Mood-Stabilizing Anticonvulsants, Spina Bifida, and Folate Supplementation: Commentary.

PURPOSE/BACKGROUND: High risks of neural tube defects and other teratogenic effects are associated with exposure in early pregnancy to some anticonvulsants, including in women with bipolar disorder. METHODS/PROCEDURES: Based on a semistructured review of recent literature, we summarized findings pertaining to this topic. FINDINGS/RESULTS: Valproate and carbamazepine are commonly used empirically (off-label) for putative long-term mood-stabilizing effects. Both anticonvulsants have high risks of teratogenic effects during pregnancy. Risks of neural tube defects (especially spina bifida) and other major malformations are especially great with valproate and can arise even before pregnancy is diagnosed. Standard supplementation of folic acid during pregnancy can reduce risk of spontaneous spina bifida, but not that associated with valproate or carbamazepine. In contrast, lamotrigine has regulatory approval for long-term use in bipolar disorder and appears not to have teratogenic effects in humans. IMPLICATIONS/CONCLUSIONS: Lack of protective effects against anticonvulsant-associated neural tube defects by folic acid supplements in anticipation of and during pregnancy is not widely recognized. This limitation and high risks of neural tube and other major teratogenic effects, especially of valproate, indicate the need for great caution in the use of valproate and carbamazepine to treat bipolar disorder in women of child-bearing age.

Lithium in Psychiatry / Litio en Psiquiatría

Background: Lithium is a light, metallic element and minerals containing it are most abundant in the Andes. John Cade introduced lithium carbonate for the treatment of mania in 1949, opening the era of modern clinical psychopharmacology. Lithium remains the most extensively studied mood-stabilizing agent. It has had a revolutionary impact in supporting bipolar manic-depressive disorder as a discrete diagnosis, and on psychiatric therapeutics. Methods: We survey the development of lithium treatment in psychiatry, including findings concerning effects on suicide. Results: Lithium is the most extensively studied treatment for bipolar disorder and the prototypical mood-stabilizing agent, despite emergence of anticonvulsants and modern antipsychotics. In addition to limiting recurrences of mania, and some reduction of recurrences of bipolar depression, lithium has demonstrated protective effects against suicide. All treatments for bipolar disorder have notable limitations, including sometimes serious adverse effects, incomplete prevention of recurrences of mania and limited prevention of depression, which accounts for three-quarters of the approximately 50% time-ill in long-term follow-up with standard treatments. Lithium can be toxic in untreated overdoses; safe dosing requires monitoring of serum concentrations. Lithium also may have mild teratogenic effects, but far less than those of anticonvulsants used for bipolar disorder. Conclusions: Lithium opened the era of modern psychopharmacology and continues as the best-established mood-stabilizing treatment for bipolar disorder as well as having strong evidence of suicide-preventing effects.

Antecedentes: Litio es un elemento metálico ligero y los minerales que lo contienen abundan predominantementeen la región andina. John Cade introdujo el uso de carbonato de litio para el tratamiento de manía en 1949, iniciando con ello la era de la moderna psicofarmacología clínica. Litio se mantiene como el más extensamente estudiando agente estabilizador del ánimo. Ha tenido un impacto revolucionario en la preservación del trastorno maniaco-depresivo o bipolar como un diagnóstico discreto y en el campo de la terapéutica psiquiátrica.Métodos: Se examina el desarrollo histórico del tratamiento con litio en psiquiatría, incluyendo hallazgos en relación a su efecto sobreconducta suicida. Hallazgos:Litio es el tipo de tratamiento más extensamente estudiado en el manejo de trastorno bipolar disorder, constituido como el prototipo de agente estabilizador del ánimo, a pesar de la emergencia de agentes anticonvulsivantes y de los antipsicóticos modernos. Además de limitar la recurrencia de episodios maniacos y reducir en algo las recurrencias de depresión bipolar, litio ha demostrado efectos protectores en relación a suicidio y conducta suicida. Todos los tipos de tratamiento de trastorno bipolar tienen limitaciones notables, incluyendo algunas veces serios efectos adversos, prevención incompleta de recurrencias de manía y prevención limitada de depresión, todo lo cual constituye las tres cuartas partes de aproximadamente el 50 % de tiempo con enfermedad en estudios de seguimiento a largo plazo con tratamientos estándar.

Evidence-based options for treatment-resistant adult bipolar disorder patients.

