Controversies regarding lithium-associated weight gain: case-control study of real-world drug safety data.

BACKGROUND: The impact of long-term lithium treatment on weight gain has been a controversial topic with conflicting evidence. We aim to assess reporting of weight gain associated with lithium and other mood stabilizers compared to lamotrigine which is considered free of metabolic adverse drug reactions (ADRs). METHODS: We conducted a case/non-case pharmacovigilance study using data from the AMSP project (German: "Arzneimittelsicherheit in der Psychiatrie"; i.e., Drug Safety in Psychiatry), which collects data on ADRs from patients treated in psychiatric hospitals in Germany, Austria, and Switzerland. We performed a disproportionality analysis of reports of weight gain (> 10% of baseline body weight) calculating reporting odds ratio (ROR). We compared aripiprazole, carbamazepine, lithium, olanzapine, quetiapine, risperidone, and valproate to lamotrigine. Additional analyses related to different mood stabilizers as reference medication were performed. We also assessed sex and age distributions of weight-gain reports. RESULTS: We identified a total of 527 cases of severe drug-induced weight gain representing 7.4% of all severe ADRs. The ROR for lithium was 2.1 (95%CI 0.9-5.1, p > 0.05), which did not reach statistical significance. Statistically significant disproportionate reporting of weight gain was reported for olanzapine (ROR: 11.5, 95%CI 4.7-28.3, p < 0.001), quetiapine (ROR: 3.4, 95%CI 1.3-8.4, p < 0.01), and valproate (ROR: 2.4, 95%CI 1.1-5.0, p = 0.03) compared to lamotrigine. Severe weight gain was more prevalent in non-elderly (< 65 years) than in elderly patients, with an ROR of 7.6 (p < 0.01) in those treated with lithium, and an ROR of 14.7 (p < 0.01) in those not treated with lithium. CONCLUSIONS: Our findings suggest that lithium is associated with more reports of severe weight gain than lamotrigine, although this difference did not reach statistical significance. However, lithium use led to fewer reports of severe weight gain than some alternative drugs for long-term medication (olanzapine, quetiapine, and valproate), which is consistent with recent studies. Monitoring of weight gain and metabolic parameters remains essential with lithium and its alternatives.

Dysfunctional self-reported interoception predicts residual symptom burden of fatigue in major depressive disorder: an observational study.

BACKGROUND: Fatigue is a core symptom of major depressive disorder (MDD) and is frequently refractory to antidepressant treatment, leading to unfavorable clinical/psychosocial outcomes. Dysfunctional self-reported interoception (i.e., maladaptive focus on the body's physiological condition) is prevalent in MDD and could contribute to residual symptom burden of fatigue. Therefore, we explored (a.) cross-sectional correlations between both dimensions and investigated (b.) prospective associations between interoceptive impairments at admission and symptom severity of fatigue at the end of hospitalization. METHODS: This observational, exploratory study included 87 patients suffering from MDD who completed self-rating scales, the Multidimensional Assessment of Interoceptive Awareness, Version 2 (MAIA-2), and the Multidimensional Fatigue Inventory (MFI-20), at the beginning and end of hospitalization. Bivariate correlations (r) and hierarchical regression analyses were performed. RESULTS: The cross-sectional analysis showed moderate to large negative correlations between the MAIA-2 and MFI-20 dimensions except for the Not-Distracting scale. Symptoms of general, physical, and mental fatigue at the end of hospitalization were predicted by reduced body Trusting (ß = -.31, p = .01; ß = -.28, p = .02; ß = -.31, p = .00, respectively). Increased Body Listening (ß = .37, p = .00), Not-Worrying (ß = .26, p = .02), and diminished Attention Regulation (ß = -.32, p = .01) predicted higher mental fatigue. CONCLUSIONS: Diminished body confidence at baseline identified patients at risk for post-treatment fatigue and could therefore serve as a target for improving antidepressant therapy. Body-centered, integrative approaches could address treatment-resistant fatigue in MDD. However, clinicians may also consider the potential adverse effect of increased Body Listening and Not-Worrying on mental fatigue in psychotherapeutic and counselling approaches. Due to the exploratory nature of this study, the results are preliminary and need to be replicated in pre-registered trials with larger sample sizes.

