Lithium mood disorders

The molten carbonate fuel ceU uses eutectic blends of Hthium and potassium carbonates as the electrolyte. A special grade of Hthium carbonate is used in treatment of affective mental (mood) disorders, including clinical depression and bipolar disorders. Lithium has also been evaluated in treatment of schizophrenia, schizoaffective disorders, alcoholism, and periodic aggressive behavior (56). 

In noncancer-related pharmacology, GSK3 is inhibited by lithium at therapeutic concentrations, implying that the long-established effectiveness of lithium in the treatment of psychiatric mood disorders (and more recently as a neuroprotective agent) may be linked to GSK3 inhibition. Antipsychotics such as haloperidol... 

Cookson JC, Sachs GS (1999). Lithium clinical use in mania and prophylaxis of affective disorders. In Buckley PF, Waddington JL, eds, Schizophrenia and Mood Disorders The New Drug Therapies in Clinical Practice. Oxford Butterworth Heinemann. 

Serretti, A., Lilli, R., Lorenzi, C., Franchini, L. Smeraldi, E. (1998). Dopamine receptor D3 gene and response to lithium prophylaxis in mood disorders. Ini. J. Neuropsychopharmacol., 1, 125-9. 

Serretti, A., Malitas, R N., Mandelli, L. etal. (2004). Further evidence for a possible association between serotonin transporter gene and lithium prophylaxis in mood disorders. Pharmacoge-nomics /., 4(4), 267-73. 

The clinical significance of this ethnic difference for psychiatry was found later. A study examining lithium tolerability found more side effects in African American patients with high RBC/plasma ratio even when the lithium levels were in the therapeutic range (Strickland etal., 1995). It is not known whether African Americans require lower doses and will respond with lower plasma levels. We do know that African Americans with mood disorders are less likely to be prescribed lithium either as primary treatment or adjunctive therapy (Valenstein etal., 2006 Kilbourne 8c Pincus, 2006). It is unknown as to whether the lack of tolerability at usual therapeutic doses is a factor. 

Lithium is the simplest therapeutic agent for the treatment of depression and has been used for over 100 years—lithium carbonate and citrate were described in the British Pharmacopoeia of 1885. Lithium therapy went through periods when it was in common use, and periods when it was discouraged. Finally, in 1949, J.J.F. Cade reported that lithium carbonate could reverse the symptoms of patients with bipolar disorder (manic-depression), a chronic disorder that affects between 1% and 2% of the population. The disease is characterized by episodic periods of elevated or depressed mood, severely reduces the patients quality of life and dramatically increases their likelihood of committing suicide. Today, it is the standard treatment, often combined with other drugs, for bipolar disorder and is prescribed in over 50% of bipolar disorder patients. It has clearly been shown to reduce the risk of suicide in mood disorder patients, and its socioeconomic impact is considerable—it is estimated to have saved around 9 billion in the USA alone in 1881. 

Kosbash I have a student in my lab who is interested in mood disorders. Over the course of last summer he did experiments with lithium in flies. He did dose-... 

Lithium is effective in the treatment of mood disorders. Its mechanism of action is unclear but is likely to be via modification of intracellular second... 

For more than 40 years, Li+ has been used to treat mania. While it is relatively inert in individuals without a mood disorder, lithium carbonate is effective in 60 to 80% of all acute manic episodes within 5 to 21 days of beginning treatment. Because of its delayed onset of action in the manic patient, Li+ is often used in conjunction with low doses of high-potency anxiolytics (e.g., lo-razepam) and antipsychotics (e.g. haloperidol) to stabilize the behavior of the patient. Over time, increased therapeutic responses to Li+ allow for a gradual reduction in the amount of anxiolytic or neuroleptic required, so that eventually Li+ is the sole agent used to maintain control of the mood disturbance. 

Patients whose first episodes of mania or bipolar depression occur between ages 30 to 60 years appear to have clearer episodes of mood disorder, have mania characterized by euphoria and irritability (rather than irritability alone), and be less likely to develop substance addiction (though they may engage in substance abuse as part of their acute episodes). Although psychosis occurs frequently and can be severe, in such late-onset cases confusion with other disorders is usually not a problem. Finally, this more classical presentation is generally responsive to lithium (Carlson, 2000). 

There has been only one double-blind, placebo-controlled long-term trial of lithium as a treatment for bipolar disorder in adults with MR (Naylor et ah, 1974). In this study, 14 adults with borderline to severe MR and bipolar disorder were treated with lithium (with levels between 0.6 and 1.0 mEq/F) for 1 year. The number of weeks of illness was significantly lower in the treatment group. A year-long, single-blind, placebo-controlled trial of lithium in five persons with bipolar mood disorder and MR treatment resulted in re-... 

Two commonly used anticonvulsant medications for the treatment and prophylaxis of bipolar mood disorder in adults with MR are carbamazepine and valproic acid. Reid et al. (1981) compared carbamazepine to placebo in a double-blind, crossover fashion in 12 overactive adults with severe MR. Those described as having elevated moods and distractibility responded to treatment, while those without mood disturbance did not. Glue (1989) treated 10 adults with MR and rapidcycling bipolar mood disorder with lithium alone, lithium and carbamazepine, and carbamazepine alone. None of the patients treated with carbamazepine alone responded, while half of the patients showed partial or complete improvement with lithium alone or in combination with carbamazepine. 

