Lithium abnormalities

Dorus E, Pandey GN, Shaughnessy R, et al. Lithium abnormality across red cell membrane a cell membrane abnormality in manic-depressive illness. Science 1979 205 932-934. 

The small lithium Li" and beryllium Be ions have high charge-radius ratios and consequently exert particularly strong attractions on other ions and on polar molecules. These attractions result in both high lattice and hydration energies and it is these high energies which account for many of the abnormal properties of the ionic compounds of lithium and beryllium. 

The abnormal properties of lithium and beryllium are summarised in Tables 6.5 and 6.6. 

It is known that 10B collects in brain tumors to a greater extent than in normal tissue. Research has been conducted on the use of the isotope 10B for treating brain tumors. Bombardment of the tumor with slow neutrons leads to the production of alpha particles (4He2+) and lithium nuclei that have enough energy to destroy the abnormal tissue. 

Abnormalities in the movement of Li+ across the erythrocyte membrane have been related to psychiatric disorders and also in response to lithium therapy itself. As yet there is relatively little definitive information about the Li+ transport mechanisms operating in therapeutically relevant cell types. 

Barak Y, Levine J, Behnaker RH Effects of inositol on lithium induced EEG abnormalities. Eur Neuropsychopharmacol 4 419-420, 1994 Barczak P, Edmunds E, Betts T Hypomania following complex partial seizures. Br J Psychiatry 152 137-139, 1988... 

Coppen A, Ghose K, Montgomery S, et al Continuation therapy with amitriptyline in depression. Br J Psychiatry 133 28-33, 1978 Coppen A, Swade C, Wood K Lithium restores abnormal platelet 5-HT transport in patients with affective disorders. Br J Psychiatry 136 235-238, 1980 Coppen A, Swade C, Jones SA, et al Depression and tetrahydrobiopterin the folate connection. J Affect Disord 16 103-107, 1989 Cordell B 3-Amyloid formation as a potential therapeutic target for Alzheimer s disease. Annu Rev Pharmacol Toxicol 34 69-89, 1994 Corkin S Acetylcholine, aging, and Alzheimer s disease imphcations of treatment. Trends Neurosci 4 287-290, 1981... 

Dubovsky SL, Lee C, Christiano J, et al Elevated platelet intracellular calcium concentration in bipolar depression. Biol Psychiatry 29 441-450, 1991a Dubovsky SL, Lee C, Christiano J, et al Lithium lowers platelet intracellular ion concentration in bipolar patients. Lithium 2 167-174, 1991b Dubovsky SL, Murphy J, Thomas M, et al Abnormal intracellular calcium ion concentration in platelets and lymphocytes of bipolar patients. Am J Psychiatry 149 118-120, 1992a... 

General Comments. The formation of deoxy sugars by hydrogenation over Raney nickel often leads to the abnormal isomer (namely, that formed by diequatorial opening of the oxirane ring) as the major product, in contrast to the product afforded by lithium aluminum hydride this suggests that a different mechanism is involved in the nickel-catalyzed reaction. 

The clinical implications of such data point to a relationship between abnormalities in the central serotonin system and self-injurious behavior. These findings have led to an interest in developing specific drugs that alter 5-HT activity to treat suicidality, impulsivity, and aggressivity independent of any specific psychiatric disorder. Central serotonin function can be enhanced by agents such as lithium and various serotonin reuptake inhibitors. Recent studies have found that the use of such agents is associated with reductions in the likelihood of suicide attempts and completions in both patients with major depression and those with cluster... 

The possible differing mechanisms of action of three mood stabilizers (i.e., lithium, valproate, carbamazepine) are incorporated into a bidimensional model of mood regulation that postulates two gating zones (one for depression and one for mania). These zones are thought to be subserved by different neurochemical abnormalities, leading to a situation in which both could be impacted by certain agents (i.e., mood stabilizers) or, alternatively, could individually be affected by unidirectional compounds (e.g., HCAs). 

