Bipolar disorder patients

Divalproex sodium is comprised of sodium valproate and valproic acid. The delayed-release and extended-release formulations are converted in the small intestine into valproic add, which is the systemically absorbed form. It was developed as an antiepileptic drug, but also has efficacy for mood stabilization and migraine headaches. It is FDA-approved for the treatment of the manic phase of bipolar disorder. It is generally equal in efficacy to lithium and some other drugs for bipolar mania. It has particular utility in bipolar disorder patients with rapid cycling, mixed mood features, and substance abuse comorbidity. Although not FDA-approved for relapse prevention, studies support this use, and it is widely prescribed for maintenance therapy. Divalproex can be used as monotherapy or in combination with lithium or an antipsychotic drug.31... 

Treatment of depressive episodes in bipolar disorder patients presents a particular challenge because of the risk of a pharmacologic mood switch to mania, although there is not complete agreement about such risk. Treatment guidelines suggest lithium or lamotrigine as first-line therapy.17,41 Olanzapine has also demonstrated efficacy in treatment of bipolar depression, and quetiapine is under review for approval of treatment of bipolar depression.42 When these fail, efficacy data support use of antidepressants. 

Bipolar disorder patients have shown abnormalities of the hypothalamic-pituitary-thyroid axis, demonstrated by an exaggerated TSH response to TRH and elevated basal... 

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. 

However, a few caveats to these positive studies should be noted. There is considerable evidence that a variety of circulatory factors may influence the activity of blood cells and elements, and bipolar disorder patients are known to have numerous neurohormonal abnormalities... 

Lochhead,R. A., Oquendo, M. A, Mann, J. J. and Parsey,R.V. Regional brain gray matter volume differences in bipolar disorder patients as assessed by optimized voxel-based morphometry. Biol. Psych. 55 1154-1162, 2004. 

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. 

Psychosis or mania Antidepressants can precipitate manic episodes in bipolar disorder patients during the depressed phase of their illness and may activate latent psychosis in other susceptible individuals. The sustained-release formulation of bupropion is expected to pose similar risks. There were no reports of activation of psychosis or mania in clinical trials conducted in nondepressed smokers. 

The HPA axis has been hypothesised to be of aetiological importance in depressive illnesses (McAllister-Williams Young, 1998 McAllister-Williams et al., 1998). Severely depressed patients (Sachar et al., 1973) and bipolar disorder patients (Linkowski et al., 1985) have signihcantly raised cortisol concentrations compared to controls. Imaging studies show an enlargement of the adrenal cortex in depressed patients compared to healthy subjects (Nemeroff... 

Klein E, Bental E, Lerer B, et al Carbamazepine and halopeiidol vs. placebo and haloperidol in excited psychoses. Arch Gen Psychiatry 41 165-170, 1984a Klein E, Hefez A, Lavie P Effects of clomipramine infusion on sleep in depressed patients. Neuropsychobiology 1 85-88, 1984b Klein E, Lavie P, Meiraz R, et al Increased motor activity and recurrent manic episodes risk factors that predict rapid relapse in remitted bipolar disorder patients after lithium discontinuation—a double blind study. Biol Psychiatry 31 279-284, 1992... 

Tondo, L., Baldessarini, R. J., Hennen, J., Floris, G., Silvetti, E, Tohen, M. 1998, Lithium treatment and risk of suicidal behavior in bipolar disorder patients, J.Clin.Psychiatry, vol. 59, no. 8, pp. 405-414. 

Soares JC, Boada F, Spencer S, Mallinger AG, Dippold CS, Wells KF, Frank E, Keshavan MS, Gershon S, Kupfer DJ. Brain hthium concentrations in bipolar disorder patients preliminary (7)Li magnetic resonance studies at 3 T Biol Psychiatry 2001 49(5) 437M3. 

Weisler RH, Kalali AH, KetterTA. A multicenter, randomized, double-blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes. J Clin Psychiatry 2004 65 478-84. 

Antipsychotic drugs commonly have been used empirically to manage manic and psychotic illness in bipolar disorder patients. Indeed, standard neuroleptics are a mainstay of the treatment of acute mania (only chlorpromazine is FDA-approved for this indication, although haloperidol has also been widely used) and for manic episodes that break through prophylactic treatment with LF or an anticonvulsant. However, the older antipsychotics are not used routinely for long-term prophylactic treatment in bipolar disorder because their effectiveness is untested, some may worsen depression, and the risk of tardive dyskinesia in these syndromes may be higher than in schizophrenia. 

The monoamine hypothesis of depression was proposed in 1965 to describe the biochemical basis of depression. Basically, it proposes that depression is caused by a depletion of monoamines (e.g. noradrenaline and/or serotonin) from the synapses. This reduces synaptic activity in the brain causing depression. Conversely, it suggests that mania is caused by an excess of monoamines in synapses, with excessive synaptic activity in the brain resulting in excessive euphoria. In bipolar disorder, patients have mood changes that cycle between depression and mania (Fig. 49.2). 

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