Catatonia Due to Lithium Neurotoxicity: A Case Report. / Lityum Nörotoksisitesine Ikincil Gelisen Katatoni Vakasi: Bir Olgu Sunumu.

Lithium may cause toxicity as it has a narrow therapeutic range. Lithium intoxication may manifest in the form of acute, acute on chronic and chronic intoxication. Neurotoxicity is a common component of chronic lithium intoxication and the symptoms include tremor, ataxia, dysarthria, extrapyramidal symptoms, hyperreflexia, seizures and status epilepticus. Although rare, catatonia could as a manifestation of lithium neurotoxicity. In this report, we present a patient with bipolar disorder presenting with catatonic symptoms secondary to lithium intoxication. We will discuss the risk factors, differential diagnosis and the treatment of catatonic symptoms. Lithium neurotoxicity may present with various clinical symptoms including catatonia, and differential diagnosis should be made well in such cases. If lithium neurotoxicity is suspected, rapid and appropriate intervention is required to prevent permanent neurological damage. Keywords: Lithium, Neurotoxicity, Catatonia.

Lithium Exposure and Risk of Major Neurocognitive Disorders: A Systematic Review and Meta-analysis.

BACKGROUND: Published studies on the association between lithium use and the decreased risk of major neurocognitive disorders (MNCDs) have shown disparities in their conclusions. We aimed to provide updated evidence of this association. METHODS: A comprehensive literature search was performed in PubMed, EMBASE, and Cochrane Library from inception until August 31, 2023. All the observational studies evaluating the association between lithium use and MNCD risk were eligible for inclusion. Pooled odds ratios (ORs) and 95% prediction intervals were computed using random-effects models. RESULTS: Eight studies with 377,060 subjects were included in the analysis. In the general population on the association between lithium use versus nonuse and dementia, the OR was 0.94 (95% confidence interval [CI] = 0.77-1.24). Further analysis also demonstrated that lithium use was not associated with an increased risk of Alzheimer's disease (OR = 0.69, 95% CI: 0.31-1.65). When the analysis was restricted to individuals with bipolar disorder to reduce the confounding by clinical indication, lithium exposure was also not associated with a decreased risk of MNCD (OR = 0.9, 95% CI = 0.71-1.15). CONCLUSION: The results of this systematic review and meta-analysis do not support a significant association between lithium use and the risk of MNCD.

Efficacy and Safety of Adding Lurasidone to Ongoing Therapy With Lithium or Valproate for the Treatment of an Acute Bipolar Depressive Episode: A Post Hoc Analysis of 2 Placebo-Controlled Trials.

PURPOSE: The aim of this study was to compare the efficacy and safety profile of lurasidone combined with either lithium or valproate, in the short-term treatment of patients with bipolar depression. METHODS: Data were pooled from two 6-week, double-blind, placebo-controlled trials of patients with bipolar depression on stable doses of lithium or valproate randomized to lurasidone (20-120 mg/d) or placebo. Efficacy measures included the Montgomery-Åsberg Depression Rating Scale, Clinical Global Impressions Bipolar Scale, and the Quick Inventory of Depressive Symptomatology via self-assessment and were analyzed using a mixed model for repeated measures approach. RESULTS: Notably larger week 6 effect sizes were observed when lurasidone was added to lithium, compared with when lurasidone was added to valproate, on 2 of the 3 depression outcome measures, Montgomery-Åsberg Depression Rating Scale total score (d = 0.45 vs 0.22) and Quick Inventory of Depressive Symptomatology via self-assessment (d = 0.63 vs 0.29); the efficacy advantage was smaller on the Clinical Global Impressions Bipolar Scale depression score (d = 0.34 vs 0.29). Similar adverse event profiles were observed for lurasidone treatment in combination with either lithium or valproate. The most frequently reported events (≥5%) in both groups were nausea, parkinsonism, somnolence, akathisia, and insomnia. Minimal changes in weight, lipids, and measures of glycemic control were observed during treatment with lurasidone combined with either lithium or valproate. CONCLUSIONS: Lurasidone added to either lithium or valproate was found to be an effective treatment for bipolar depression, with a larger antidepressant effect observed when lurasidone was combined with lithium. There were no clinically meaningful differences in the safety or tolerability of lurasidone when used adjunctively with lithium or valproate.

