The ReCoDe addiction research consortium: Losing and regaining control over drug intake-Findings and future perspectives.

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.

Conflict monitoring and emotional processing in 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine users - A comparative neurophysiological study.

In stimulant use and addiction, conflict control processes are crucial for regulating substance use and sustaining abstinence, which can be particularly challenging in social-affective situations. Users of methamphetamine (METH, "Ice") and 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") both experience impulse control deficits, but display different social-affective and addictive profiles. We thus aimed to compare the effects of chronic use of the substituted amphetamines METH and MDMA on conflict control processes in different social-affective contexts (i.e., anger and happiness) and investigate their underlying neurophysiological mechanisms. For this purpose, chronic but recently abstinent users of METH (n = 38) and MDMA (n = 42), as well as amphetamine-naïve healthy controls (n = 83) performed an emotional face-word Stroop paradigm, while event-related potentials (ERPs) were recorded. Instead of substance-specific differences, both MDMA and METH users showed smaller behavioral effects of cognitive-emotional conflict processing (independently of emotional valence) and selective deficits in emotional processing of anger content. Both effects were underpinned by stronger P3 ERP modulations suggesting that users of substituted amphetamines employ altered stimulus-response mapping and decision-making. Given that these processes are modulated by noradrenaline and that both MDMA and METH use may be associated with noradrenergic dysfunctions, the noradrenaline system may underlie the observed substance-related similarities. Better understanding the functional relevance of this currently still under-researched neurotransmitter and its functional changes in chronic users of substituted amphetamines is thus an important avenue for future research.

Longitudinal Digital Mood Charting in Bipolar Disorder: Experiences with ChronoRecord Over 20 Years.

INTRODUCTION: Longitudinal study is an essential methodology for understanding disease trajectories, treatment effects, symptom changes, and long-term outcomes of affective disorders. Daily self-charting of mood and other illness-related variables is a commonly recommended intervention. With the widespread acceptance of home computers in the early 2000s, automated tools were developed for patient mood charting, such as ChronoRecord, a software validated by patients with bipolar disorder. The purpose of this study was to summarize the daily mood, sleep, and medication data collected with ChronoRecord, and highlight some of the key research findings. Lessons learned from implementing a computerized tool for patient self-reporting are also discussed. METHODS: After a brief training session, ChronoRecord software for daily mood charting was installed on a home computer and used by 609 patients with affective disorders. RESULTS: The mean age of the patients was 40.3±11.8 years, a mean age of onset was 22±11.2 years, and 71.4% were female. Patients were euthymic for 70.8% of days, 15.1% had mild depression, 6.6% had severe depression, 6.6% had hypomania, and 0.8% had mania. Among all mood groups, 22.4% took 1-2 medications, 37.2% took 3-4 medications, 25.7 took 5-6 medications, 11.6% took 7-8 medications, and 3.1% took >8 medications. CONCLUSION: The daily mood charting tool is a useful tool for increasing patient involvement in their care, providing detailed patient data to the physician, and increasing understanding of the course of illness. Longitudinal data from patient mood charting was helpful in both clinical and research settings.

How Does Meditation-Based Lifestyle Modification Affect Pain Intensity, Pain Self-Efficacy, and Quality of Life in Chronic Pain Patients? An Experimental Single-Case Study.

INTRODUCTION: Chronic pain is a growing worldwide health problem and complementary and integrative therapy options are becoming increasingly important. Multi-component yoga interventions represent such an integrative therapy approach with a promising body of evidence. METHODS: The present study employed an experimental single-case multiple-baseline design. It investigated the effects of an 8-week yoga-based mind-body intervention, Meditation-Based Lifestyle Modification (MBLM), in the treatment of chronic pain. The main outcomes were pain intensity (BPI-sf), quality of life (WHO-5), and pain self-efficacy (PSEQ). RESULTS: Twenty-two patients with chronic pain (back pain, fibromyalgia, or migraines) participated in the study and 17 women completed the intervention. MBLM proved to be an effective intervention for a large proportion of the participants. The largest effects were found for pain self-efficacy (TAU-U = 0.35), followed by average pain intensity (TAU-U = 0.21), quality of life (TAU-U = 0.23), and most severe pain (TAU-U = 0.14). However, the participants varied in their responses to the treatment. CONCLUSION: The present results point to relevant clinical effects of MBLM for the multifactorial conditions of chronic pain. Future controlled clinical studies should investigate its usefulness and safety with larger samples. The ethical and philosophical aspects of yoga should be further explored to verify their therapeutic utility.

