Manic depression, treatment

Lithium ion (Li+) Environmental GSK3P [normal GSK Ser phosphorylation inhibition by insulin-activated PKB bipolar mood disorder manic depression treatment]... 

Treatment of Manic—Depressive Illness. Siace the 1960s, lithium carbonate [10377-37-4] and other lithium salts have represented the standard treatment of mild-to-moderate manic-depressive disorders (175). It is effective ia about 60—80% of all acute manic episodes within one to three weeks of adrninistration. Lithium ions can reduce the frequency of manic or depressive episodes ia bipolar patients providing a mood-stabilising effect. Patients ate maintained on low, stabilising doses of lithium salts indefinitely as a prophylaxis. However, the therapeutic iadex is low, thus requiring monitoring of semm concentration. Adverse effects iaclude tremor, diarrhea, problems with eyes (adaptation to darkness), hypothyroidism, and cardiac problems (bradycardia—tachycardia syndrome). 

Other agents are also used for the treatment of manic-depressive disorders based on preliminary clinical results (177). The antiepileptic carbamazepine [298-46-4] has been reported in some clinical studies to be therapeutically beneficial in mild-to-moderate manic depression. Carbamazepine treatment is used especially in bipolar patients intolerant to lithium or nonresponders. A majority of Hthium-resistant, rapidly cycling manic-depressive patients were reported in one study to improve on carbamazepine (178). Carbamazepine blocks noradrenaline reuptake and inhibits noradrenaline exocytosis. The main adverse events are those found commonly with antiepileptics, ie, vigilance problems, nystagmus, ataxia, and anemia, in addition to nausea, diarrhea, or constipation. Carbamazepine can be used in combination with lithium. Several clinical studies report that the calcium channel blocker verapamil [52-53-9] registered for angina pectoris and supraventricular arrhythmias, may also be effective in the treatment of acute mania. Its use as a mood stabilizer may be unrelated to its calcium-blocking properties. Verapamil also decreases the activity of several neurotransmitters. Severe manic depression is often treated with antipsychotics or benzodiazepine anxiolytics. 

Perhaps one of the most exciting new applications stems from the discovery in 1949 that small daily doses (l-2g) of LI2C03 taken orally provide an effective treatment for manic-depressive psychoses. The mode of action is not well understood but there appear to be no undesirable side effects. The dosage maintains the level of Li in the blood at about I mmol l and its action may be related to the influence of Li on the Na/K balance and (or) the Mg/Ca balance since Li is related chemically to both pairs of elements. 

Lithium compounds are used in ceramics, lubricants, and medicine. Small daily doses of lithium carbonate are an effective treatment for bipolar (manic-depressive) disorder but scientists still do not fully understand why. Lithium soaps—the lithium salts of long-chain carboxylic acids—are used as thickeners in lubricating greases for high-temperature applications because they have higher melting points than more conventional sodium and potassium soaps. 

Turning to the pharmacotherapy for mania, for decades lithium was the only effective drug treatment. More recently, a number of antiepileptic drugs including carba maze pine, lamotrigine and valproate have been shown to also act as mood stabilisers and are becoming established for the treatment and prophylaxis of both unipolar mania and bipolar manic depressive disorders. 

The clinical value of lithium has been recognized since 1949. Lithium carbonate is used in manic depressive psychoses for the treatment of recurrent mood changes.261,262 Mood stability may only occur after months rather than weeks. The drug is administered orally in doses up to 2 g day-1 (30 mmol day-1). The serum Li concentration should be in the range of 0.4-0.8 mmol 1. ... 

Detection of Li+ in artificial serum with a voltammetric Li-selective electrode in a flowthrough system was demonstrated [64], Lithium salts such as lithium carbonate have been extensively used for treatment of manic depressive and hyperthyroidism disorders. The therapeutic range of Li concentration is generally accepted to be 0.5-1.5mM in blood serum. The authors used normal pulse voltammetry in which a stripping potential was applied between pulses in order to renew the membrane surface and expel all of the extracted ions from the membrane, similar to galvanostatically controlled potentiometric sensors described above. Unfortunately, the insufficient selectivity... 

We still need much better medicines to cure cancer, heart disease, stroke, and Alzheimer s disease. We need better drugs to deal with obesity, diabetes, arthritis, and schizophrenia. The treatments of diabetes, arthritis, and mental defects such as schizophrenia or manic depression are not yet cures, just ways to keep the symptoms under control. Cures are needed. Insights from genetics may help guide us toward elegant and rational cures, but we will also make use of screens to identify natural products and libraries of randomly generated synthetic compounds (combinatorial chemistry). A semi-empirical approach may be the best hope over the next two decades to yield drugs to alleviate these diseases. 

Manji, H. K. and Lenox, R. H. Ziskind-Somerfeld Research Award. Protein kinase C signaling in the brain molecular transduction of mood stabilization in the treatment of manic-depressive illness. Biol. Psych. 46 1328-1351,1999. 