Lithium versus anticonvulsants and the risk of physical disorders - Results from a comprehensive long-term nation-wide population-based study emulating a target trial.

Bipolar disorder is associated with increased rates of many physical disorders, but the effects of medication are unclear. We systematically investigated the associations between sustained use of first line maintenance agents, lithium versus lamotrigine and valproate, and the risk of physical disorders using a nation-wide population-based target trial emulation covering the entire 5.9 million inhabitants in Denmark. We identified two cohorts. Cohort 1: patients with a diagnosis of bipolar disorder prior to first purchase (N = 12.607). Cohort 2: all 156.678 adult patients who had their first ever purchase (since 1995) of either lithium, lamotrigine or valproate between 1997 and 2021 regardless of diagnosis. Main analyses investigated the effect of sustained exposure defined as exposure for all consecutive 6-months periods during a 10-year follow-up. Outcomes included a diagnosis of incident stroke, arteriosclerosis, angina pectoris, myocardial infarction, diabetes mellitus, myxedema, osteoporosis, dementia, Parkinson's disease, chronic kidney disease and cancer (including subtypes). In both Cohorts 1 and 2, there were no systematic statistically significant differences in associations between sustained use of lithium versus lamotrigine and valproate, respectively, and any physical disorder, including subtypes of disorders, except myxedema, for which exposure to lithium increased the absolute risk of myxedema with 7-10 % compared with lamotrigine or valproate. In conclusion, these analyses emulating a target trial of "real world" observational register-based data show that lithium does not increase the risk of developing any kind of physical disorders, except myxedema, which may be a result of detection bias.

A case of pregnancy with severe polyhydramnios related to long-term use of lithium.

OBJECTIVES: Severe polyhydramnios during pregnancy may be associated with long-term lithium use and presents considerable challenges. This complication, which has been linked to induced nephrogenic diabetes insipidus (NDI), underscores the necessity for cautious management of pregnant women with bipolar disorder. This case report aims to elucidate the relationship between long-term lithium use, pregnancy, and the development of severe polyhydramnios, emphasizing the importance of diagnosing NDI in order to prevent obstetric and neonatal complications. METHODS: We present the case of a 42-year-old primigravida undergoing long-term lithium treatment for bipolar disorder type I, who developed severe polyhydramnios at 34 weeks of gestation. Clinical data including obstetric monitoring and neonatal outcomes were analyzed. RESULTS: This case emphasizes the need for heightened awareness and proactive measures to mitigate the risk associated with lithium treatment during pregnancy. Close monitoring and timely interventions are essential to ensure optimal outcomes for both mother and fetus. CONCLUSIONS: Our article puts forth the hypothesis that there is a link between lithium use during pregnancy and the occurrence of polyhydramnios and Nephrogenic Diabetes Insipidus (NDI), which may lead to severe obstetric and neonatal complications. This case report contributes to the limited literature on the subject and gives doctors practical advice that may help them make a better risk-benefit analysis. Further research is warranted in order to refine risk assessment protocols and management strategies in this complex clinical scenario.

[Mood Stabilizers: An Overview].

Bipolar disorder, a mental illness that affects mood, behavior, and motivation is characterized by alternating depressive and manic (hypomanic) episodes (some mixed episodes include both types of symptoms), with periods of remission between episodes. Symptoms and progress vary across patients. Treatment includes anti-seizure medications and maintenance therapy to prevent seizures. Classically, lithium carbonate and valproate are the most commonly used medications; however, in addition to lamotrigine, atypical antipsychotics including aripiprazole, quetiapine, and lurasidone are being used in recent years. Theoretically, patients are administered monotherapy; however, it is not uncommon to use combination treatment in clinical practice.