Lithium Therapy in Old Age: Recommendations from a Delphi Survey.

INTRODUCTION: While lithium (Li) has been well established for the treatment of bipolar disorder, geriatric patients require special attention when it comes to issues of drug safety. Declining renal function, amongst other medical conditions, and polypharmacy may pose increased risks. Only a few previous studies have addressed the management of Li in geriatric patients. METHODS: Twenty-four German medical experts on geriatric medicine and Li treatment participated in a Delphi survey, consisting of two rounds of questionnaires and a final formulation of treatment recommendations. Three major issues of Li therapy were outlined: initiation of treatment, monitoring of ongoing therapy, and withdrawal due to medical reasons. Final recommendations were consented to at a threshold of at least 80% expert agreement. RESULTS: Final consensus was achieved on 21 clinical recommendations. The approved recommendations covered aspects of necessary laboratory checks, concomitant medication, and target Li serum concentration in geriatric patients. Concerning the termination of Li therapy, an agreement was reached on the appropriate time span for tapering and on potential alternatives to Li. No consensus was achieved on whether concomitant dementia or frailty should be considered contraindications for Li treatment and the appropriate threshold of the estimated glomerular function rate for withdrawing Li. CONCLUSION: According to the view of German experts, Li may be used in geriatric patients, but it should be monitored carefully. However, the lack of consent in several specific treatment situations underlines the need for research on specific issues of Li therapy.

Exploring Associations between C-Reactive Protein and Self-Reported Interoception in Major Depressive Disorder: A Bayesian Analysis.

Major depressive disorder (MDD) is associated with dysfunctional self-reported interoception (i.e., abnormal perception of the body's physiological state) and systemic inflammation, both of which adversely affect treatment response. In this study, we explored associations between C-reactive protein (CRP) and self-reported interoception, to gain more insight into the pathophysiology of interoceptive impairments in MDD. We also aimed to replicate previous findings on the associations of depression and fatigue severity with CRP. The study included 97 depressed individuals, who completed self-administered questionnaires (Multidimensional Assessment of Interoceptive Awareness (MAIA-2); Beck Depression Inventory-II, Multidimensional Fatigue Inventory). CRP concentrations were analyzed in the serum using a particle-enhanced turbidimetric immunoassay. We applied Bayesian inference to estimate robust effect parameters from posterior distributions based on MCMC sampling, and computed Bayes factors (BF10) as indices of relative evidence. The bivariate analysis supported evidence against associations between CRP and self-reported interoception (BF10 ≤ 0.32), except for one dimension (Not-Distracting: r = 0.11, BF10 > 0.43, absence of evidence). Positive correlations with overall depression (r = 0.21, BF10 = 3.19), physical fatigue (r = 0.28, BF10 = 20.64), and reduced activity (r = 0.22, BF10 = 4.67) were found. The multivariate analysis showed moderate evidence that low-grade inflammation predicted higher scores on the MAIA-2 Not-Worrying scale (ß = 0.28, BF10 = 3.97), after controlling for relevant confounders. Inflammatory responses, as measured by CRP, may not be involved in the pathophysiology of dysfunctional self-reported interoception. However, systemic low-grade inflammation could potentially exert a protective effect against worries about pain or discomfort sensations. An immunological involvement in interoceptive impairments cannot be ruled out until future studies considering additional biomarkers of inflammation replicate our findings.

Lithium induced hypercalcemia: an expert opinion and management algorithm.

BACKGROUND: Lithium is the gold standard prophylactic treatment for bipolar disorder. Most clinical practice guidelines recommend regular calcium assessments as part of monitoring lithium treatment, but easy-to-implement specific management strategies in the event of abnormal calcium levels are lacking. METHODS: Based on a narrative review of the effects of lithium on calcium and parathyroid hormone (PTH) homeostasis and its clinical implications, experts developed a step-by-step algorithm to guide the initial management of emergent hypercalcemia during lithium treatment. RESULTS: In the event of albumin-corrected plasma calcium levels above the upper limit, PTH and calcium levels should be measured after two weeks. Measurement of PTH and calcium levels should preferably be repeated after one month in case of normal or high PTH level, and after one week in case of low PTH level, independently of calcium levels. Calcium levels above 2.8 mmol/l may require a more acute approach. If PTH and calcium levels are normalized, repeated measurements are suggested after six months. In case of persistent PTH and calcium abnormalities, referral to an endocrinologist is suggested since further examination may be needed. CONCLUSIONS: Standardized consensus driven management may diminish the potential risk of clinicians avoiding the use of lithium because of uncertainties about managing side-effects and consequently hindering some patients from receiving an optimal treatment.

