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.

To compare the efficacy of sodium valproate administered as adjunct to neuroleptic medication for patients with acute mania with the efficacy of neuroleptics alone, the authors conducted a 21-day, randomized, double-blind, parallel-group, placebo-controlled trial. The study design closely reflected a clinical psychiatric setting in Europe where patients with acute mania commonly receive neuroleptic medication. In this trial, 136 hospitalized patients met the ICD-10 criteria for acute manic episodes; these patients received a fixed dose of 20 mg/kg of body weight of sodium valproate (Orfiril, Desitin Arzneimittel GmbH, Hamburg, Germany) orally, in addition to basic neuroleptic medication, preferably haloperidol and/or perazine. The primary outcome measure was the mean dose of neuroleptic medication (after conversion into haloperidol-equivalents) for the 21-day study period. Severity of symptoms was measured using the Young Mania Rating Scale (YMRS), the Global Assessment Scale, and the Clinical Global Impression Scale. Intent-to-treat analysis was based on 69 patients treated with valproate and 67 patients who received placebo. Groups were comparable with regard to demographic and clinical baseline data. Premature discontinuations occurred in only 13% of the patients. The mean neuroleptic dose declined continuously in the valproate group, whereas only slight variations were observed in the placebo group; the difference was statistically significant (p = 0.0007) for study weeks 2 and 3. The combination of neuroleptic and valproate proved superior to neuroleptics in attempts to alleviate manic symptoms. The proportion of responders (a 50% improvement rate shown on the YMRS) was higher for the combination with valproate than for the group receiving only neuroleptics (70% vs. 46%; p = 0.005). Adverse events consisted of those known for valproate or neuroleptics; the only adverse event was asthenia, which occurred more frequently with the combination therapy. Valproate represents a useful adjunct medication for the treatment of acute manic symptoms. Valproate is beneficial because it allows the administration of fewer neuroleptic medications and produces improved and quicker remission of manic symptoms.

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. 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. Overall, 29.5% of subjects experienced at least one low value of eGFR ( 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. Control data for age-matched subjects not exposed to lithium were lacking. 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.

Depressive disorders are a leading cause of the global burden of disease and are associated with high recurrent often continuing morbidity and high excess mortality by suicide and cardiovascular disease. Whilst there are established, effective and cost-effective treatments for depression, their long-term management is often neglected: there is continuing controversy over the case of need for long-term treatment including lifelong treatment and safety issues. In this narrative review, we critically examine the evidence for the effectiveness and safety of lithium salts in the long-term management of unipolar depression. We refer to existing recent international guidelines as well as the scientific literature selectively and against the background of our longstanding experience with patients suffering from unipolar depression who are often under treated or inappropriately treated. According to many studies mostly dating back to the 1970/1980s, lithium is efficacious in the prophylaxis of unipolar depression particularly depression with melancholia and delusional depression and showing a clearly episodic course. Also the efficacy of lithium maintenance treatment following recovery by ECT has been clearly shown. Moreover, convincing evidence exists that lithium has added value and benefit for its unique anti-suicidal effects as well as reducing mortality by other causes. The anti-suicidal effect has been convincingly demonstrated in bipolar as well as in unipolar patients. Nevertheless its use in the management of patients with unipolar depression has not been properly recognized by a majority of textbooks and guidelines. Whilst it has been well considered as an effective treatment for depression that has not responded to antidepressants as an adjunct treatment, also called augmentation, it has been much less recommended for the prevention of recurrent episodes of unipolar depression. One of the reasons for this neglect is the blurring of the diagnosis “unipolar depression” by modern diagnostic tools. Lithium will hardly work in a patient with “unipolar depression spectrum disease”. We conclude that lithium is an effective prophylactic treatment for carefully selected patients with unipolar depression and is safe when prescribed in recommended doses/plasma lithium levels and with regular, careful monitoring. We propose that lithium prophylaxis can be indicated in patients with unipolar depression and that the occurrence of 2 episodes of depression within 5 years is a practical criterion for starting lithium prophylaxis particularly in severe depression with psychotic features and high suicidal risk. Furthermore, an indication might be considered especially in unipolar patients in whom a bipolar background is suspected. In some cases, lithium prophylaxis may be recommended after a single episode of depression that is severe with high suicidal risk and continued life-long.

The suicide-related mortality among patients with affective disorders is approximately 30 times higher, and overall mortality 2 to 3 times higher, than suicide-related mortality in the general population. Lithium has demonstrated possibly specific antisuicidal effects apart from its prophylactic efficacy: it significantly reduces the high excess mortality of patients with affective disorders. To date, suicide-prevention effects have not been shown for antidepressant or anticonvulsant long-term treatment. Clozapine appears to reduce the suicide rate in schizophrenia patients. Against this background, guidelines and algorithms for selecting an appropriate prophylactic strategy for affective disorders should consider the presence of suicidality in patient history. Appropriate lithium prophylaxis prevents approximately 250 suicides yearly in Germany, although lithium salts are infrequently prescribed within the National Health Scheme (specifically, to 0.06% of the population). Rational treatment strategies most likely would demand that prescription rates be about 10 times higher.

The article reviews the existing evidence and the concept of the anti-suicidal effect of lithium long-term treatment in bipolar patients. The core studies supporting the concept of a suicide preventive effect of lithium in bipolar patients come from the international research group IGSLI, from Sweden, Italy, and recently also from the U.S. Patients on lithium possess an eight- time lower suicide risk than those off lithium. The anti-suicidal effect is not necessarily coupled to lithium's episode suppressing efficacy. The great number of lives potentially saved by lithium adds to the remarkable benefits of lithium in economical terms. The evidence that lithium can effectively reduce suicide risk has been integrated into modern algorithms in order to select the optimal maintenance therapy for an individual patient.