Efficacy and safety profiles of mood stabilizers and antipsychotics for bipolar depression: a systematic review.

The whole picture of psychotropics for bipolar depression (BPD) remains unclear. This review compares the differences in efficacy and safety profiles among common psychotropics for BPD. MEDLINE, EMBASE, and PsycINFO were searched for proper studies. The changes in the depressive rating scale, remission/response rates, nervous system adverse events (NSAEs), gastrointestinal adverse events (GIAEs), metabolic parameters, and prolactin were compared between medication and placebo or among medications with the Cohen's d or number needed to treat/harm. The search provided 10 psychotropics for comparison. Atypical antipsychotics (AAPs) were superior to lithium and lamotrigine at alleviating acute depressive symptoms. Lithium was more likely to induce dry mouth and nausea. Cariprazine and aripiprazole seemed to be associated with an increased risk of akathisia and upper GIAEs. Lurasidone was associated with an increased risk of developing akathisia and hyperprolactinemia. Olanzapine, olanzapine-fluoxetine combination (OFC), and quetiapine were associated with an increased risk of NSAEs, metabolic risk, dry mouth, and constipation. Cariprazine, lurasidone, OFC, or quetiapine was optimal monotherapy for BPD. Further studies are needed to assess the efficacy and safety of lamotrigine for treating BPD. Adverse events varied widely across different drug types due to variations in psychopharmacological mechanisms, dosages, titration, and ethnicities.

[Effects of lithium, valproic acid, carbamazepine and antipsychotic agents on cognition in bipolar disorders-A systematic review]. / Auswirkungen von Lithium, Valproat, Carbamazepin und Antipsychotika auf die Kognition bei bipolarer Störung ­ ein systematisches Review.

BACKGROUND: Until now the long-term consequences of the medical treatment for bipolar disorder have barely been examined, especially the consequences with respect to cognitive impairment and dementia. Some studies show signs that some treatment options have a better effect on the brain than others. This review summarizes the current state of research. OBJECTIVE: The effects of long-term consequences of lithium, valproic acid, carbamazepine and antipsychotic agents on the development of dementia or cognitive impairments in patients with bipolar disorder were investigated. METHODS: A systematic literature search was carried out in the PubMed data base from May to July 2022. RESULTS: The majority of studies showed that lithium has a neuroprotective effect and can lower the risk of developing dementia, whereas an increased risk was found in patients taking valproic acid. There are only very few studies that deal with antipsychotic medication and the long-term consequences concerning dementia. CONCLUSION: Lithium should be recommended for the long-term treatment of bipolar disorder. Valproic acid should not or carefully be used as it can affect the risk of developing dementia. With respect to antipsychotics there is no recommendation as more studies are needed to evaluate the long-term consequences.

Pharmacological treatment of bipolar disorder and risk of diabetes mellitus: A nationwide study of 30,451 patients.