[Follow-up Evaluation of a Multimodal Treatment Program for Pregnant Women, Mothers and Fathers who Consume Methamphetamine]. / Verlaufsevaluation eines multimodalen Therapieprogrammes für Methamphetamin-konsumierende Schwangere, Mütter und Väter.

OBJECTIVE: Follow-up evaluation of the addiction therapy part of the multimodal treatment program "Mama Denk an mich" ("Mummy, think of me"), an interdisciplinary cooperation of several departments of the University Hospital Dresden with the local youth welfare offices and addiction counseling centers. METHOD: Description of treatment course and sample of the first 100 patients with a methamphetamine-related disorder and prospective observational study of treatment outcome. RESULTS: Besides a high proportion of first-time treated subjects (51%) and a young mean age (29 years), the sample was notable for precarious socioeconomic conditions and numerous comorbidities. Nevertheless, the comparatively high adherence rate (68%) suggests a good efficacy of the therapeutic methods used. CONCLUSION: Parenthood or pregnancy represent an opportunity to motivate methamphetamine addicts for effective outpatient addiction therapy even in the presence of severe addiction and psychiatric comorbidities.

Development of Novel Tasks to Assess Outcome-Specific and General Pavlovian-to-Instrumental Transfer in Humans.

INTRODUCTION: The emergence of Pavlovian-to-instrumental transfer (PIT) research in the human neurobehavioral domain has been met with increased interest over the past two decades. A variety of PIT tasks were developed during this time; while successful in demonstrating transfer phenomena, existing tasks have limitations that should be addressed. Herein, we introduce two PIT paradigms designed to assess outcome-specific and general PIT within the context of addiction. MATERIALS AND METHODS: The single-lever PIT task, based on an established paradigm, replaced button presses with joystick motion to better assess avoidance behavior. The full transfer task uses alcohol and nonalcohol rewards associated with Pavlovian cues and instrumental responses, along with other gustatory and monetary rewards. We constructed mixed-effects models with the addition of other statistical analyses as needed to interpret various behavioral measures. RESULTS: Single-lever PIT: both versions were successful in eliciting a PIT effect (joystick: p < 0.001, ηp2 = 0.36, button-box: p < 0.001, ηp2 = 0.30). Full transfer task: it was determined that the alcohol and nonalcoholic reward cues selectively primed their respective reward-associated responses (gustatory version: p < 0.001, r = 0.59, and monetary version: p < 0.001, r = 0.84). The appetitive/aversive cues resulted in a general transfer effect (gustatory: p < 0.001, ηp2 = 0.09, and monetary: p < 0.001, ηp2 = 0.17). DISCUSSION/CONCLUSION: Single-lever PIT: PIT was observed in both task versions. We posit that the use of a joystick is more advantageous for the analysis of avoidance behavior. It evenly distributes movement between approach and avoid trials, which is relevant to analyzing fMRI data. Full transfer task: While gustatory conditioning has been used in the past to elicit transfer effects, we present the first paradigm that successfully elicits both specific and general transfers in humans with gustatory alcohol rewards.

Housing Correlates in Pregnant and Parenting Women Using Methamphetamine and Accessing Psychiatric Care.

Background: Integrated care is a promising model for pregnant and parenting women with problems related to methamphetamine use. Yet more research is imperative to guide services for this vulnerable population as methamphetamine use contributes to housing instability, which is associated with heavier use and overdose death. Method: This prospective observational study analyzed how housing at discharge from psychiatric care was related to patient characteristics, program participation, and aftercare in 102 pregnant and/or parenting women. Results: Twelve of 23 women who were unstably housed at admission (three of six homeless) achieved stable housing by discharge from integrated care. Women were more likely unstably housed at discharge when unstably housed at admission, single, living apart from at least one minor, or when the other parent had a substance use disorder (p < 0.05). Unstably housed women at discharge were also more likely to have used social and inpatient services, and to transition to inpatient rehabilitation (p < 0.05). Among baseline characteristics, logistic regression identified unstable housing at admission (OR = 6.07) and being single (OR = 4.01) as the strongest unique contributors to unstable housing at discharge (p < 0.05). Conclusion: Unstably housed women and single women seem particularly at risk of remaining in precarious living conditions despite accessing integrated care for problems associated with methamphetamine use. Future work should investigate whether stronger partnerships with government and community agencies could be a way forward to help these women attain and maintain stable housing.

