Lithium treatment

Dorus W, Ostrow DG, Anton R, et al Lithium treatment of depressed and nondepressed alcoholics. JAMA 262 1646—1632, 1989... 

Crucial factors affecting overall cost are the responsiveness to medication (for example, less than 70% of patients are lithium responders ), adherence to recommended treatment, and adverse events resulting from medication. A particular hazard of lithium treatment is the risk of rapid re-emergence of mania, which occurs in up to 50% of patients if the dmg is abruptly discontinued (see Cookson, 1997). Disappointingly, it has not been found that the introduction of widespread treatment with lithium has been associated with a reduction in the number of patients admitted and discharged from hospital with a diagnosis of mania. In order to achieve the best result with the available... 

In view of bcl-2 s major neuroprotective and neurotrophic roles, a study was undertaken to determine if lithium, administered at therapeutically relevant concentrations, affects neurogenesis in the adult rodent brain. To investigate the effects of chronic lithium on neurogenesis, mice were treated with therapeutic lithium (plasma levels 0.97 0.20 mM), for 4 weeks. After treatment with lithium for 14 days, the mice were administered single doses of BrdU (bromodeoxyuridine, a thymidine analog which is incorporated into the DNA of dividing cells) for 12 consecutive days. Lithium treatment continued throughout the duration of the... 

Fig. 20.3 Chronic lithium increases hippocampal neurogenesis. C57BL/6 mice were treated with lithium for 14 days, and then received once daily BrdU injections for 12 consecutive days while lithium treatment continued. 24 hours after the last injection, the brains were processed for BrdU immunohistochemistry.

Chen RW, Chuang DM. Long term lithium treatment suppresses p53 and Bax expression but increases bcl-2 expression. J Biol Chem 1999 274 6039-6042. 

Nonaka S, Chuang DM. Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N -methyl-D-aspartate receptor-mediated calcium influx. Proc Natl Acad Sci USA 1998 95 2642-2647. 

A 36-year-old male with a bipolar disorder is treated with lithium. Among the following adverse effects, which is associated with lithium treatment ... 

The answer is c. (Katzung, p 493.) Lithium treatment frequently causes polyuria and polydipsia. The collecting tubule of the kidney loses the capacity to conserve water via anti diuretic hormone. This results in significant free-water clearance, which is referred to as nephrogenic diabetes insipidus. 

Antidepressant treatment has, in recent studies, been shown to upregulate the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) cascade and expression of BDNF [59]. This upregulation of CREB and BDNF raises the possibility that antidepressant treatment could oppose the cell death pathway, possibly via increased expression of the oncogene Bcl-2. Studies are necessary to determine if antidepressant treatment increases Bcl-2 expression. Increased expression of Bcl-2 in brain and cultured cells, and inhibition of apoptosis of cultured cerebellar granule neurons have been reported with lithium treatment [57]. Mice lacking the BDNF TrkB receptor fail to show behavioral and neurogenic responses to antidepressants. 

To date, there have only been a limited number of studies directly examining PKC in bipolar disorders [77], Although undoubtedly an oversimplification, particulate (membrane) PKC is sometimes viewed as the more active form of PKC, and thus an examination of the subcellular partitioning of this enzyme can be used as an index of the degree of activation. Friedman etal. [78] investigated PKC activity and PKC translocation in response to serotonin in platelets obtained from bipolar-disorder patients before and during lithium treatment. They reported that the ratios of platelet-membrane-bound to cytosolic PKC activities were elevated in the manic patients. In addition, serotonin-elicited platelet PKC translocation was found to be enhanced in those patients. With respect to brain tissue, Wang and Friedman [74] measured PKC isozyme levels, activity and translocation in postmortem brain tissue from patients with bipolar disorder, and reported increased PKC activity and translocation in the brains of bipolar patients compared with controls, effects which were accompanied by elevated levels of selected PKC isozymes in cortices of bipolar disorder patients. 

In a study of psychiatric patients after 1 week of lithium treatment, the serum Li+ level was typically 1 mM, whereas in brain and muscle the levels were 0.4 and 0.5 mM, respectively. Within the brain itself, the distribution of Li+ appears to be uneven however no particular region appears to accumulate Li+ to any significant extent [47]. It has been... 

The next higher homologs of 28-30 have all been prepared without difficulty as shown in Scheme 5.37. Single and double addition of dibromocarbene to 1,5-hexa-diene (biallyl) (240) leads to the adducts 241 and 242, respectively, which on methyl-lithium treatment are debrominated/rearranged to 32 and 34 in the usual way [43, 96, 97]. 

Thyroid Hormone (Thyroxine, Synthroid). The most common use of thyroxine in bipolar patients is the treatment of lithium-induced hypothyroidism. Approximately 5% of patients receiving long-term lithium treatment ultimately develop hypothyroidism. When this occurs, the patient with bipolar disorder may present with symptoms of a depressive episode. Therefore, periodic thyroid axis monitoring, that is, a serum thyroid stimulating hormone (TSH) test, is required for all patients taking lithium and should always be performed when the bipolar patient experiences a depressive episode. 