OBJECTIVE: While treatment with antipsychotics and antiepileptics have been associated with an increased risk of diabetes mellitus (DM), lithium may have the opposite effect via inhibition of glycogen synthase kinase-3. The aim of this study was to investigate whether treatment of bipolar disorder with lithium, antipsychotics, or antiepileptics is associated with the risk of DM in a real-world clinical setting. METHODS: Using nationwide registers, we identified all patients diagnosed with bipolar disorder in Danish Psychiatric Services from January 1, 1996, to January 1, 2019 (N = 30,451). The risk of developing DM was operationalized via hospital diagnoses and redeemed prescriptions for glucose-lowering drugs. For lithium, antipsychotics, valproate, and lamotrigine, we calculated hazard rate ratios (HRR) for developing DM via adjusted Cox proportional hazards models. Potential cumulative dose-response-like associations were examined using the log-rank test. RESULTS: During follow-up (245,181 person-years), 2107 (6.9%) patients developed DM. Compared with non-users of the respective drugs, we found no clinically or statistically significant difference in the risk of developing DM among patients receiving lithium (n = 11,690; incidence rate of DM/1000 person-years (IR) = 8.87, 95% CI: 8.02-9.90; HRR = 0.94, 95% CI: 0.84-1.06) or lamotrigine (n = 11,785; IR = 7.58, 95% CI: 6.69-8.59; HRR = 0.89, 95% CI: 0.77-1.02), respectively. Conversely, for patients receiving valproate (n = 5171; IR = 12.68, 95% CI: 10.87-14.80; HRR = 1.34, 95% CI: 1.14-1.58) and antipsychotics (n = 22,719; IR = 12.00, 95% CI: 11.14-12.94; HRR = 1.65, 95% CI: 1.45-1.88), respectively, there was increased risk of developing DM. For antipsychotics, we observed a clear cumulative dose-response-like association with the risk of DM. CONCLUSIONS: Treatment with valproate and antipsychotics-but not with lithium and lamotrigine-was associated with increased risk of DM in a real-world cohort of patients with bipolar disorder.

Degree of exposure to psychotropic medications and mortality in people with bipolar disorder.

OBJECTIVES: To investigate the associations between psychotropic medication dosage and mortality in patients with bipolar disorder. METHODS: A nationwide cohort of individuals aged ≥15 years who had received a diagnosis of bipolar disorder in 2010 was identified from the Taiwanese national health-care database linked with the mortality registry and followed up for 5 years. The mean defined daily dose (DDD) of mood stabilizers, antipsychotics, antidepressants, and sedative-hypnotics was estimated, and survival analyses were conducted to assess the effects of degree of exposure to psychotropic medications on mortality. RESULTS: A total of 49,298 individuals (29,048 female individuals, 58.92%) with bipolar disorder were included. Compared with individuals without exposure to mood stabilizers, those prescribed mood stabilizers had a decreased overall mortality risk, regardless of exposure dosage. By contrast, compared with a reference group with no exposure to antipsychotics, individuals using antipsychotics had dose-dependent, increased mortality in both overall causes of deaths and deaths due to cardiovascular diseases, with hazard ratios of 1.13 (95% CI: 1.21-1.42) in the low-dose (<0.5 DDD) group, 1.69 (1.51-1.90) in the moderate-dose (0.5-1.5 DDD) group, and 2.08 (1.69-2.57) in the high-dose (>1.5 DDD) group for overall mortality. CONCLUSIONS: In sum, mood stabilizers were associated with decreased overall mortality in individuals with bipolar disorder, regardless of the dosage. However, the use of antipsychotics appeared to be associated with a dose-dependent increased mortality risk. Owing to study limitations, precise information on prior use of psychotropic medications, and patient's adherence to medication are not available. Potential adverse effects and benefits should be carefully considered when prescribing psychotropic medications for long-term use in patients with bipolar disorder.

Risk of Mania After Methylphenidate in Patients With Bipolar Disorder.