Integrated Care for Pregnant Women and Parents With Methamphetamine-Related Mental Disorders.

Background: Methamphetamine use is a rapidly increasing cause of morbidity and mortality. Pregnant women and new parents who consume methamphetamine are at high risk since they seldom seek health services despite having multiple needs. We addressed this care gap by implementing an easily accessible program that pools resources from psychiatric, obstetric, and pediatric departments as well as community and government agencies. Method: This real-life observational study evaluated an integrated care program in 27 expecting parents and 57 parents of minors. The outcome criteria were treatment retention, psychosocial functioning, and abstinence. We compared participant demographics according to outcome and applied ordinal logistic regression to predict treatment success. Results: Patients received integrated care for almost 7 months on average. Nearly half achieved stable abstinence and functional recovery. Only one pregnant woman dropped out before a care plan could be implemented, and all women who gave birth during treatment completed it successfully. Three-fourths of patients had psychiatric comorbidities. Patients with depressive disorders were almost 5 times less likely to succeed with treatment. Attention-deficit hyperactivity disorder (ADHD) was diagnosed in nearly 30% of patients who dropped out of a care plan, which was about 4 times more often than in the successful outcome group. Conclusion: Our program engaged pregnant women and parents in treatment and helped them recover from methamphetamine-related mental disorders. Management of comorbid ADHD and depression should be an integral part of care initiatives to counter the methamphetamine crisis that affects parents and children across the globe.

Probabilistic Reversal Learning Deficits in Patients With Methamphetamine Use Disorder-A Longitudinal Pilot Study.

Methamphetamine use disorder (MUD) is increasing worldwide and commonly associated with learning deficits. Little is known the about underlying trajectories, i.e., how the affected higher-order cognitive functions develop over time and with respect to abstinence and relapse. A probabilistic reversal learning (PRL) paradigm was implemented to uncover the microstructure of impulsive choice and maladaptive learning strategies in 23 patients with MUD in comparison with 24 controls. Baseline data revealed fewer optimal choices and a pattern of altered learning behavior from negative and positive feedback in patients suggesting impairments in flexibly-adapting behavior to changes of reward contingencies. Integrating longitudinal data from a follow-up assessment after 3 months of specific treatment revealed a group-by-time interaction indicating a normalization of these cognitive impairments in patients with MUD. In summary, our study demonstrates behavioral correlates of maladaptive decision-making processes in patients with MUD, which may recover after 3 months of MUD-specific therapy paving the way for further learning-based interventions. Limited by a small sample size, the results of this pilot study warrant replication in larger populations.

Neurocognitive Dysfunctions and Their Therapeutic Modulation in Patients With Methamphetamine Dependence: A Pilot Study.

AIM: Methamphetamine (MA) abuse and dependence are increasing worldwide and are commonly associated with cognitive deficits. Some studies indicate that such impairments can improve if users become abstinent, but overall results remain inconclusive. Hence, we have performed a longitudinal case-control study investigating key surrogates for attention and impulsive decision-making before and after treatment. METHODS: Thirty patients with MA dependence and 24 non-substance-abusing control participants were recruited. Groups were matched on age, sex and education. All subjects performed a baseline assessment to obtain neurocognitive measures of sustained attention and delay discounting. Patients subsequently participated in an MA-specific relapse prevention program including repeated monitoring of relapse status. After 3 months, participants of both groups were reevaluated for neurocognitive performance. RESULTS: At baseline, MA patients showed a significantly higher number of omissions compared to controls, indicative of lower sustained attention. Interestingly, we observed a steep decrease of omissions in MA patients to control-group level post treatment. On the other hand, MA patients discounted delayed rewards significantly stronger than controls, indicating a more impulsive choice behavior both before and after treatment. LIMITATION: The results should be interpreted with care because of the small sample and short follow-up period. CONCLUSION: Our data support earlier findings on partial recovery of cognitive deficits in MA patients. They also strengthen the indication for recently recommended psychotherapeutic interventions and may provide a behavioral monitoring tool to inform treatment progress.

Effectiveness of the First German-Language Group Psychotherapy Manual to Accompany Short-Term Treatment in Methamphetamine Dependence.

