ-48 is developed as a public domain self-report questionnaire, in line with growing efforts to develop clinical instruments that are free of charge. The SQ-48 has excellent test-retest reliability and good responsiveness to therapeutic change or patient progress. There were no significant differences in terms of responsiveness between the SQ-48 and BSI or OQ-45. The SQ-48 can be used as a routine evaluation outcome measure for quality assurance in clinical practice. Providing feedback on patient progress via outcome measures could contribute to the enhancement of treatment outcomes.

Detoxification with titration and tapering in gamma-hydroxybutyrate (GHB) dependent patients: The Dutch GHB monitor project.

BACKGROUND AND AIMS: Gamma-hydroxybutyrate (GHB) detoxification procedures have been insufficiently studied for effectiveness and safety. Based on case reports, benzodiazepines are generally regarded as first-choice agents in GHB detoxification. Detoxification by titration and tapering (DeTiTap) with pharmaceutical GHB in an open-label consecutive case series of 23 GHB-dependent patients showed to be feasible, effective and safe. This study further explored the feasibility, effectiveness and safety of this detoxification procedure in a large group of patients. METHOD: A large observational multicenter study was carried out in six addiction treatment centers in the Netherlands. GHB-dependent inpatients (229 unique patients, 274 admissions) were titrated on and tapered off with pharmaceutical GHB. RESULTS: Successful detoxification was achieved in 85% of cases. Detoxification was carried out in 12.5days in most patients. The DeTiTap procedure proved to be feasible and significantly reduced the experienced withdrawal symptoms and craving (p≤0.001). Several symptoms were found to influence the course of subjective withdrawal symptoms. During detoxification, psychological symptoms such as depression, anxiety, and stress decreased (p≤0.05). The main complications were hypertension and anxiety. Six patients were sent to the general hospital for observation, but all six were able to continue detoxification in the addiction treatment centers. Most patients (69%) relapsed within three months after detoxification. CONCLUSIONS: The DeTiTap procedure using pharmaceutical GHB seems a safe alternative to benzodiazepines as a GHB detoxification procedure. However, the high relapse rates warrant further investigation.

Pharmacological Treatment in γ-Hydroxybutyrate (GHB) and γ-Butyrolactone (GBL) Dependence: Detoxification and Relapse Prevention.

The misuse of γ-hydroxybutyrate (GHB) for recreational purposes has resulted in an increase in GHB-related problems such as intoxications, dependence and withdrawal in several countries in Europe, Australia and the US over the last decade. However, prevalence rates of misuse of GHB and its precursor, γ-butyrolactone (GBL), are still relatively low. In this qualitative review paper, after a short introduction on the pharmacology of GHB/GBL, followed by a summary of the epidemiology of GHB abuse, an overview of GHB dependence syndrome and GHB/GBL withdrawal syndrome is provided. Finally, the existing literature on management of GHB detoxification, both planned and unplanned, as well as the available management of GHB withdrawal syndrome, is summarized. Although no systematic studies on detoxification and management of withdrawal have been performed to date, general recommendations are given on pharmacological treatment and preferred treatment setting.

Catecholaminergic Neuromodulation Shapes Intrinsic MRI Functional Connectivity in the Human Brain.

UNLABELLED: The brain commonly exhibits spontaneous (i.e., in the absence of a task) fluctuations in neural activity that are correlated across brain regions. It has been established that the spatial structure, or topography, of these intrinsic correlations is in part determined by the fixed anatomical connectivity between regions. However, it remains unclear which factors dynamically sculpt this topography as a function of brain state. Potential candidate factors are subcortical catecholaminergic neuromodulatory systems, such as the locus ceruleus-norepinephrine system, which send diffuse projections to most parts of the forebrain. Here, we systematically characterized the effects of endogenous central neuromodulation on correlated fluctuations during rest in the human brain. Using a double-blind placebo-controlled crossover design, we pharmacologically increased synaptic catecholamine levels by administering atomoxetine, an NE transporter blocker, and examined the effects on the strength and spatial structure of resting-state MRI functional connectivity. First, atomoxetine reduced the strength of inter-regional correlations across three levels of spatial organization, indicating that catecholamines reduce the strength of functional interactions during rest. Second, this modulatory effect on intrinsic correlations exhibited a substantial degree of spatial specificity: the decrease in functional connectivity showed an anterior-posterior gradient in the cortex, depended on the strength of baseline functional connectivity, and was strongest for connections between regions belonging to distinct resting-state networks. Thus, catecholamines reduce intrinsic correlations in a spatially heterogeneous fashion. We conclude that neuromodulation is an important factor shaping the topography of intrinsic functional connectivity. SIGNIFICANCE STATEMENT: The human brain shows spontaneous activity that is strongly correlated across brain regions. The factors that dynamically sculpt these inter-regional correlation patterns are poorly understood. Here, we test the hypothesis that they are shaped by the catecholaminergic neuromodulators norepinephrine and dopamine. We pharmacologically increased synaptic catecholamine levels and measured the resulting changes in intrinsic fMRI functional connectivity. At odds with common understanding of catecholamine function, we found (1) overall reduced inter-regional correlations across several levels of spatial organization; and (2) a remarkable spatial specificity of this modulatory effect. Our results identify norepinephrine and dopamine as important factors shaping intrinsic functional connectivity and advance our understanding of catecholamine function in the central nervous system.