OBJECTIVES: Many patients diagnosed with bipolar disorder (BD) respond incompletely or unsatisfactorily to available treatments. Given the potentially devastating nature of this prevalent disorder, there is a pressing need to improve clinical care of such patients. METHODS: We performed a literature review of the research findings related to treatment-resistant BD reported through February 2012. RESULTS: Therapeutic trials for treatment-resistant bipolar mania are uncommon, and provide few promising leads other than the use of clozapine. Far more pressing challenges are the depressive-dysthymic-dysphoric-mixed phases of BD and long-term prophylaxis. Therapeutic trials for treatment-resistant bipolar depression have assessed anticonvulsants, modern antipsychotics, glutamate [N-methyl-D-aspartate (NMDA)] antagonists, dopamine agonists, calcium-channel blockers, and thyroid hormones, as well as behavioral therapy, sleep deprivation, light therapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation, and deep brain stimulation-all of which are promising but limited in effectiveness. Several innovative pharmacological treatments (an anticholinesterase, a glutamine antagonist, a calcium-channel blocker, triiodothyronine, olanzapine and topiramate), ECT, and cognitive-behavior therapy have some support for long-term treatment of resistant BD patients, but most of trials of these treatments have been methodologically limited. CONCLUSIONS: Most studies identified were small, involved supplementation of typically complex ongoing treatments, varied in controls, randomization, and blinding, usually involved brief follow-up, and lacked replication. Clearer criteria for defining and predicting treatment resistance in BD are needed, as well as improved trial design with better controls, assessment of specific clinical subgroups, and longer follow-up.

Coffee and cigarette use: association with suicidal acts in 352 Sardinian bipolar disorder patients.

OBJECTIVE: Abuse of illicit drugs and alcohol is prevalent in bipolar disorder (BPD) patients, and is an adverse prognostic factor. Much less is known about correlates of nicotine and caffeine consumption, but tobacco smoking is tentatively associated with suicidal behavior. METHODS: Retrospective analysis of demographic and clinical factors among 352 longitudinally assessed DSM-IV types I and II BPD patients contrasted patients with versus without consumption of nicotine or caffeine, based on univariate comparisons and multiple regression modeling. RESULTS: Current smoking (46%) and coffee drinking (74% of cases) were common, and significantly and independently associated with suicidal acts [coffee: odds ratio (OR) = 2.42, 95% confidence interval (CI): 1.15-5.09; smoking: OR = 1.79, CI: 1.02-3.15; both p < 0.001]. Risk increased with more smoking (cigarettes/day; r(s) = 0.383; p < 0.0001) and greater coffee consumption (cups/day; r(s) = 0.312; p = 0.008). Neither intake was related to yearly rates of all episodes, depressions, or manias. CONCLUSIONS: This is the first report to associate suicidal acts with coffee consumption in BPD patients, and it confirmed an association with smoking. Pending further evidence, the findings underscore the importance of monitoring use of even legal and mildly psychotropic substances by BPD patients.

Neurosyphilis, malaria, and the discovery of antipsychotic agents.

Four of the most disabling human diseases are syphilis, malaria, schizophrenia, and manic-depressive illness. The history of the development of treatments for these seemingly unrelated disorders intersects at several points. Treatment of tertiary cerebral syphilis (general paresis) by inducing fever with malaria led to a Nobel Prize. Although attempts to synthesize quinine, a plant product effective against malaria, failed, these efforts encouraged industrial organic chemists to synthesize many useful substances, including dyes, antibiotics, and antihistamines. The aniline-derived dye methylene blue was a member of a new class of polycyclic chemicals, the phenothiazines. Efforts to modify phenothiazines to find an antimalarial agent also failed but led to novel antiemetic-sedative antihistamines, including promethazine, promazine, and eventually chlorpromazine--the first effective treatment for schizophrenia and mania. Chlorpromazine has antipsychotic and antimanic properties, and it revolutionized the therapeutics of psychotic illnesses.

Synthesis and dopamine receptor binding of sulfur-containing aporphines.

We investigated acid-catalyzed rearrangement of thebaine 14 and its N-propyl analog 15 with methanesulfonic acid in the presence of the nucleophiles methanethiol and hydrogen sulfide. R(-)-2-methylthioapocodeine 16, R(-)-2-methylthioapomorphine 18, and their N-n-propyl analogs 17, 19 were obtained by rearrangement in the presence of methanethiol. However, with hydrogen sulfide, rearrangement of thebaine 14 and its N-n-propyl analog 15 produced sulfide-linked bis-aporphines 21-24 instead of expected R(-)-2-mercaptoapocodeines 12, 13 and R(-)-2-mercaptoapomorphines 10, 11. R(-)-2-Methylthio-N-n-propylnorapomorphine 19 had higher affinity (Ki = 3.7 nM) at D2 receptors in rat forebrain tissue than other novel 2-substituted sulfur-containing aporphines (Ki > or = 50 nM). Behavioral testing of the novel agents in rat indicated moderate locomotor arousal after systemic injection, and none after intragastric administration, indicating poor oral bioavailability.