At one time, sustained-release preparations were thought to reduce renal toxicity, but more recent evidence has cast doubt on this assumption ( 313). A patient on long-term maintenance lithium should have renal function monitored periodically (i.e., every 12 months) with a urinalysis, BUN, and creatinine. If abnormal, a more intensive evaluation should include 24-hour urine osmolality and creatinine clearance. It is advisable to reduce maintenance lithium to optimal minimal dose-blood levels and, if possible, to avoid concomitant antipsychotics, which may enhance toxicity. Some data support the use of a once-a-day dose schedule to minimize peak lithium concentrations over a 24-hour period (314). 

The appearance of laboratory abnormalities does not require cessation of treatment however, if enzyme levels do not stabilize or return to normal, VPA should be discontinued and an alternate mood-stabilizing agent such as lithium used in its place. Liver function tests should be monitored more often during the first several weeks of therapy and every 6 to 12 months afterward. Routine liver function testing probably does not significantly prevent the occurrence of these unpredictable drug effects. Therefore, patients should be cautioned to immediately report symptoms of possible early hepatotoxicity such as easy bruising, decreased appetite, malaise, jaundice, and periorbital or dependent edema. In summary ... 

Halman et al. (491) conducted a retrospective chart review on 11 patients who were HIV-positive and presented with an acute manic episode. Whereas the six patients with abnormal MRI findings demonstrated intolerance to standard drug treatment (i.e., lithium, conventional neuroleptics), all benefited from a trial with an anticonvulsant (e.g., valproate, CBZ, clonazepam). 

Antidiuretic hormone antagonists are used to manage SIADH when water restriction has failed to correct the abnormality. This generally occurs in the outpatient setting, where water restriction cannot be enforced, or in the hospital when large quantities of intravenous fluid are needed for other purposes. Lithium carbonate has been used to treat this syndrome, but the response is unpredictable. Demeclocycline, in dosages of 600-1200 mg/d, yields a more predictable result and is less toxic. Appropriate plasma levels (2 mcg/mL) should be maintained by monitoring. Unlike demeclocycline, conivaptan is administered by IV injection, so it is not suitable for chronic use in outpatients. Lixivaptan and tolvaptan should soon be available for oral use. 

Tremor is one of the most common adverse effects of lithium treatment, and it occurs with therapeutic doses. Propranolol and atenolol, which have been reported to be effective in essential tremor, also alleviate lithium-induced tremor. Other reported neurologic abnormalities include choreoathetosis, motor hyperactivity, ataxia, dysarthria, and aphasia. Psychiatric disturbances at toxic concentrations are generally marked by mental confusion and... 

Carbamazepine. The anticonvulsant carbamazepine was actually the first to be shown to be effective in the manic phase of bipolar disorder, but it has not been approved for this use by regulatory authorities such as the U.S. Food and Drug Administration (FDA). Its mechanism of action may be to enhance GABA function, perhaps in part by actions on sodium and/or potassium channels (Fig. 7—24). Because its efficacy is less well documented and its side effects can include sedation and hematological abnormalities, it is not as well accepted for first-line use in the treatment of mood disorders as either lithium or valproic acid. 

They observed that, when a solution of lithium in tritiated ammonia was mixed with a solution of ammonium bromide in ordinary ammonia, the evolved hydrogen contained much less tritium than when a solution of lithium in ordinary ammonia was mixed with a solution of ammonium bromide in tritiated ammonia. These results were taken as evidence that the NH4+ + e reaction is an order of magnitude faster than the NH4 + + NH3 reaction. However when one considers that electrons in ammonia have an abnormally high mobility, and that they probably migrate without carrying ammonia molecules with them (11, 23), this interpretation seems doubtful. It is possible that the electrons diffused into the ammonium bromide solutions much more rapidly than the ammonium ions diffused into the lithium solutions, and that consequently the evolved hydrogen was always characteristic of the ammonium bromide solutions. Thus these experiments yield little information about the relative rates of the NH4+ + e reaction and NH4+ + NH3 reaction. 

---