Catecholamine-Mediated Increases in Gain Enhance the Precision of Cortical Representations.

UNLABELLED: Neurophysiological evidence suggests that neuromodulators, such as norepinephrine and dopamine, increase neural gain in target brain areas. Computational models and prominent theoretical frameworks indicate that this should enhance the precision of neural representations, but direct empirical evidence for this hypothesis is lacking. In two functional MRI studies, we examine the effect of baseline catecholamine levels (as indexed by pupil diameter and manipulated pharmacologically) on the precision of object representations in the human ventral temporal cortex using angular dispersion, a powerful, multivariate metric of representational similarity (precision). We first report the results of computational model simulations indicating that increasing catecholaminergic gain should reduce the angular dispersion, and thus increase the precision, of object representations from the same category, as well as reduce the angular dispersion of object representations from distinct categories when distinct-category representations overlap. In Study 1 (N = 24), we show that angular dispersion covaries with pupil diameter, an index of baseline catecholamine levels. In Study 2 (N = 24), we manipulate catecholamine levels and neural gain using the norepinephrine transporter blocker atomoxetine and demonstrate consistent, causal effects on angular dispersion and brain-wide functional connectivity. Despite the use of very different methods of examining the effect of baseline catecholamine levels, our results show a striking convergence and demonstrate that catecholamines increase the precision of neural representations. SIGNIFICANCE STATEMENT: Norepinephrine and dopamine are among the most widely distributed and ubiquitous neuromodulators in the mammalian brain and have a profound and pervasive impact on cognition. Baseline catecholamine levels tend to increase with increasing task engagement in tasks involving perceptual decisions, yet there is currently no direct evidence of the specific impact of these increases in catecholamine levels on perceptual encoding. Our results fill this void by showing that catecholamines enhance the precision of encoding cortical object representations, and by suggesting that this effect is mediated by increases in neural gain, thus offering a mechanistic account of our key finding.

The Neurobiological Mechanisms of Gamma-Hydroxybutyrate Dependence and Withdrawal and Their Clinical Relevance: A Review.

OBJECTIVE: x03B3;-Hydroxybutyrate (GHB) has gained popularity as a drug of abuse. In the Netherlands the number of patients in treatment for GHB dependence has increased sharply. Clinical presentation of GHB withdrawal can be life threatening. We aim, through this overview, to explore the neurobiological pathways causing GHB dependency and withdrawal, and their implications for treatment choices. METHODS: In this work we review the literature discussing the findings from animal models to clinical studies focused on the neurobiological pathways of endogenous but mainly exogenous GHB. RESULTS: Chronic abuse of GHB exerts multifarious neurotransmitter and neuromodulator effects on x03B3;-aminobutyric acid (GABA), glutamate, dopamine, serotonin, norepinephrine and cholinergic systems. Moreover, important effects on neurosteroidogenesis and oxytocin release are wielded. GHB acts mainly via a bidirectional effect on GABAB receptors (GABABR; subunits GABAB1 and GABAB2), depending on the subunit of the GIRK (G-protein-dependent ion inwardly rectifying potassium) channel involved, and an indirect effect of the cortical and limbic inputs outside the nucleus accumbens. GHB also activates a specific GHB receptor and ß1-subunits of α4-GABAAR. Reversing this complex interaction of neurobiological mechanisms by the abrupt cessation of GHB use results in a withdrawal syndrome with a diversity of symptoms of different intensity, depending on the pattern of GHB abuse. CONCLUSION: The GHB withdrawal symptoms cannot be related to a single mechanism or neurological pathway, which implies that different medication combinations are needed for treatment. A single drug class, such as benzodiazepines, gabapentin or antipsychotics, is unlikely to be sufficient to avoid life-threatening complications. Detoxification by means of titration and tapering of pharmaceutical GHB can be considered as a promising treatment that could make polypharmacy redundant.