Goodwin FK, Goldstein MA. Optimizing lithium treatment in bipolar disorder a review of the literature and clinical recommendations. J Psychiatr Pract 2003 9(5) 333-343. 

Many of the adverse effects of lithium can be ascribed to the action of lithium on adenylate cyclase, the key enz)nne that links many hormones and neurotransmitters with their intracellular actions. Thus antidiuretic hormone and thyroid-stimulating-hormone-sensitive adenylate cyclases are inhibited by therapeutic concentrations of the drug, which frequently leads to enhanced diuresis, h)rpoth)n oidism and even goitre. Aldosterone synthesis is increased following chronic lithium treatment and is probably a secondary consequence of the enhanced diuresis caused by the inhibition of antidiuretic-hormone-sensitive adenylate cyclase in the kidney. There is also evidence that chronic lithium treatment causes an increase in serum parathyroid hormone levels and, with this, a rise in calcium and magnesium concentrations. A decrease in plasma phosphate and in bone mineralization can also be attributed to the effects of the drug on parathyroid activity. Whether these changes are of any clinical consequence is unclear. 

Prolactin secretion, at least in experimental animals, is increased following chronic lithium treatment, probably as a consequence of the enhanced sensitivity of posts)maptic 5-HT receptors and the decreased sensitivity of dopamine receptors. In patients on therapeutic doses of the drug, however, the plasma prolactin levels would not appear to be markedly altered. There is little evidence that circulating gonadotrophin concentrations are affected by therapeutic doses of lithium. 

Preclinical studies examining the mechanism of action of mood stabilizers has extended research attention in the neurobiology of BD from a focus on biogenic amines to include study of the second messenger systems. These studies have found that chronic lithium treatment at therapeutic levels in adult rats alters ac-... 

Hagino, O.R., Weller, E.B., Weller, R.A., Washing, D., Fristad, M.A., and Kontras, S.B. Untoward effects of lithium treatment in children aged four through six years. / Am Acad Child Adolesc Psychiatry 34 1584-1590. 

Rifkin, A., Karajgi, B., Dicker, R., Perl, E., Boppana, V., Hasan, N., and Pollack, S. (1997) Lithium treatment of conduct disorders in adolescents. Am Psychiatry 154 554-555. 

A thorough discussion of this topic is beyond the scope of this chapter. However, a recent review of controlled studies of mood stabilizers (Keck et al, 2000) provides a reasonable summary. Pooling response data from five studies (from 1954 to 1994) and 124 acute manic patients revealed that 70% of the patients had at least partial improvement with lithium treatment. Response took 2-3 weeks, was superior to antipsychotics in ameliorating affective symptoms, produced an improvement in psychosis, but was less effective in treating psychomotor agitation. DSM-III and earlier criteria were used to diagnose the patients in these trials, so these samples may not be comparable to patients in more modern studies. Table 37.2 summarizes a compilation of clinical... 

Although adolescents who discontinue maintenance treatment have a high (92%) rate of relapse compared to those who maintain lithium treatment (37%) (Strober et al., 1990), reliable continuation of medication is a serious problem in bipolar adolescents, particularly those with comorbid behavior disorders (Carlson et al., 2000a). 

Delong, G.R., and Aldershof, A.L. (1987) Long-term experience with lithium treatment in childhood correlation with clinical diagnosis. Am Acad Child Adolesc Psychiatry 26 389-394. 

Are childhood psychiatric histories of bipolar adolescents associated with family history, psychosis, and response to lithium treatment / Affect Disord 51 153-164. 

Aman s (1993) review of lithium treatment for self-injury revealed that the drug has only inconsistently been shown to suppress such behaviors. The available case reports have been far more positive than the placebo controlled research. Kastner et al. s (1993) positive but uncontrolled study of lithium in adolescents and adults practicing aggression and self-injury was described earlier (see Conduct Disorder, above). Finally, single-subject studies of carbamazepine have yielded mixed results (Aman, 1993). 

Rivinus, T.M. and Harmatz, J.S. (1979) Diagnosis and lithium treatment of affective disorders in the retarded five case studies. Am Psychiatry 136 551-544. 

Baldessarini, R.J., Tondo, L., Floris, G., and Rudas, N. (1997) Reduced morbidity aftet gtadual discontinuation of lithium treatment for bipolar I and II disorders a replication study. Am J Psychiatry 154 551—553. 

Suppes, T., Baldessarini, R.J., Faedda, G.L., and Tohen, M. (1991) Risk of recurrence following discontinuation of lithium treatment in bipolar disorder. Arch Gen Psychiatry 48 1082—1088. 

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