BACKGROUND: Bipolar disorder and attention-deficit/hyperactivity disorder are common comorbidities. Attention-deficit/hyperactivity disorder is commonly treated with stimulants (eg, methylphenidate), which, however, have been suggested to cause treatment-emergent mania in patients with bipolar disorder. Here, we assessed the risk of mania, depressive episodes, and psychiatric admissions after initiation of methylphenidate treatment in patients with bipolar disorder. METHODS: Using Danish health registries, we identified all individuals registered with a diagnosis of bipolar disorder from January 1, 2000, to January 1, 2018, who were treated with methylphenidate. We applied a 1-year mirror-image model to compare the occurrence of mania, depression, and psychiatric admissions in the period leading up to and after methylphenidate treatment initiation. We furthermore assessed the trend in these outcomes from 4 years before to 1 year after initiation of methylphenidate treatment. RESULTS: A total of 1043 patients with bipolar disorder initiated treatment with methylphenidate. The number of manic episodes decreased by 48% after methylphenidate treatment initiation (P = 0.01), both among patients using mood stabilizers (-50%) and among patients not using mood stabilizers (-45%). The number of manic episodes, however, peaked approximately 6 months before methylphenidate. The results were similar for the secondary outcomes. CONCLUSIONS: Initiation of methylphenidate treatment was not associated with an increased risk of mania in patients with bipolar disorder. A decrease in mania, depressive episodes, and psychiatric admissions was observed after methylphenidate. However, these decreases seemed to be driven by regression to the mean after clinical deterioration preceding methylphenidate treatment, rather than by the methylphenidate treatment itself.

A cumulative Bayesian network meta-analysis on the comparative efficacy of pharmacotherapies for mania over the last 40 years.

RATIONALE: Mania (or manic episodes) is a common symptom of bipolar disorder and is frequently accompanied by hyperactivity and delusions; given the cost and resources available, there is a paucity of evidence for direct comparison of different drugs. OBJECTIVES: We aimed to provide evidence-based recommendations on the efficacy of overall currently used pharmacological treatments for patients with acute bipolar mania. METHOD: We conducted a systematic review and network meta-analysis (NMA) using a Bayesian network frame. We searched the primary literature databases without language restrictions until Dec 18, 2021, for reports of randomized controlled trials (RCTs) of suspected antimanic drugs used as monotherapy for patients with acute bipolar mania, with the primary outcomes being efficacy (mean difference (MD), standardized mean difference (SMD) in the change of mania score). RESULTS: Eighty-seven studies were included in which 18,724 manic participants (mean age = 34.6 years, with 50.36% males) were allocated at random to one of 25 active medication drug therapies or placebo, resulting in 87 direct comparisons on 192 data points. Tamoxifen (- 22·00 [- 26·00 to - 18·00]) had the best efficacy over the placebo. Meanwhile, risperidone (- 6·60 [- 8·40 to - 4·90]) was substantially more effective than placebo in treating acute mania. Carbamazepine, haloperidol, ziprasidone, cariprazine, olanzapine, quetiapine, aripiprazole, lithium, paliperidone, asenapine, and divalproex were noticeably more effective than placebo. CONCLUSIONS: Overall, tamoxifen appears to be the most effective of the currently known pharmaceutical therapy available to treat acute mania or manic episodes; however, this conclusion is restricted by the scale of RCTs conducted, and risperidone was found to be the most effective medication among antipsychotics. Carbamazepine, haloperidol, ziprasidone, cariprazine, olanzapine, quetiapine, aripiprazole, lithium, paliperidone, asenapine, and divalproex were noticeably effective in treating acute mania or manic episodes.

Effect of valproate and lithium on dementia onset risk in bipolar disorder patients.

Although valproate and lithium are most commonly prescribed for bipolar disorder patients, studies comparing their effects on the risk of dementia are limited. Choosing a safer mood stabilizer is clinically crucial as elderly bipolar disorder patients are at high risk of dementia onset. Therefore, we aim to evaluate and compare the effects of valproate and lithium on the risk of dementia in elderly bipolar disorder patients. This study involved 4784 bipolar disorder patients aged 50 years or older from the Korean Health Insurance Review and Assessment Service database. We estimated the risk of dementia in valproate-only users, lithium-only users, and both users compared to both medication non-users using multivariable Cox proportional hazard models. Compared to non-users, valproate-only users and both users showed a higher risk of dementia (59% and 62%, respectively). In sub-group analysis, valproate increased the dementia risk when prescribed for at least 59 days or 23 cumulative defined daily doses. However, the dementia risk associated with lithium is unclear. Therefore, we concluded that lithium has the potential to be the safer choice as a mood stabilizer over valproate for elderly bipolar disorder patients considering the risk of dementia.