Effects of clonidine and scopolamine on multiple target detection in rapid serial visual presentation.

RATIONALE: The specific role of neuromodulator systems in regulating rapid fluctuations of attention is still poorly understood. OBJECTIVES: In this study, we examined the effects of clonidine and scopolamine on multiple target detection in a rapid serial visual presentation task to assess the role of the central noradrenergic and cholinergic systems in temporal attention. METHOD: Eighteen healthy volunteers took part in a crossover double-dummy study in which they received clonidine (150/175 µg), scopolamine (1.2 mg), and placebo by mouth in counterbalanced order. A dual-target attentional blink task was administered at 120 min after scopolamine intake and 180 min after clonidine intake. The electroencephalogram was measured during task performance. RESULTS: Clonidine and scopolamine both impaired detection of the first target (T1). For clonidine, this impairment was accompanied by decreased amplitudes of the P2 and P3 components of the event-related potential. The drugs did not impair second-target (T2) detection, except if T2 was presented immediately after T1. The attentional blink for T2 was not affected, in line with a previous study that found no effect of clonidine on the attentional blink. CONCLUSIONS: These and other results suggest that clonidine and scopolamine may impair temporal attention through a decrease in tonic alertness and that this decrease in alertness can be temporarily compensated by a phasic alerting response to a salient stimulus. The comparable behavioral effects of clonidine and scopolamine are consistent with animal studies indicating close interactions between the noradrenergic and cholinergic neuromodulator systems.

Electroconvulsive therapy in the intensive care unit for the treatment of catatonia: a case series and review of the literature.

OBJECTIVE: Catatonia is an underdiagnosed syndrome that may occur in severely ill patients. The malignant subtype, consisting of motor symptoms, autonomic instability and fever, is associated with high mortality rates, though exact current mortality rates are unknown. This subtype requires a fast detection and treatment with high doses of a benzodiazepine or electroconvulsive therapy (ECT), preferably in an intensive care unit (ICU) setting. METHOD: Case series and qualitative literature review. RESULTS: This paper presents four patients admitted to the ICU of an academic hospital diagnosed with malignant catatonia. All patients received ECT after an ineffective trial of high-dose intravenous benzodiazepine treatment. The duration of ECT ranged from 6 to 23 treatments after which the catatonic features partially or fully remitted. In addition, we have reviewed the diagnostic challenges, neurobiology, possible causes, differential diagnosis and treatment options of catatonia, focusing on the treatment with ECT and the importance of detection and multidisciplinary collaboration. CONCLUSION: Malignant catatonia is an underdiagnosed, potentially life-threatening syndrome that requires fast recognition and prompt treatment, preferably in an ICU setting.

Burnout, depression and anxiety in preclinical medical students: a cross-sectional survey.

OBJECTIVE: The purpose of this study was to assess the prevalences and correlates of adverse affective states (burnout-, depression- and anxiety-related symptoms) among preclinical medical students. METHODS: Self-report questionnaires were sent to all preclinical medical students of Leiden University Medical Center (n=1311). Burnout-related symptoms were measured using the Maslach Burnout Inventory-General Survey (MBI-GS), depression and anxiety-related symptoms and vitality using the Symptom Questionnaire-48 (SQ-48). Furthermore, duration of sleep, quality of life (SF-36), need for recovery, happiness and dispositional optimism were assessed and analysed in relation to affective symptoms using regression analysis. RESULTS: Among the 433 responders (response rate=33.0%), prevalences of self-reported burnout-, depression- and anxiety-related symptoms were 46.0% (n=199), 27.0% (n=117) and 29.1% (n=126), respectively. Independent correlates for burnout-related symptoms were <6 h sleep per night (p=0.02), low happiness (p<0.001) and a high need for recovery (p<0.001). Independent correlates for both depression- and anxiety-related symptoms were low optimism (p<0.001; p<0.001, respectively), low happiness (p<0.001; p=0.001, respectively) and a high need for recovery (p=0.03; p<0.001, respectively). CONCLUSION: Prevalences for adverse affective states were high among preclinical medical students and mainly associated with personality trait-related factors and need for recovery, rather than work-related factors. These findings suggest that being a medical student increases one's risk to adverse affective states, and should inspire preventative initiatives.

Noradrenergic and cholinergic modulation of late ERP responses to deviant stimuli.