[Touch Medicine - a complementary therapeutic approach exemplified by the treatment of depression]. / Berührungsmedizin ­ ein komplementärer therapeutischer Ansatz unter besonderer Berücksichtigung der Depressionsbehandlung.

Skin-to-skin-contact presents the earliest sensory experience of men and animals. Deprivation of age-relevant touch experiences during infancy results in compromised psychosocial and biological development. The 2021 Nobel Prize in Physiology or Medicine has been awarded for the discoveries of receptors for temperature and touch. Clinical studies have demonstrated the benefit of professional salutary touch for prevention and treatment of various illnesses. However, in the present practice of medicine the application of salutary touch does not meet adequate interest. Proposing a new medical discipline "Touch Medicine" we link the findings of modern touch research to clinical medicine. The treatment of depression which we conceive primarily as a disease afflicting the body will serve as an example to demonstrate the usefulness of touch therapy. Controlled studies and systematic reviews have convincingly shown antidepressive, anxiolytic and analgesic effects of salutary touch. The effectiveness and efficacy of touch therapy has also been demonstrated in many areas such as neonatology, pediatrics, oncology, and geriatrics. We discuss the underlying mechanisms on various explanatory levels including interoceptive and oxytocinergic mechanisms as well as the role of C tactile afferent nerve fibers.

Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder.

Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with "exemplary phenotypes"-those whose clinical features are reliably associated with LiR and non-response (LiNR)-are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (n = 1266 across 7 centers; 34.7% responders), we computed a "clinical exemplar score," which measures the degree to which a subject's clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (n = 321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the "best clinical exemplars") were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the "poor clinical exemplars"). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p = 0.0032) among poor clinical exemplars. Variants in the Alzheimer's amyloid-secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers.

Touch Research-Quo Vadis? A Plea for High-Quality Clinical Trials.

Recently, the issue of a lack of interpersonal touch has gained much public interest due to the social distancing ordered by the authorities in the present pandemic situation [...].

Effects of Psychoactive Massage in Outpatients with Depressive Disorders: A Randomized Controlled Mixed-Methods Study.

The clinical picture of depressive disorders is characterized by a plethora of somatic symptoms, psychomotor retardation, and, particularly, anhedonia. The number of patients with residual symptoms or treatment resistance is high. Touch is the basic communication among humans and animals. Its application professionally in the form of, e.g., psychoactive massage therapy, has been shown in the past to reduce the somatic and mental symptoms of depression and anxiety. Here, we investigated the effects of a specially developed affect-regulating massage therapy (ARMT) vs. individual treatment with a standardized relaxation procedure, progressive muscle relaxation (PMR), in 57 outpatients with depression. Patients were given one ARMT or PMR session weekly over 4 weeks. Changes in somatic and cognitive symptoms were assessed by standard psychiatric instruments (Hamilton Depression Scale (HAMD) and the Bech-Rafaelsen-Melancholia-Scale (BRMS)) as well as a visual analogue scale. Furthermore, oral statements from all participants were obtained in semi-structured interviews. The findings show clear and statistically significant superiority of ARMT over PMR. The results might be interpreted within various models. The concept of interoception, as well as the principles of body psychotherapy and phenomenological aspects, offers cues for understanding the mechanisms involved. Within a neurobiological context, the significance of C-tactile afferents activated by special touch techniques and humoral changes such as increased oxytocin levels open additional ways of interpreting our findings.

Clinical use of lithium salts: guide for users and prescribers.

