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.

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.

Touch medicine: bridging the gap between recent insights from touch research and clinical medicine and its special significance for the treatment of affective disorders.

Interpersonal touch represents the primal sensory experience between humans, fostering social bonding from the cradle to the death bed. In recent decades "affective touch" has been intensely studied, stimulated by the discovery of a population of mechanosensitive unmyelinated C-tactile afferents in mammalian skin. A lack of touch in childhood is associated with negative consequences for psychosocial and physical health and the benefits of professional touch techniques in the prevention and treatment of various diseases have been shown over and over again in clinical studies. However, its application in mainstream clinical applications remains limited. To bridge the gap between recent discoveries in touch research and clinical medicine, we propose the establishment of a new discipline: 'Touch Medicine'. Here, we unfold the potential of Touch Medicine by focusing on the treatment of depression, which in our view is primarily a disorder of the lived body. Controlled studies and systematic reviews have demonstrated the antidepressant, anxiolytic and analgesic effects of specific massage techniques. Underlying mechanisms of action are currently under investigation, ranging from interoceptive, endocrinological, to stress-related or psychological underpinnings. Touch Medicine represents a novel interdisciplinary field connected to various medical specialities such as neonatology, pediatrics, pain medicine, neurology, psychiatry, and geriatrics - but also clinical psychology and psychosomatic medicine might benefit from the integration of these findings into their daily practice.

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.

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.

Commentary on a recent review of lithium toxicity: what are its implications for clinical practice?

A recent paper by McKnight et al. in The Lancet has provided the first formal meta-analysis of the more common adverse reactions to lithium. The authors analyzed 385 studies and focused mainly on the harmful effects of lithium on the kidney, the thyroid and parathyroid glands, body weight, skin and congenital malformations. Their contribution is important and welcome, but as a guide for practice, it needs to be complemented by other relevant observations and individual patient-focused perspectives.The findings from that meta-analysis somewhat underestimate the renal side-effects, and distort to some degree or exclude other adverse effects. The glomerular filtration rate is reduced but not more than 0 to 5 ml/min/year of observation; this may not fully reflect the present state of knowledge. A quarter of patients in the study had abnormalities of the thyroid and/or parathyroid gland, and lithium was found to increase body weight significantly less than did olanzapine. Unfortunately, the authors did not consider the observations from spontaneous reporting systems, which may have changed the picture.We feel that some specific limitations of the study were related to the inclusion of patients regardless of adequacy of treatment, quality of monitoring, drug combinations, age and sex, and stabilization response.

[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.

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.

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.

Influence of atypical features on the quality of prophylactic effectiveness of long-term lithium treatment in bipolar disorders.

OBJECTIVES: There is still debate about whether the quality of long-term efficacy of lithium in patients with bipolar disorders is influenced by atypical features. Extended Cox regression models allow for the use of all follow-up data on diseases with multiple episodes. The aim of the present analysis was to apply the best suited of these models to analyze the influence of atypical features on the widely used outcome measure of time to recurrence in a large multicenter cohort of lithium responders established by the International Group for the Study of Lithium Treated Patients. METHODS: A conditional extended Cox model with a random frailty term was applied to the data of 336 bipolar I and II disorder patients, all of whom were responders to lithium with treatment for up to 30 years. RESULTS: Differences were found in the long-term outcome, even in patients who have demonstrated a relatively good response to lithium treatment. The hazard for recurrence was negatively influenced by the presence of atypical features, mainly mood-incongruent psychotic symptoms, interepisodic residual symptomatology, and rapid cycling. CONCLUSIONS: As a result of the findings, physicians should regularly reassess the quality of response in bipolar disorder patients with atypical features and, if necessary, modify treatment. Extended Cox regression models are well suited for evaluating long-term outcome and should be used more extensively to analyze treatment outcome in psychiatric and somatic disorders.

Lithium reduces pathological aggression and suicidality: a mini-review.

From a practical point of view, the well-proven antisuicidal and anti-aggressive effects of lithium are of utmost importance for a rational, safe and economical treatment of patients with affective disorders. Regular lithium long-term treatment reduces the otherwise 2- to 3-fold increased mortality of untreated patients with severe affective disorders down to the level of the general population. This is mainly due to the reduced suicide risk. Many international studies have confirmed this fascinating property of lithium which so far has not been demonstrated with comparable evidence for any other psychotropic compound. The antisuicidal effects of lithium might possibly be related to its anti-aggressive effects which have been shown in various species, populations and settings, such as animals, inhabitants of nursing homes for the elderly, mentally handicapped subjects, children and adolescents with hyperactive, hostile and aggressive behavior, and particularly in hyperaggressive inmates of correction units and prisons.

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.

A critical appraisal of lithium's efficacy and effectiveness: the last 60 years.

The history that depicts the evaluation of lithium's efficacy presents an interesting contrast: on the one hand, conviction that, of all psychotropic drugs, lithium has the best demonstrated efficacy; on the other hand, repeated attempts to question it. Those contesting lithium's stabilizing abilities have argued from several angles, for example that the proof was methodologically incorrect or insufficient, that the number of responders is small, or that the response is poor in practice and does not last. But there is a good explanation for this paradox. While the early challenges to lithium's value in recurrent mood disorders reflected mainly that psychiatry had not yet developed a methodology suitable for testing long-term efficacy, more recent questioning has resulted mostly from retesting its efficacy and effectiveness in a substantially broadened bipolar spectrum, outside the classical diagnosis. Lithium, however, continues to stabilize very well the patients suffering from typical bipolar disorder--the condition for which its efficacy was originally demonstrated. More recently, lithium has also proven to dramatically reduce suicidal behavior and mortality and to augment markedly the efficacy of antidepressants in unresponsive patients.

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.