Researchers have proposed several hypotheses about the neuromodulator systems involved in generating P3 components of the ERP. To test some of these hypotheses, we conducted a randomized placebo-controlled crossover study in which we investigated how the late positive ERP response to deviant stimuli is modulated by (a) clonidine, an α2 agonist that attenuates baseline noradrenergic activity; and (b) scopolamine, a muscarinic antagonist of acetylcholine receptors. We collected EEG data from 18 healthy volunteers during the performance of an auditory oddball task with several active and passive task conditions. We then used temporospatial principal component analysis (PCA) to decompose the ERP waveforms. The PCA revealed two distinct late positive ERP components: the classic parietal P300 and the frontal novelty P3. Statistical analysis of the temporospatial factor scores indicated that in most conditions the amplitude of the classic P300 was increased by clonidine and scopolamine. In contrast, the amplitude of the novelty P3 was decreased by both drugs. The similar pattern of results for clonidine and scopolamine probably reflects the strong interactions between the noradrenergic and cholinergic systems. The results, in combination with previous pharmacological studies, suggest a critical role for both neuromodulator systems in the generation of the P300 and the novelty P3.

Aberrant CYP2D6 metabolizer phenotypes do not show increased frequency in patients undergoing ECT after antidepressant therapy.

We investigated the accumulation of aberrant CYP2D6 genotypes and predicted metabolizer phenotypes (ultrarapid metabolizer, intermediate metabolizer and poor metabolizer) potentially affecting the antidepressant treatment response in depressive patients indicated for electroconvulsive therapy (ECT) compared with patients with a single episode of depression. Seventy-six Dutch White patients with unipolar or bipolar treatment-resistant depression who underwent ECT were genotyped using the Amplichip CYP450 Test for CYP2D6. Two hundred and eight patients with a single episode of unipolar or bipolar depression were used as controls. No difference was observed in the prevalence of CYP2D6 phenotypes (poor metabolizer, intermediate metabolizer, extensive metabolizer and ultrarapid metabolizer) between the ECT and the control patients (5.3, 38.7, 56.0 and 0.0% vs. 6.4, 51.0, 42.6 and 0.0%, respectively). The types of depression (odds ratio = 0.33, P = 0.018) and age (odds ratio = 1.55 for a 10-year increase, P < 0.001), but not CYP2D6 phenotype or activity score were associated with the response to antidepressant treatment. In conclusion, preemptive genotyping for CYP2D6 currently appears to have no clinical implications in treatment-resistant depressive patients indicated for ECT.

Beta receptor-mediated modulation of the oddball P3 but not error-related ERP components in humans.

RATIONALE: The P3 is a ubiquitous component of stimulus-driven neural activity that can be observed in scalp electrophysiological recordings. Multiple lines of evidence suggest an important role for the noradrenergic system in the generation of the P3. However, pharmacological studies of the P3 using noradrenergic manipulations have so far been limited to agents that affect α2-receptor signaling. OBJECTIVES: The present study investigated whether ß-adrenergic receptors are involved in the generation of the P3 and the error positivity (Pe), a component of the event-related potential that is elicited by errors and that bears many similarities to the P3. METHODS: We used a double-blind, placebo-controlled, crossover design in which we examined in human participants (N = 16) the effect of a single dose of propranolol (80 mg) on the amplitudes of the P3 observed in visual and auditory oddball tasks and the Pe observed in a flanker task. RESULTS: We found that P3s to auditory stimuli were increased in amplitude following treatment with propranolol. Propranolol also modulated the P3 to visual stimuli, but in a direction dependent on participants' level of trait anxiety: In participants with lower trait anxiety, propranolol resulted in a (non-significant) decrease in P3 amplitudes; in participants with higher trait anxiety, propranolol significantly enhanced P3 amplitude. Propranolol did not modulate the amplitude of the Pe or behavioral measures of conflict/error-related performance adjustments. CONCLUSIONS: These results provide the first evidence for involvement of ß-adrenergic receptors in P3 generation. We speculate that propranolol affected the P3 through actions at ß2-receptors in the locus coeruleus.

Pharmacogenetics in electroconvulsive therapy and adjunctive medications.

Electroconvulsive therapy (ECT) has shown apparent efficacy in treatment of patients with depression and other mental illnesses who do not respond to psychotropic medications or need urgent control of their symptoms. Pharmacogenetics contributes to an individual's sensitivity and response to a variety of drugs. Clinical insights into pharmacogenetics of ECT and adjunctive medications not only improves its safety and efficacy in the indicated patients, but can also lead to the identification of novel treatments in psychiatric disorders through understanding of potential molecular and biological mechanisms involved. In this review, we explore the indications of pharmacogenetics role in safety and efficacy of ECT and present the evidence for its role in patients with psychiatric disorders undergoing ECT.