BACKGROUND: Lithium has been used clinically for 70 years, mainly to treat bipolar disorder. Competing treatments and exaggerated impressions about complexity and risks of lithium treatment have led to its declining use in some countries, encouraging this update about its safe clinical use. We conducted a nonsystematic review of recent research reports and developed consensus among international experts on the use of lithium to treat major mood disorders, aiming for a simple but authoritative guide for patients and prescribers. MAIN TEXT: We summarized recommendations concerning safe clinical use of lithium salts to treat major mood disorders, including indications, dosing, clinical monitoring, adverse effects and use in specific circumstances including during pregnancy and for the elderly. CONCLUSIONS: Lithium continues as the standard and most extensively evaluated treatment for bipolar disorder, especially for long-term prophylaxis.

Are the antidepressive effects of massage therapy mediated by restoration of impaired interoceptive functioning? A novel hypothetical mechanism.

Interoception is an individual person's sense of the physiological condition of his/her entire body. Recent research has shown that depression is associated with impaired interoceptive accuracy. Treatments that can improve disturbed interoception are scarce in clinical practice and could complement established therapies. Accumulating evidence suggests that massage therapy significantly alleviates symptoms of depression. However, the mechanisms underlying these effects have remained unclear. We are going to propose a novel mechanism linking these antidepressive effects to a massage-induced modulation of interoceptive states. Particularly affective massage therapy applies slow, rhythmic, and caress-like touch that stimulates C tactile (CT) afferents in the non-glabrous skin. CT mediated touch elicits responses in interoceptive brain areas (e.g. the insular cortex) that have been associated with abnormal interoceptive representations in depressed subjects. Thus, we hypothesize that antidepressive effects of massage therapy are mediated by restoration of the impaired interoceptive functioning through stimulation of CT afferents or related interoceptive structures. If our proposed mechanism is valid, massage is probably one of the most ancient interoceptive treatments.

Major Depressive Disorder Is Associated with Impaired Interoceptive Accuracy: A Systematic Review.

Interoception is the sense of the physiological condition of the entire body. Impaired interoception has been associated with aberrant activity of the insula in major depressive disorder (MDD) during heartbeat perception tasks. Despite clinical relevance, studies investigating interoceptive impairments in MDD have never been reviewed systematically according to the guidelines of the PRISMA protocol, and therefore we collated studies that assessed accuracy in detecting heartbeat sensations (interoceptive accuracy, IAc) in MDD (databases: PubMed/Medline, PsycINFO, and PsycARTICLES). Out of 389 records, six studies met the inclusion criteria. The main findings suggest that (i) moderately depressed samples exhibit the largest interoceptive deficits as compared with healthy adults. (ii) difficulties in decision making and low affect intensity are correlated with low IAc, and (iii) IAc seems to normalize in severely depressed subjects. These associations may be confounded by sex, anxiety or panic disorder, and intake of selective serotonin reuptake inhibitors. Our findings have implications for the development of interoceptive treatments that might relieve MDD-related symptoms or prevent relapse in recurrent depression by targeting the interoceptive nervous system.

Suicidal Ideation and Suicidal Behavior as Rare Adverse Events of Antidepressant Medication: Current Report from the AMSP Multicenter Drug Safety Surveillance Project.

Background: Suicidal ideations, suicide attempts, and fatal suicides are rare adverse drug reactions to antidepressant drugs, but they essentially are clinically relevant. Drawing on a larger dataset of the European drug surveillance program, the present naturalistic study updates a previous contribution (Stübner et al., 2010). Methods: First an analysis of the comprehensive data collected in 81 psychiatric hospitals from 1993 to 2014 by the European drug surveillance program Arzneimittelsicherheit in der Psychiatrie was made. All documented single cases of suicidal ideations or behavior judged as adverse drug reactions to antidepressant drugs were carefully assessed as to their clinical features and drug prescriptions. Results: Among 219,635 adult hospitalized patients taking antidepressant drugs under surveillance, 83 cases of suicidal adverse drug reactions occurred (0.04%): 44 cases of suicidal ideation, 34 attempted suicides, and 5 committed suicides were documented. Restlessness was present in 42 patients, ego-dystonic intrusive suicidal thoughts or urges in 39 patients, impulsiveness in 22 patients, and psychosis in 7 patients. Almost all adverse drug reactions occurred shortly after beginning antidepressant drug medication or increasing the dosage. Selective serotonin reuptake inhibitors caused a higher incidence of suicidal ideation and suicidal behavior as adverse drug reactions than noradrenergic and specific serotonergic antidepressants or tricyclic antidepressants, as did monotherapy consisting of one antidepressant drug, compared to combination treatments. Conclusions: The study supports the view that antidepressant drug-triggered suicidal ideation and suicidal behavior (primarily with selective serotonin reuptake inhibitors) are rare. Special clinical features (restlessness, ego-dystonic thoughts or urges, impulsiveness) may be considered as possible warning signs. A combination therapy might be preferable to antidepressant drug monotherapy when beginning treatment.

