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Lithium carbonate remains the mainstay of treatment in bipolar disorder, although sodium valproate is equally effective in acute mania. Carbamazepine is also efficacious. The response rate to lithium carbonate is 70 to 80 percent in acute mania, with beneficial effects appearing in 1 to 2 weeks. A prophylactic effect in prevention of recurrent mania, and, to a lesser extent, in the prevention of recurrent depression is documented. A simple cation, lithium is rapidly absorbed from the gastrointestinal tract and remains unbound to plasma or tissue proteins. Ninety-five percent of a given dose is excreted unchanged through the kidneys within 24 h.

Serious side effects from lithium administration are rare, but minor complaints such as gastrointestinal discomfort, nausea, diarrhea, polyuria, weight gain, skin eruptions, alopecia, and edema are common. Over time, urine concentrating ability may be decreased, but changes in function do not result in significant nephrotoxicity. In a small subset of patients in whom excessive polyuria occurs (>3000 mL per 24 h), dose or schedule adjustments or the adjunctive use of diuretics should be considered. Lithium exerts an antithyroid effect by interfering with the synthesis and release of thyroid hormones. Approximately 5 percent of patients taking lithium for 18 months or longer develop hypothyroidism, with women more likely to be affected than men. Iatrogenic hypothyroidism should be ruled out in any patient who experiences recurrence of depressive symptomatology during lithium treatment. More serious side effects include tremor, interference with concentration and memory, ataxia, dysarthria, and incoordination. Electrocardiographic (ECG) changes of T wave flattening and conduction delays may occur. There is suggestive but not conclusive, evidence that lithium is teratogenic, inducing cardiac malformations in the first trimester.

In the treatment of acute mania, lithium is initiated at 300 mg bid or tid, and the dose is then increased by 300 mg every 2 to 3 days to achieve blood levels of 0.8 to 1.2 mEq/L. Because the therapeutic effect of lithium may not appear until 7 to 10 days of treatment, adjunctive usage of lorazepam (1 to 2 mg every 4 h) or clonazepam (0.5 to 1 mg every 4 h), may be beneficial to control agitation. Antipsychotics are warranted in patients with severe agitation and who respond only partially to benzodiazepines. These agents should be discontinued in the transition to maintenance lithium therapy. Patients using lithium should be monitored closely, since the blood levels required to achieve a therapeutic benefit are close to those associated with neurotoxicity. Risk factors for neurotoxicity include concomitant medical illness, decrease in salt intake, or concurrent use of medications that may increase the serum level of lithium (neuroleptics, diuretics, and calcium channel blockers).

Valproic acid is an alternative in patients who cannot tolerate lithium or respond poorly to it. Valproic acid may be better than lithium for patients who have a rapid-cycling course (i.e., more than four episodes a year) or who present with a mixed or dysphoric mania. Valproic acid is usually started at 500 to 750 mg/d bid or tid. The dose is increased every several days to achieve blood levels in the range of 50 to 100 ug/mL, which typically are achieved at a dose of 1000 to 2500 mg/d. The most serious adverse effect of valproic acid is hepatoxicity, which may be fatal. Such cases are fortunately rare, but regular monitoring of liver enzymes, particularly during the first 90 days of treatment and periodically thereafter, is indicated.
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Carbamazepine, although not formally approved by the Food and Drug Administration (FDA) for bipolar disorder, has clinical efficacy in the treatment of acute mania. Carbamazepine is initiated at 400 to 600 mg/d in divided doses, and the dose is increased to achieve a blood level of 4 to 12 mg/L. Carbamazepine may induce a benign leukopenia, but the risk of aplastic anemia is minimal. Nevertheless, it is wise to obtain a complete blood count (CBC) periodically.

The recurrent nature of bipolar mood disorder necessitates maintenance treatment. Maintenance of at least 0.8 mg/L blood lithium levels is important to achieve optimal prophylaxis. Antidepressant medications are sometimes required for the treatment of severe breakthrough depressions, but their use should generally be avoided during maintenance treatment because of the possible risk of precipitating mania or accelerating the cycle frequency. Loss of efficacy over time may be observed with any of the mood-stabilizing agents. In such situations, an alternative agent or combination therapy usually restores the therapeutic benefit.