Mood Stabilizers and Antipsychotics for Acute Mania: Systematic Review and Meta-Analysis of Augmentation Therapy vs Monotherapy From the Perspective of Time to the Onset of Treatment Effects.

BACKGROUND: Existing meta-analytic evidence on bipolar mania treatment has revealed that augmentation therapy (AUG) with antipsychotics and mood stabilizers is more effective than monotherapy. However, the speed of the onset of treatment effects and subsequent changes in risk/benefit are unclear. METHODS: We searched the Cochrane CENTRAL, MEDLINE, and EMBASE databases until January 2021. Our primary outcomes were response and tolerability. We set 3 time points: 1, 3, and 6 weeks after randomization. RESULTS: Seventeen studies compared AUG therapy and MS monotherapy (comparison 1), and 8 studies compared AUG therapy and antipsychotics monotherapy (comparison 2). In comparison 1, AUG therapy resulted in significantly more responses than monotherapy, with an odds ratio of 1.45 (95% confidence interval [CI]: 1.17 to 1.80) at 3 weeks and 1.59 (95% CI: 1.28 to 1.99) at 6 weeks. Significant improvement was observed in the first week with a standardized mean difference of -0.25 (95% CI: -0.38 to -0.12). In comparison 2, AUG therapy was significantly more effective than monotherapy, with an odds ratio of 1.73 (95% CI: 1.25 to 2.40) at 3 weeks and 1.74 (95% CI: 1.11 to 2.73) at 6 weeks. Significant improvement was observed in the first week with an standardized mean difference of -0.23 (95% CI: -0.39 to -0.07). Regarding tolerability, there was no significant difference between AUG therapy and monotherapy at 3 and 6 weeks in both comparisons. CONCLUSIONS: Early AUG therapy should be considered, as it has shown efficacy from weeks 1 to 6, although attention to side effects is necessary for acute mania treatment.

Comparison of the efficacy and safety of quetiapine and lithium for bipolar depression: A systematic review and meta-analysis of randomized controlled trials.

AIM: Pharmacological treatments recommended for bipolar depression are inconsistent across guidelines. We compared the efficacy and safety of antipsychotics and mood stabilizers for bipolar depression. METHODS: A systemic review and meta-analysis of randomized controlled trials comparing antipsychotics and mood stabilizers for bipolar depression was conducted based on a literature search of major electronic databases. RESULTS: Three studies comparing quetiapine with lithium were identified and analyzed; no other antipsychotic-mood stabilizer combinations were found. The meta-analysis revealed no significant differences between quetiapine and lithium for the following outcomes: (1) remission from depressive episodes (risk ratio [RR]: 1.80, 95% CI: 0.51-6.40, P = 0.36), (2) changes in depressive symptom (standardized mean difference: -0.22, 95% CI: -0.52-0.08, P = 0.15), (3) changes in social function (standardized mean difference: -0.00, 95% CI: -0.19-0.18, P = 0.98), (4) suicide-related events (odds ratio [OR]: 2.35, 95% CI: 0.40-13.65, P = 0.34), (5) severe adverse events (OR: 1.63, 95% CI: 0.51-5.20, P = 0.41), (6) dropouts due to adverse events (RR: 1.19, 95% CI: 0.76-1.87, P = 0.45, 7) dropout for any reasons (RR: 0.95, 95% CI: 0.74-1.22, P = 0.70). CONCLUSION: Although this study found no differences in the efficacy and safety of quetiapine and lithium for bipolar depression, a comprehensive comparison of antipsychotics and mood stabilizers was not performed. Further studies are needed to clarify which of these, not just quetiapine and lithium, is more useful for bipolar depression.

Valproic Acid-Induced Anxiety and Depression Behaviors are Ameliorated in p39 Cdk5 Activator-Deficient Mice.