Lithium Clinics in Berlin and Dresden: a 50-Year Experience.

Although lithium's serendipitous discovery as a medication for depression dates back more than 200 years, the first scientific evidence that it prevents mania and depression arose only in the 1960s. However, at that time there was a lack of knowledge about how to administer and monitor lithium therapy safely and properly. The lithium clinics in Dresden and Berlin were remarkably similar in their beginnings in the late 1960s regarding patient numbers and scientific expertise without being aware of one another due to the Iron Curtain separating Germany into a western and eastern part until 1990. In what were initially lithium-care programs run independently from one another, the lithium clinics embedded in academic settings in Dresden and Berlin represent a milestone in the history of psychopharmacological treatment of affective disorders in Germany and trailblazers for today's lithium therapy. Nowadays, lithium's clinical applications are unquestioned, such as its use in strategies to prevent mood episodes and suicide, and to treat depression. The extensively documented knowledge of lithium treatment is the fruit of more than 50 years of observing disease courses and of studying side effects and influencing factors of lithium prophylaxis. Its safe and proper administration-in determining the correct indication, baseline and follow-up examinations, recommended dosages, monitoring, or the management of side effects-is well established. Subsequently, both national and international guidelines continue recommending lithium as the gold standard in treating patients with unipolar and bipolar disorders.

Long-term lithium treatment in bipolar disorder: effects on glomerular filtration rate and other metabolic parameters.

BACKGROUND: Concerns about potential adverse effects of long-term exposure to lithium as a mood-stabilizing treatment notably include altered renal function. However, the incidence of severe renal dysfunction; rate of decline over time; effects of lithium dose, serum concentration, and duration of treatment; relative effects of lithium exposure vs. aging; and contributions of sex and other factors all remain unclear. METHODS: Accordingly, we acquired data from 12 collaborating international sites and 312 bipolar disorder patients (6142 person-years, 2669 assays) treated with lithium carbonate for 8-48 (mean 18) years and aged 20-89 (mean 56) years. We evaluated changes of estimated glomerular filtration rate (eGFR) as well as serum creatinine, urea-nitrogen, and glucose concentrations, white blood cell count, and body-mass index, and tested associations of eGFR with selected factors, using standard bivariate contrasts and regression modeling. RESULTS: Overall, 29.5% of subjects experienced at least one low value of eGFR (<60 mL/min/1.73 m2), most after ≥15 years of treatment and age > 55; risk of ≥2 low values was 18.1%; none experienced end-stage renal failure. eGFR declined by 0.71%/year of age and 0.92%/year of treatment, both by 19% more among women than men. Mean serum creatinine increased from 0.87 to 1.17 mg/dL, BUN from 23.7 to 33.1 mg/dL, glucose from 88 to 122 mg/dL, and BMI from 25.9 to 26.6 kg/m2. By multivariate regression, risk factors for declining eGFR ranked: longer lithium treatment, lower lithium dose, higher serum lithium concentration, older age, and medical comorbidity. Later low eGFR was also predicted by lower initial eGFR, and starting lithium at age ≥ 40 years. LIMITATIONS: Control data for age-matched subjects not exposed to lithium were lacking. CONCLUSIONS: Long-term lithium treatment was associated with gradual decline of renal functioning (eGFR) by about 30% more than that was associated with aging alone. Risk of subnormal eGFR was from 18.1% (≥2 low values) to 29.5% (≥1 low value), requiring about 30 years of exposure. Additional risk factors for low eGFR were higher serum lithium level, longer lithium treatment, lower initial eGFR, and medical comorbidity, as well as older age.