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together with other controlled evidence (Calabrese et al., 1999), this may suggest that
its main benefit comes from treating and preventing depressive symptoms.
A recent review (Grunze et al., 2002b) also highlighted effects of mood stabi-
lizers on potassium channels. Unfortunately, aberrations of potassium currents or
genes coding for potassium channels have not been explored so far with a special
focus on mixed states and rapid cycling. But again, as valproate as well as
lamotrigine and carbamazepine seems to act on potassium channels (which is
not described for lithium), a key function of potassium channels in atypical
manifestations of bipolar disorder can be hypothesized. Nevertheless, proof for
this is still needed in both basic and clinical research.


Other mechanisms of mood stabilizers possibly related to rapid cycling
and mixed states
The effects of antiepileptic drugs that are efficacious in mixed states and rapid
cycling also include a variety of intracellular action targeting the protein kinase
activity, the inositol phosphate metabolism, and finally the expression of early
genes and cytoprotective proteins. These issues have also been reviewed exten-
sively in a recent publication of the authors (Grunze et al., 2002b). More than
any transient effects on the cell surface, they may supply a key to remission and
successful long-term prophylactic treatment with mood stabilizers in bipolar
disorder. Data for valproate and lithium showing these effects are available, but
are not yet available for the newer anticonvulsants or atypical antipsychotics.
However, these data originate from the lab bench and are not reproduced even
in animal models, not to mention rapid-cycling or mixed patients. Thus, relating
any of these interesting activities of the drug to mixed states and rapid cycling is
purely speculative. Additionally, as far as we know, lithium is at least as effective
as valproate on this intracellular level. Thus, we may not find any specificity
for influencing a rapid-cycling course or mixed state on this level.
Again speculative, but only little attention has so far been given to the effect of
changes of the intracellular proton equilibrium (pH) in bipolar patients. Already
very moderate changes in intracellular pH have a strong effect on both receptor
sensitivity and second messenger systems. Even small fluctuations may have a
strong impact on the expression of mood. Thus, looking for an easy trigger of rapid
cycling and mixed states, changes in intracellular pH may qualify. As a matter of
fact, a decrease in intracellular pH in the frontal lobe has been described in drug-
free bipolar patients (Kato et al., 1998), suggesting aberrations of the proton
equilibrium in bipolar disorder. Controlled studies with magnetic resonance
spectroscopy in mixed and rapid-cycling patients and correlation with mood
states are therefore, in our opinion, urgently required.
319 Rapid cycling and mixed states



Conclusions
There is a very obvious gap between our knowledge of biological courses of rapid
cycling and mixed states and their clinical frequency and importance. There are
some hints which imply a role of the noradrenergic system and a pronounced
disturbance of the LHPA axis in well-characterized 48-h rapid-cycling patients
where an underlying biological explanation appears very likely. However, general-
ization to rapid cycling and mixed states at large cannot be made with a reasonable
level of confidence. As far as transmembranous ion fluxes and changes in intra-
cellular metabolism are concerned, we can only extrapolate from the action of
mood stabilizers, mainly antiepileptic drugs, which are useful in treating these
clinical conditions. Thus, this field is still very open for new and innovative
research which is urgently needed for a better understanding of these manifes-
tations of bipolar disorder and for developing better drugs to treat these often
highly refractory patients.




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15


The treatment of bipolar mixed states
John Cookson and Saad Ghalib
Royal London Hospital, London, UK




Mixed states pose particular problems in their classification, diagnosis, and
treatment, because they may be conceptualized as arising in a variety of ways
(Table 15.1).


Mixture of elements (mood, activity, thinking)
Mixed states may represent a mixture of different elements of depressed and manic
conditions. For Kraepelin, the core pathology of clinical depression was expressed
in separate areas of functioning: lowering of mood, and slowed or retarded mental
and physical activity. The opposite applied in mania: euphoria, flight of ideas, and
hyperactivity. Kraepelin (1913) recognized six mixed states, the most common
being depressive or anxious mania, excited depression, and depression with flight
of ideas. Others were manic stupor, mania with poverty of thought, and inhibited
mania (without flight of ideas). Other combinations were theoretically possible
but rarely recognized in practice. Kraepelin distinguished ˜˜autonomous™™ mixed
episodes from those occurring during transitions from one mood phase to another
(see transition state during a cycle, below) and thought them to be ˜˜the most

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