Valproic acid (VPA) is a drug used for the treatment of epilepsy, seizures, migraines, and bipolar disorders. Cyclin-dependent kinase 5 (Cdk5) is a Ser/Thr kinase activated by p35 or p39 in neurons and plays a role in a variety of neuronal functions, including psychiatric behaviors. We previously reported that VPA suppressed Cdk5 activity by reducing the expression of p35 in cultured cortical neurons, leaving p39 unchanged. In this study, we asked for the role of Cdk5 in VPA-induced anxiety and depression behaviors. Wild-type (WT) mice displayed increased anxiety and depression after chronic administration of VPA for 14 days, when the expression of p35 was decreased. To clarify their relationship, we used p39 knockout (KO) mice, in which p35 is the only Cdk5 activator. When p39 KO mice were treated chronically with VPA, unexpectedly, they exhibited fewer anxiety and depression behaviors than WT mice. The effects were p39 cdk5r2 gene-dosage dependent. Together, these results indicate that Cdk5-p39 plays a specific role in VPA-induced anxiety and depression behaviors.

Relationship between lithium carbonate and the risk of Parkinson-like events in patients with bipolar disorders: A multivariate analysis using the Japanese adverse drug event report database.

The present study attempted to identify risk factors for Parkinson-like events using the Japanese adverse drug event report database. A total of 3521 patients with bipolar disorders were extracted from the database, and Parkinson-like events were detected in 111 (3.15%) using the standardized Medical Dictionary for Regulatory Activities queries. A multiple logistic regression analysis identified age ≥50 years and the use of sodium valproate or aripiprazole as risk factors. Lithium carbonate was not associated with an increased risk of Parkinson-like events, but was related to these events in patients taking sodium valproate.

Association of Lithium Treatment With the Risk of Osteoporosis in Patients With Bipolar Disorder.

Importance: Osteoporosis, a systemic skeletal disorder associated with substantial morbidity and mortality, may be particularly common among individuals with bipolar disorder. Lithium, a first-line mood-stabilizing treatment for bipolar disorder, may have bone-protecting properties. Objective: To evaluate if treatment with lithium is associated with a decrease in risk of osteoporosis among patients with bipolar disorder. Design, Setting, and Participants: This retrospective cohort study included 22 912 adults from the Danish Psychiatric Central Research Register who received an initial diagnosis of bipolar disorder in the period from January 1, 1996, to January 1, 2019. For each patient with bipolar disorder, 5 age- and sex-matched individuals were randomly selected from the general population as reference individuals. Individuals with bipolar disorder prior to January 1, 1996, those with a diagnosis of schizophrenia or schizoaffective disorder prior to being diagnosed with bipolar disorder, and those with osteoporosis prior to the index date were excluded. Of the 114 560 reference individuals included, 300 were diagnosed with bipolar disorder during follow-up and were censored from the reference group from the date of diagnosis forward. For patients with bipolar disorder, treatment periods with lithium, antipsychotics, valproate, and lamotrigine were identified. Analyses were performed between January 2021 and January 2022. Exposures: Bipolar disorder and treatment with lithium, antipsychotics, valproate, and lamotrigine. Main Outcomes and Measures: The primary outcome was osteoporosis, identified via hospital diagnoses and prescribed medications. First, incidence of osteoporosis was compared between patients with bipolar disorder and reference individuals (earliest start of follow-up at age 40 years) using Cox regression. Subsequently, incidence of osteoporosis for patients receiving treatment with lithium, antipsychotics, valproate, and lamotrigine, respectively, was compared with that of patients who were not treated with these medications. Results: A total of 22 912 patients with bipolar disorder (median [IQR] age, 50.4 [41.2-61.0] years; 12 967 [56.6%] women) and 114 560 reference individuals (median [IQR] age, 50.4 [41.2-61.0] years; 64 835 [56.6%] women) were followed up for 1 213 695 person-years (median [IQR], 7.68 [3.72-13.24] years). The incidence of osteoporosis per 1000 person-years was 8.70 (95% CI, 8.28-9.14) among patients and 7.90 (95% CI, 7.73-8.07) among reference individuals, resulting in a hazard rate ratio (HRR) of 1.14 (95% CI, 1.08-1.20). Among patients with bipolar disorder, 8750 (38.2%) received lithium, 16 864 (73.6%) received an antipsychotic, 3853 (16.8%) received valproate, and 7588 (33.1%) received lamotrigine (not mutually exclusive). Patients with bipolar disorder treated with lithium had a decrease in risk of osteoporosis (HRR, 0.62; 95% CI, 0.53-0.72) compared with patients not receiving lithium. Treatment with antipsychotics, valproate, and lamotrigine was not associated with reduced risk of osteoporosis. Conclusions and Relevance: In this study, bipolar disorder was associated with an increase in risk of osteoporosis, and lithium treatment was associated with a decrease in risk of osteoporosis. These findings suggest that bone health should be a priority in the clinical management of bipolar disorder and that the potential bone-protective properties of lithium should be subjected to further study, both in the context of bipolar disorder and in osteoporosis.