Li+ has been reported to affect virtually every component of the endocrine system to some extent however any resulting clinical manifestations are very rare [169]. Although these influences do not appear to be related to its mechanism of action in manic-depression, some are involved in the side effects experienced by Li+-treated patients. Apart from elevated levels of thyroid stimulating hormone (TSH), Li+ does not appear to affect the basal levels of hormones significantly however some hormone responses are reported to be altered by Li+ treatment of bipolar patients [170]. Neuronal activity stimulates the adrenal medulla to release norepinephrine and epinephrine into the blood and, consequently, the plasma from people with mania and depression shows increased levels of both neurotransmitters [171]. 

The observed Li+-induced stimulation of corticotropin (ACTH) secretion from cells in culture, requiring extracellular Ca2+, involves a corresponding and apparently associated increase in the concentration of Ins(l)P, indicating some interaction with phosphoinositide metabolism [176], Pretreatment with Li+ desensitizes the cells, reducing this Li+-induced stimulation of ACTH secretion. Li+ initially raises plasma cortisol levels in manic-depressives however the levels are subsequently reduced with chronic Li+ treatment in both patients and controls [177]. This effect is probably secondary to the stimulation and subsequent desensitization of ACTH secretion by Li+, as observed in cultured cells. 

Inositol monophosphatase catalyzes the hydrolysis of inositol-1-phosphate, inositol-4-phosphate, and various nucleoside 2 -phosphates. The enzyme has attracted considerable interest in recent years because it is believed to be an important target for lithium therapy in treatment of manic-depression. Inositol monophosphatase inhibited in the presence... 

Data from Torrey EF, Knable MB. Surviving Manic Depression A Manual on Bipolar Disorder for Patients, Families and Providers. New York Basic Book, 2002 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed.. Text Revision. Washington, DC American Psychiatric Association, 2000 382-401 and American Psychiatric Association, Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry2002 159 1-50. 

Lithium, while not required for life, is used therapeutically in the form of lithium carbonate for the treatment of manic depression although its mechanism of action remains a mystery. Effective treatment requires attaining serum lithium concentrations of between 0.8 and 1.2 mmol/L. 

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. 

Lithium chloride (Li" + Cl —> LICl) is used as an antidepressant, especially in the treatment of manic depression and bipolar disorders. 

The term "bipolar disorder" originally referred to manic-depressive illnesses characterized by both manic and depressive episodes. In recent years, the concept of bipolar disorder has been broadened to include subtypes with similar clinical courses, phenomenology, family histories and treatment responses. These subtypes are thought to form a continuum of disorders that, while differing in severity, are related. Readers are referred to the Diagnostic and Statisticial Manual of Mental Disorders of the American Psychiatric Association (DSM-IV) for details of this classification. 

Of the various types of psychotropic drugs which have been used to treat mania, lithium salts are universally acclaimed to be the most important and effective treatment of mania and manic-depression. 

At the postsynaptic level, lithium has been shown to reduce the function of beta adrenoceptors, presumably by affecting the coupling between the receptor and the secondary messenger system. This effect only becomes apparent following chronic treatment, which may help to explain the delay of several days, or even weeks, before an optimal beneficial effect is observed. All antidepressants are known to reduce the functional activity of postsynaptic beta receptors, which may explain why lithium has both an antimanic and an antidepressant effect in patients with manic-depression. 

Despite the fact that the initial biochemical abnormalities responsible for depression and manic-depressive conditions have not been completely discovered, some facts suggest that depressive conditions may be caused by a lack of norepinephrine (noradrenaline) and serotonin. The majority of drugs used in treatment of such illnesses act by affecting the system of biogenic amines of the brain, thus leading to action of a mechanism that is capable of increasing their contents in respective parts of the brain. 

MAO inhibitors are used in treating severe endogenous, exogenous, and reactive depressions that do not react to treatment with tricyclic antidepressants, as well as for controlling depressive phases in manic-depressive psychoses. 

For the treatment of psychoneurotic patients with depression or anxiety depression or anxiety associated with alcoholism or organic disease psychotic depressive disorders with associated anxiety including involutional depression and manic-depressive disorders. 

MAPROTILINE HYDROCHLORIDE For the treatment of depressive illness in patients with depressive neurosis (dysthymic disorder) and manic-depressive illness, depressed type (major depressive disorder) also effective for the relief of anxiety associated with depression. 

Mania For the treatment of manic episodes of manic-depressive illness. Maintenance therapy prevents or diminishes the frequency and intensity of subsequent manic episodes in those manic-depressive patients with a history of mania. 

A considerable number of tricyclic antidepressants have been developed in the past, although with slight differences in their pharmacological activities, ah with similar efficacy. They are primarily indicated for the treatment of endogenous depression. However this does not exclude efficacy in patients in whom the depression is associated with organic disease or in patients with reactive depression or depression combined with anxiety. They may also benefit patients during the depressive phase of manic-depressive disorder. For some also efficacy has been claimed in panic states, phobic disorders, and in obsessive-compulsive disorders. 

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