Background: Methamphetamine abuse is expanding in Europe, leading to a shortfall in medical care for related disorders in many regions. Research focusing on the effectiveness and feasibility of methamphetamine-specific treatment programs is scarce, especially in short-term settings. Methods: To this end, we treated 31 patients with methamphetamine dependence using a new group psychotherapy manual added to standard psychiatric care. Trained research assistants recorded demographic, illness and treatment variables using a standardized interview at baseline and a follow-up visit 3 months later. Outcome and process variables for this intervention encompassing 15 modules for qualified detoxification and motivation of patients with methamphetamine dependence are reported. Results: Retention and abstinence rates as well as acceptance and feasibility in daily routine were assessed positively. Patients with an unsuccessful outcome were characterized by longer regular methamphetamine use (t = -2.513, df = 29, p = 0.018) and a shorter abstinence period at baseline (U = 74.500, z = -1.808, p = 0.072). Among the demographic and clinical variables, the only predictor significantly increasing the odds of a successful outcome was a shorter period of regular methamphetamine use (OR = 1.318, CI 95% for OR = 1.021-1.700, b = 0.276, SE = 0.130, p = 0.034). Conclusions: This freely available therapy manual can help counter the shortfall in available psychotherapeutic interventions for patients with methamphetamine dependence in German-speaking countries. The routinely assessed parameters duration of regular methamphetamine use and abstinence before treatment were associated with outcome and may be used to personalize therapeutic strategies.

["CrystalClean" - A German-Language Manual for Qualified Detoxification and Motivation Treatment in Cases of "Crystal Meth" Dependency - Feasibility and Acceptance]. / "CrystalClean" ­ Ein deutschsprachiges Manual zur qualifizierten Entgiftungs- und Motivationsbehandlung bei "Crystal Meth"-Abhängigkeit ­ Durchführbarkeit und Akzeptanz.

INTRODUCTION: Over the last decade, methamphetamine use has spread rapidly in Europe, leading to a significant medical shortfall in many regions. To date, there are no standardized German-language therapy programs for qualified detoxification and motivation treatment. We have developed a therapy manual ("CrystalClean") over 15 therapy modules, which was evaluated in the present pilot study with regard to feasibility and acceptability. METHODS: Observational study with systematic interviews over 3 months on 31 patients with methamphetamine dependence. RESULTS: Acceptability of most modules was rated as high by both patients and therapists. In addition, the manual was considered to be well feasible in inpatient daily routine. However, contact terminations frequently occurred when switching to outpatient treatment. CONCLUSION: Results from our study point to a high acceptance of the manual for the accompaniment of qualified detoxification and motivation treatment in patients with methamphetamine dependence. Feasibility in the clinical setting can be improved by reducing the number of modules to the 12 best evaluated and by increasing the frequency of therapies.

Addiction Research Consortium: Losing and regaining control over drug intake (ReCoDe)-From trajectories to mechanisms and interventions.

One of the major risk factors for global death and disability is alcohol, tobacco, and illicit drug use. While there is increasing knowledge with respect to individual factors promoting the initiation and maintenance of substance use disorders (SUDs), disease trajectories involved in losing and regaining control over drug intake (ReCoDe) are still not well described. Our newly formed German Collaborative Research Centre (CRC) on ReCoDe has an interdisciplinary approach funded by the German Research Foundation (DFG) with a 12-year perspective. The main goals of our research consortium are (i) to identify triggers and modifying factors that longitudinally modulate the trajectories of losing and regaining control over drug consumption in real life, (ii) to study underlying behavioral, cognitive, and neurobiological mechanisms, and (iii) to implicate mechanism-based interventions. These goals will be achieved by: (i) using mobile health (m-health) tools to longitudinally monitor the effects of triggers (drug cues, stressors, and priming doses) and modify factors (eg, age, gender, physical activity, and cognitive control) on drug consumption patterns in real-life conditions and in animal models of addiction; (ii) the identification and computational modeling of key mechanisms mediating the effects of such triggers and modifying factors on goal-directed, habitual, and compulsive aspects of behavior from human studies and animal models; and (iii) developing and testing interventions that specifically target the underlying mechanisms for regaining control over drug intake.

Short group psychoeducation followed by daily electronic self-monitoring in the long-term treatment of bipolar disorders: a multicenter, rater-blind, randomized controlled trial.

