Lithium is the paradigmatic mood stabilizer. It is effective in the acute and prophylactic treatment of both mania and, to a lesser magnitude, depression. These characteristics are generally paralleled by the widely accepted anticonvulsant mood stabilizers valproate, carbamazepine (Table 6.2.4.1), and potentially by the less well studied putative mood stabilizers oxcarbazepine, zonisamide, and the dihydropyridine L-type calcium channel blocker nimodipine. In contrast, lamotrigine has a profile of better antidepressant effects acutely and prophylactically than antimanic effects. Having grouped lithium, valproate, and carbamazepine together, it is important to note they have subtle differences in their therapeutic profiles and differential clinical predictors of response (Table 6.2.4.1). Response to one of these agents is not predictive of either a positive or negative response to the others. Thus, clinicians are left with only rough estimates and guesses about which drug may be preferentially effective in which patients. Only sequential clinical trials of agents either alone or in combination can verify responsivity in an individual patient. Individual response trumps FDA-approval. Given this clinical conundrum, it is advisable that patients, family members, clinicians, or others carefully rate patients on a longitudinal scale in order to most carefully assess responses and side effects. These are available from the Depression Bipolar Support Alliance (DBSA), the STEP-BD NIMH Network, or www.bipolarnetworknews.org and are highly recommended. The importance of careful longitudinal documentation of symptoms and side effects is highlighted by the increasing use of multiple drugs in combination. This is often required because patients may delay treatment-seeking until after many episodes, and very different patterns and frequencies of depressions, manias, mixed states, as well as multiple comorbidities may be present. Treating patients to the new accepted goal of remission of their mood and other anxillary symptoms usually requires use of several medications. If each component of the regimen is kept below an individual's side-effects threshold, judicious use of multiple agents can reduce rather than increase the overall side-effect burden. There is increasing evidence of reliable abnormalities of biochemistry, function, and anatomy in the brains of patients with bipolar disorder, and some of these are directly related to either duration of illness or number of episodes. Therefore, as treatment resistance to most therapeutic agents is related to number of prior episodes, and brain abnormalities may also increase as well, it behooves the patient to begin and sustain acute and long-term treatment as early as possible. Despite the above academic, personal, and public health recommendations, bipolar disorder often takes ten years or more to diagnose and, hence, treat properly. In fact, a younger age of onset is highly related to presence of a longer delay from illness onset to first treatment, and as well, to a poorer outcome assessed both retrospectively and prospectively. New data indicate that the brain growth factor BDNF (brain-derived neurotrophic factor) which is initially important to synaptogenesis and neural development, and later neuroplasticity and long-term memory in the adult is involved in all phases of bipolar disorder and its treatment. It appears to be: 1) both a genetic (the val-66-val allele of BDNF) and environmental (low BDNF from childhood adversity) risk factor; 2) episode-related (serum BDNF decreasing with each episode of depression or mania in proportion to symptom severity; 3) related to some substance abuse comorbidity (BDNF increases in the VTA with defeat stress and cocaine self-administration); and 4) related to treatment. Lithium, valproate, and carbamazepine increase BDNF and quetiapine and ziprasidone block the decreases in hippocampal BDNF that occur with stress (as do antidepressants). A greater number of prior episodes is related to increased likelihood of: 1) a rapid cycling course; 2) more severe depressive symptoms; 3) more disability; 4) more cognitive dysfunction; and 5) even the incidence of late life dementia. Taken together, the new data suggest a new view not only of bipolar disorder, but its treatment. Adequate effective treatment may not only (a) prevent affective episodes (with their accompanying risk of morbidity, dysfunction, and even death by suicide or the increased medical mortality associated with depression), but may also (b) reverse or prevent some of the biological abnormalities associated with the illness from progressing. Thus, patients should be given timely information pertinent to their stage of illness and recovery that emphasizes not only the risk of treatments, but also their potential, figuratively and literally, life-saving benefits. Long-term treatment and education and targeted psychotherapies are critical to a good outcome. We next highlight several attributes of each mood stabilizer, but recognize that the choice of each agent itself is based on inadequate information from the literature, and sequencing of treatments and their combinations is currently more an art than an evidence-based science. We look forward to these informational and clinical trial deficits being reduced in the near future and the development of single nucleotide polymorphism (SNP) and other neurobiological predictors of individual clinical response to individual drugs. In the meantime, patients and clinicians must struggle with treatment choice based on: 1) the most appropriate targetting of the predominant symptom picture with the most likely effective agent (Table 6.2.4.1 and 6.2.4.2) the best side-effects profile for that patient (Table 6.2.4.2 and 6.2.4.3) using combinations of drugs with different therapeutic targets and mechanisms of action (Table 6.2.4.3 and 6.2.4.4) careful consideration of potential advantageous pharmacodynamic interactions and disadvantageous pharmacokinetic drug-drug interactions that need to be avoided or anticipated.
General pharmacokinetic/pharmacodynamic concepts of mood stabilizers in the treatment of bipolar disorder
