Atypical antipsychotics as mood stabilizers: not just for psychotic

mania
When atypical antipsychotics were approved for schizophrenia, it was not surprising
that these agents would work for psychotic symptoms associated with mania, since the D2
antagonist actions predict efficacy for psychosis in general (discussed in Chapter 5).
However, it was somewhat surprising when these agents proved effective for the core
nonpsychotic symptoms of mania and for maintenance treatment to prevent the recurrence
of mania. These latter actions are similar to lithium and various anticonvulsants that act by
very different mechanisms. More surprising yet is that some atypical antipsychotics are
effective for bipolar depression. The question that arises is, how do atypical antipsychotics
work as mood stabilizers? Also, do they act as mood stabilizers by the same pharmacologic
mechanism as they do as antipsychotics? Finally, do they work for the symptoms of mania
by the same pharmacologic mechanisms as they do for bipolar depression?

Putative pharmacologic mechanism of atypical antipsychotics in mania and bipolar

depression

The answer to the question of how atypical antipsychotics work in mania is that we do not
really know (Figure 5-36). In fact, theories about atypical antipsychotic pharmacologic
actions in bipolar disorder are less well developed than they are for schizophrenia, such as
those discussed extensively in Chapter 5. Indeed, it is still a quandary how bipolar disorder
itself can create seemingly opposite symptoms during various phases of the illness, as well
as the combination of both manic and depressive symptoms simultaneously. Ideas about
dysfunctional circuits in the depressed phase of bipolar disorder (discussed in Chapter 6
and illustrated in Figure 6-45) are contrasted with different dysfunctions in both
overlapping and distinctive circuits during the manic phase of the illness (discussed in
Chapter 6 and illustrated in Figure 6-48). Rather than being conceptualized as having
activity that is simply “too low” in depression and “too high” in mania, the idea is that
dysfunctional circuits in bipolar disorder are “out of tune” and chaotic. According to this
notion, mood stabilizers have the ability to “tune” dysfunctional circuits, increasing the
efficiency of information processing in symptomatic circuits, thus decreasing symptoms
whether manic or depressed.

If so, the D2 antagonist or partial agonist properties of atypical antipsychotics as well as

conventional antipsychotics may account for reduction of psychotic symptoms in mania,
but the 5HT2A antagonist and 5HT1A partial agonist properties of atypical antipsychotics
may account for reduction of nonpsychotic manic and depressive symptoms by some (but
not all) atypical antipsychotics. This could occur via reduction of glutamate hyperactivity
from overly active pyramidal neurons by 5HT2A antagonist actions (discussed in Chapter
5 and illustrated in Figure 5-15). This could reduce symptoms associated with glutamate
hyperactivity, which could include both manic and depressive symptoms, depending upon
the circuit involved. Anti-glutamate actions of atypical antipsychotics are consistent with
the known pharmacologic mechanisms of several known anticonvulsants that are also
mood stabilizers. Adding together different mechanisms that decrease excessive glutamate
activity could explain the observed therapeutic benefits of combining atypical
antipsychotics with proven anticonvulsant mood stabilizers.