This case report (Figures 6-4Ato 6-4C) (McDermut et al. 1995) of selective response to dihydropyridine CCBs but not a phenylalkylamine CCB is of considerable interest in relationship to the patient s history of nonre-sponsivity to multiple tricyclic antidepressants, the selective serotonin reuptake inhibitors, lithium, carbamazepine (the patient developed drug-induced hepatitis on carbamazepine and was unable to be evaluated), alprazolam, trazodone, and phenelzine. This suggests that patients with refractory mood disorders may have differential responses to various CCBs and that nonresponse to one CCB does not preclude response to another CCB, particularly if the other CCB is from a different category (Table 6-3). 

Mandell AJ, Knapp S, Ehlers C, et al The stability of constrained randomness lithium prophylaxis at several neurobiological levels, in Neurobiology of Mood Disorders. Edited by Post RM, Ballenger JC. Baltimore, MD, WiUiams Wilkins, 1984, pp 744-776... 

Post RM, Chuang D-M Mechanism of action of lithium comparison and contrast with carbamazepine, in Lithium and the Cell Pharmacology and Biochemistry. Edited by Birch NJ. London, Academic Press, 1991, pp 199-241 Post RM, Weiss SRB The neurobiology of treatment-resistant mood disorders, in Psychopharmacology The Fourth Generation of Progress. Edited by Bloom FE, Kupfer DJ. New York, Raven, 1995... 

Lithium has been proven effective for acute and prophylactic treatment of both manic and depressive episodes in patients with bipolar illness (American Psychiatric Association 2002). However, patients with rapid-cycling bipolar disorder (i.e., patients who experience four or more mood disorder episodes per year) have been reported to respond less well to lithium treatment (Dunner and Fieve 1974 Prien et al. 1984 Wehr et al. 1988). Lithium is also effective in preventing future depressive episodes in patients with recurrent unipolar depressive disorder (American Psychiatric Association 2002) and as an adjunct to antidepressant therapy in depressed patients whose illness is partially refractory to treatment with antidepressants alone (discussed in Chapter 2). Furthermore, hthium may be useful in maintaining remission of depressive disorders after electroconvulsive therapy (Coppen et al. 1981 Sackeim et al. 2001). Lithium also has been used effectively in some cases of aggression and behavioral dyscontrol. 

Cohen LS, Eriedman JM, Jefferson JW, et al A reevaluation of risk of in utero exposure to lithium. JAMA 271 146-150, 1994 Coppen A, Abou-Saleh MX, Milln P, et al Lithium continuation therapy following electroconvulsive therapy. Br J Psychiatry 139 284-287, 1981 Coyle JT, Duman RS Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron 38 157-160, 2003 Dean JC, Penry JK Valproate, in The Medical Treatment of Epilepsy. Edited by Resor SR Jr, Kutt H. New York, Marcel Dekker, 1992, pp 265-278... 

It is well established that monotherapy with various antidepressants or mood stabilizers is relatively ineffective (i.e., they are necessary but not sufficient) for treating mood disorders with associated psychosis. Thus, psychotically depressed patients are best managed with a combination of antipsychotic-antidepressant or with electroconvulsive therapy. Although antipsychotics have a more rapid onset of action than lithium in an acute manic episode, we are unaware of clinical trials that examine the differential effect of antipsychotics or lithium for nonpsychotic versus psychotic mania. This topic is discussed further in... 

This group investigated patients presenting with acute schizophrenic symptoms who underwent a drug-free washout period, received lithium only initially, and then antipsychotics later (374). Lithium was ineffective for classic schizophrenia, but some patients who met criteria for schizophreniform disorder did respond to lithium. Whether schizophreniform illness is a variant of mood disorders (a reasonable hypothesis in view of their lithium response) or a separate entity that is lithium-sensitive is still unclear. It is known that these patients have family histories that include mood-disordered as well as schizophrenic relatives. In a small pilot study, physostigmine (a drug with possible antimanic but no antipsychotic properties) benefited schizophreniform patients who responded to lithium, but had no effect in those who did not (Carver DL, personal communication). 

The steady-state distribution of lithium has provided some evidence to support this hypothesis. Thus, patients with bipolar illness have higher mean intracellular and extracellular red blood cell to lithium ratios, as do their first-degree relatives ( 73). These findings have led to speculation about genetic control of the lithium ratio and its role in the pathogenesis, as well as pharmacotherapy, of mood disorders. 

Post and Kramlinger (386) have also suggested that lithium added to carbamazepine may be useful in treatment-resistant mood-disordered patients. One possible basis for this approach is that carbamazepine, which has a tricyclic ring structure similar to imipramine, may sensitize postsynaptic serotonin receptors in a similar way to standard drugs such as imipramine. A mood stabilizer (e.g., lithium, valproate, carbamazepine) plus antidepressant may benefit some rapid cycling or mixed bipolar patients, attenuating the propensity to switch from mania to depression. 

Braden et al. (95) did a similar study in primarily schizophrenic or schizoaffective patients, but the sample also included some affectively-ill cases (i.e., 21% met Feighner criteria for mood disorder). Of the 43 patients on lithium, 15 dropped out because they did not improve, worsened, or were unmanageable or confused. By comparison, only one of 35 treated with CPZ dropped out in the first 10 days. CPZ produced better results in the overactive group, whereas both drugs were comparable in the less active group. As with the VA study, the poor results with lithium in the overactive group may have been an artifact of insufficient duration due to the high dropout rate, or because of the inclusion of patients with a core schizophrenic illness. 

Although lithium has been a major advance in the pharmacotherapy of severe mood disorders, a number of problems limit its usefulness, including the following ... 

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