BACKGROUND: Despite various pharmacological and psychological treatment interventions, bipolar disorders rank among the leading causes of global disease burden. Group psychoeducation has been demonstrated an effective add-on to pharmacotherapy, but it may be difficult to implement in practice depending on the clinical setting and available human resources. METHODS: Multicenter, rater-blind, randomized controlled trial to investigate the efficacy of a new intervention program consisting of an initial 6-week psychoeducation protocol plus a subsequent structured daily computer-based self-charting program (ChronoRecord) over 54 weeks in remitted patients with bipolar disorders. The control condition included non-structured group sessions followed by daily computer-based self-reports (unstructured like a diary). Both groups received treatment-as-usual. RESULTS: Over 2 years, 41 mood episodes occurred in the experimental group (n = 39) compared to 27 in the control group (n = 34), without reaching statistical significance. Time to recurrence did not significantly differ between the experimental and control group (25% relapsed after 112 and 273 days, respectively). There were no significant group-by-time interactions in mood symptoms, quality of life, self-efficacy expectations or perceived involvement in care. CONCLUSIONS: Six weekly psychoeducational group sessions followed by daily self-monitoring via ChronoRecord for 54 weeks may not be superior to non-structured group meetings followed by unstructured self-reporting. Other psychotherapeutic interventions may be needed to optimize the treatment of patients with bipolar disorders, especially for those at later disease stages. Trial registration Retrospectively registered at German Clinical Trials Register on May 24, 2019; DRKS00017319.

Treatment of bipolar depression with supraphysiologic doses of levothyroxine: a randomized, placebo-controlled study of comorbid anxiety symptoms.

BACKGROUND: Symptoms of anxiety co-occur in a variety of disorders including in depressive episodes of bipolar disorder and in patients with thyrotoxicosis. Treatment of refractory bipolar disorder with supraphysiologic doses of levothyroxine (L-T4) has been shown to improve the phenotypic expression of the disorder and is associated with an increase of circulating thyroid hormones. However, it might be associated with somatic and mental adverse effects. Here we report the investigation of the influence of treatment with supraphysiologic doses of L-T4 on symptoms of anxiety in patients with refractory bipolar depression. METHODS: Post-hoc analysis from a 6-week, multi-center, randomized, double-blind, placebo-controlled study of the effects of supraphysiologic L-T4 treatment on anxiety symptoms in bipolar depression. Anxiety symptoms were measured weekly with the Hamilton anxiety/somatization factor (HASF) score of the Hamilton Depression Rating Scale (HAMD) and the State- and Trait Anxiety Inventory (STAI). RESULTS: Treatment of both groups was associated with a significant reduction in anxiety symptoms (p < 0.001) with no statistical difference between groups (LT-4: from 5.9 (SD = 2.0) at baseline to 3.7 (SD = 2.4) at study end; placebo: from 6.1 (SD = 2.4) at baseline to 4.4 (SD = 2.8) at study end; p = 0.717). Severity of anxiety at baseline did not show a statistically significant correlation to the antidepressive effect of treatment with supraphysiologic doses of L-T4 (p = 0.811). Gender did not show an influence on the reduction of anxiety symptoms (females: from 5.6 (SD = 1.7) at baseline to 3.5 (SD = 2.4) at study end; males: from 6.1 (SD = 2.3) at baseline to 4.0 (SD = 2.4) at study end; p = 0.877). CONCLUSIONS: This study failed to detect a difference in change of anxiety between bipolar depressed patients treated with supraphysiologic doses of L-T4 or placebo. Comorbid anxiety symptoms should not be considered a limitation for the administration of supraphysiologic doses of L-T4 refractory bipolar depressed patients. Trial registration ClinicalTrials, ClinicalTrials.gov identifier: NCT01528839. Registered 2 June 2012-Retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT01528839.

Addiction as Learned Behavior Patterns.