Differential Diagnosis The differential diagnosis of mania includes ruling out activation by stimulant and sympathomimetic compounds as well as secondary mania induced by hyperthyroidism, AIDS, or neurologic disorders, such as Huntington’s or Wilson’s disease, or cerebrovascular accidents. This distinction may be difficult to make, because comorbidity with alcohol and substance abuse is common, either because of poor judgment and increased impulsivity or because of an attempt at self-medication.

Etiology And Pathophysiology Evidence for a genetic predisposition to bipolar disorder is significant. The concordance rate for monozygotic twin pairs approaches 80 percent, and segregation analyses are consistent with autosomal dominant transmission. Several chromosomal locations for the gene have been proposed in the last decade on the basis of linkage analysis in affected families. None has yet received independent confirmation. Two independent groups reported the results of complete genome scans. One reported weak evidence for linkage to loci on chromosomes 6, 13, and 15, while the other found a major gene locus and haplotype on 18q22-23 in two large Costa Rican pedigrees.
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The pathophysiologic mechanisms underlying the profound and recurrent mood swings of bipolar disorder remain unknown. Cellular models of changes in membrane Na+ and K+ activated ATPase and proposals of disordered signal transduction mechanisms involving either the phosphoinositol system or guanine nucleotide binding proteins have received the most attention. Lithium reduces the supply of free inositol used to maintain the lipid precursors involved in intracellular signaling and blocks stimulation-induced increases in GTP binding capacity. Reduction of GTP and downstream effects on protein kinase C are being investigated as possible explanations for the therapeutic effects of the drug.

Neurophysiologic studies suggest that bipolar patients have altered circadian rhythmicity. A possible phase advance induced by desynchronization among controlling circadian oscillators is consistent with a finding that lithium increases period length and may exert its therapeutic benefit through a resynchronization of intrinsic rhythms keyed to the light/dark cycle. Neuroimaging techniques have also identified a higher rate of subcortical white matter abnormalities in bipolar patients than in age matched controls.

Bipolar disorder affects approximately 3 million persons in the United States. It is characterized by unpredictable swings in mood from mania (or hypomania) to depression. Some patients suffer only from recurrent attacks of mania, which in its pure form is associated with increased psychomotor activity, excessive social extroversion, decreased need for sleep, impulsivity and impairment in judgment, and expansive, grandiose, and sometimes irritable mood. In severe mania, patients may experience delusions and paranoid thinking indistinguishable from that associated with schizophrenia. About half of all patients with bipolar disorder present with a mixture of psychomotor agitation and activation with dysphoria, anxiety, and irritability. It may be difficult to distinguish mixed mania from agitated depression. In some bipolar patients (bipolar II disorder), the full criteria for mania are lacking, and recurrent depressions are separated by periods of mild activation and increased energy (hypomania). In cyclothymic disorder, there are numerous hypomanic periods, usually of relatively short duration, alternating with clusters of depressive symptoms that fail to meet the criteria of major depression, either in severity or duration. The mood fluctuations are chronic and should be present for at least 2 years before the diagnosis is made.
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Manic episodes typically emerge over a period of days to weeks, but onset within hours is possible, usually in the early morning hours. An untreated episode of either depression or mania can last as short as several weeks or as long as 8 to 12 months, and rare patients have an unremitting chronic course. The term “rapid cycling” is used for patients who have four or more episodes of either depression or mania in a given year. This pattern occurs in 15 percent of all patients, almost all of whom are women. In some cases, rapid cycling is linked to an underlying thyroid dysfunction and, in others, iatrogenically triggered by prolonged antidepressant treatment.

Although bipolar illness is associated with frequent episodic recurrence, it was once thought to have a favorable prognosis and outcome. More recent data, however, show that approximately half of patients with the disorder have sustained difficulties in work performance and psychosocial functioning. The most frequent age of onset for bipolar disorder is between 20 and 30 years of age, but many individuals report premorbid symptoms in late childhood or early adolescence. The prevalence is similar for men and women, but there are gender differences in course, with women likely to have more depressive and men more manic episodes over a lifetime.