Mini-review: Anomalous association between lithium data and lithium use.

This mini-review aims to show a discrepancy between favorable data of lithium's therapeutic activity and the decreased use of the drug worldwide. The data point to lithium as the best mood stabilizer in the maintenance treatment of bipolar disorder for the prevention of manic and depressive recurrences. The second most encouraging psychiatric use of lithium is the augmentation of antidepressants in treatment-resistant depression. In addition to its mood-stabilizing properties, lithium is the most efficacious antisuicidal drug among all mood stabilizers. The drug also exerts antiviral, immunomodulatory, and neuroprotective effects which may be of major clinical value. On the other hand, the data of lithium use show that its therapeutic application in many countries has declined. A reason for this can be the introduction and heavy promotion of other mood-stabilizers, while lithium is an "orphan" drug with the minimal interest of any drug company. Probably, very important is also a perception of lithium as a "toxic drug", pointing to its side effects, mainly thyroid, renal and cognitive ones. In recent years, several proposals to turn back this anomalous association appeared, challenging a negative perception of lithium and optimizing its long-term administration. They show the data on lithium superiority over other mood stabilizers and point to the proper management of the lithium-induced side effects. This endeavor aims to allow a larger number of mood disorder patients to become beneficiaries of lithium use.

Calcium Channel Antagonists for Mood Disorders.

PURPOSE: Development of new thymoleptic medications has primarily centered on anticonvulsants and antipsychotic drugs. Based on our studies of intracellular calcium ion signaling in mood disorders, we were interested in the use of novel medications that act on this mechanism of neuronal activation as potential mood stabilizers. METHOD: We reviewed the dynamics of the calcium second messenger system and the international body of data demonstrating increased baseline and stimulated intracellular calcium levels in peripheral cells of patients with bipolar mood disorders. We then examined studies of the effect of established mood stabilizers on intracellular calcium ion levels and on mechanisms of mobilization of this second messenger. After summarizing studies of calcium channel blocking agents, whose primary action is to attenuate hyperactive intracellular calcium signaling, we considered clinical experience with this class of medications and the potential for further research. FINDINGS: Established mood stabilizers normalize increased intracellular calcium ion levels in bipolar disorder patients. Most case series and controlled studies suggest an antimanic and possibly mood stabilizing effect of the calcium channel blocking medications verapamil and nimodipine, with fewer data on isradipine. A relatively low risk of teratogenicity and lack of cognitive adverse effects or weight gain suggest possible applications in pregnancy and in patients for whom these are considerations. IMPLICATIONS: Medications that antagonize hyperactive intracellular signaling warrant more interest than they have received in psychiatry. Further experience will clarify the applications of these medications alone and in combination with more established mood stabilizers.