Bipolar Disorders: Mixed States, Rapid-Cycling, and Atypical Forms

336 J. Cookson and S. Ghalib19 acutely manic patients, the 12 who responded to carbamazepine had higherscores of severity of mania and tended to be more dysphoric (Post et al., 1987).Antipsychotics in maniaThe response to antipsychotic medication in mania has recently been subject tocareful investigation in clinical trials of atypical antipsychotics, particularly olanzapineand risperidone. These studies are reviewed in detail in Chapter 16. Two studiesincluded, as a comparator, the classical antipsychotic haloperidol which is themost widely used antipsychotic for mania (see Cookson, 2001). All three drugs(haloperidol, olanzapine, and risperidone) tended to produce as great an improvementin mania ratings in the more severe and psychotic groups of patients as in lesssevere non-psychotic patients (in keeping with model 2).Cortisol levels during response to antipsychoticsElevated serum cortisol levels are found in mania. This elevation is correlatedsignificantly with the severity of mania (Cookson et al., 1985a), but is particularlyhigh in mixed states (Swann et al., 1992). Evans and Nemeroff (1983) found thatmixed manics showed more resistance of plasma cortisol to suppression bydexamethasone than pure manics, although Swann et al. (1992) found cortisolnon-suppression in both pure and mixed mania. Krishnan et al. (1983) foundnon-suppression in all of 10 consecutive patients with mixed states.During treatment with pimozide, cortisol levels gradually return towards normal,with a time course similar to that of clinical improvement (Cookson, 1985).By contrast, during treatment with haloperidol, there appears to be a dissociationbetween an early normalization of cortisol levels within 3 days and a more gradualclinical improvement during 2 weeks of treatment (Cookson et al., 1985b). Thisapparent difference between haloperidol and pimozide might be related to thedifferent pharmacology of the two drugs. Both drugs block dopamine receptors,but haloperidol in addition blocks norepinephrine alpha 1 -receptors in humans(Szabadi et al., 1981). Alpha 1 -receptors are known to be involved in the control ofcortisol secretion (Rees et al., 1970). Alpha 1 -receptor blockade is thought tocontribute to the sedative effects of antipsychotics (Peroutka and Snyder, 1980).It may account for the early transient sedative effects seen in mania with haloperidol(Cookson et al., 1983). Levels of norepinephrine in the CSF are raised in mania (Postet al., 1978), and particularly in mixed mania (Swann et al., 1987, 1994), andcorrelated with levels of dysphoria, anger, and anxiety in dysphoric mania (Postet al., 1989). Blockade of norepinephrine receptors by haloperidol may be part of themechanism of the drug’s antimanic effect, and may be particularly important indysphoric mania. Certain atypical antipsychotics such as olanzapine and risperidone