Individuals with substance use disorders (SUDs) have to cope with drug-related cues and contexts which can affect instrumental drug seeking, as shown with Pavlovian-to-instrumental transfer (PIT) tasks among humans and animals. Our review addresses two potential mechanisms that may contribute to habitual or even compulsive drug seeking and taking. One mechanism is represented by Pavlovian and PIT effects on drug intake. The other is a shift from goal-directed to habitual drug intake, which can be accessed via model-based versus model-free decision-making in respective learning tasks. We discuss the impact of these learning mechanisms on drug consumption. First, we describe how Pavlovian and instrumental learning mechanisms interact in drug addiction. Secondly, we address the effects of acute and chronic stress exposure on behavioral and neural PIT effects in alcohol use disorder (AUD). Thirdly, we discuss how these learning mechanisms and their respective neurobiological correlates can contribute to losing versus regaining control over drug intake. Utilizing mobile technology (mobile applications on smartphones including games that measure learning mechanisms, activity bracelets), computational models, and real-world data may help to better identify patients with a high relapse risk and to offer targeted behavioral and pharmacotherapeutic interventions for vulnerable patients.

Algorithms For Treatment of Major Depressive Disorder: Efficacy and Cost-Effectiveness.

In spite of multiple new treatment options, chronic and treatment refractory courses still are a major challenge in the treatment of depression. Providing algorithm-guided antidepressant treatments is considered an important strategy to optimize treatment delivery and avoid or overcome treatment-resistant courses of major depressive disorder (MDD). The clinical benefits of algorithms in the treatment of inpatients with MDD have been investigated in large-scale, randomized controlled trials. Results showed that a stepwise treatment regimen (algorithm) with critical decision points at the end of each treatment step based on standardized and systematic measurements of response and an algorithm-guided decision-making process increases the chances of achieving remission and optimizes prescription behaviors for antidepressants. In conclusion, research in MDD revealed that systematic and structured treatment procedures, the diligent assessment of response at critical decision points, and timely dose and treatment type adjustments make the substantial difference in treatment outcomes between algorithm-guided treatment and treatment as usual.

Long-term treatment with supraphysiologic doses of levothyroxine in treatment-refractory mood disorders - A prospective study of cardiovascular tolerability.

BACKGROUND: To investigate long-term effects of adjunctive prophylactic treatment with supraphysiologic doses of levothyroxine (L-T4) on cardiovascular tolerability in 23 patients with treatment-refractory mood disorders. METHODS: Starting point for a comprehensive cardiovascular assessment in patients was the indication for long-term maintenance treatment with L-T4 (mean dose 463 mcg/day). Prospective longitudinal assessment of the cardiovascular risk profile included in addition to a physical examination and blood pressure measurement, several technical investigations: resting electrocardiogram, transthoracic echocardiogram, cardiac stress test, and holter electrocardiogram. Statistical analysis was performed by linear mixed effects models (LMM) for evaluation of longitudinal changes in various heart measures. RESULTS: During the mean observational period of 20.4 months none of the heart measures reached statistical significance in change over time. None of the assessed cardiac parameters of each single patient was in a range predictive for cardiac dysfunction. LIMITATIONS: Small sample size, no technical cardiac investigations prior to L-T4 initiation, no patient control group with mood disorders who did not receive L-T4. CONCLUSIONS: Results of this study indicated no increased risk for cardiovascular disorders during treatment with supraphysiologic L-T4 doses in patients with refractory mood disorders.

Regularity of self-reported daily dosage of mood stabilizers and antipsychotics in patients with bipolar disorder.

BACKGROUND: Polypharmacy is often prescribed for bipolar disorder, yet medication non-adherence remains a serious problem. This study investigated the regularity in the daily dosage taken of mood stabilizers and second generation antipsychotics. METHODS: Daily self-reported data on medications taken and mood were available from 241 patients with a diagnosis of bipolar disorder who received treatment as usual. Patients who took the same mood stabilizer or second generation antipsychotic for ≥ 100 days were included. Approximate entropy was used to determine serial regularity in daily dosage taken. Generalized estimating equations were used to estimate if demographic or clinical variables were associated with regularity. RESULTS: There were 422 analysis periods available from the 241 patients. Patients took drugs on 84.4% of days. Considerable irregularity was found, mostly due to single-day omissions and dosage changes. Drug holidays (missing 3 or more consecutive days) were found in 35.8% of the analysis periods. Irregularity was associated with an increasing total number of psychotropic drugs taken (p = 0.009), the pill burden (p = 0.026), and the percent of days depressed (p = 0.049). CONCLUSION: Despite low missing percent of days, daily drug dosage may be irregular primarily due to single day omissions and dosage changes. Drug holidays are common. Physicians should expect to see partial adherence in clinical practice, especially with complex drug regimens. Daily dosage irregularity may impact the continuity of drug action, contribute to individual variation in treatment response, and needs further study.