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with mixed mania with moderate to severe depression (Hamilton-D score 15).
343 The treatment of bipolar mixed states


They confirmed the poor acute response to treatment of mixed as opposed to pure
manics, and followed up patients treated for 2 years after recovery from mania. Those
who had mixed episodes were also at higher risk of recurrence on treatment than the
pure manics. Lithium alone or in combination with imipramine was highly effective
in prevention for the pure group, but not for the mixed group. Only 1/17 pure manics
on lithium had any recurrence, compared with six manic recurrences, five depressive
recurrences, and one mixed recurrence in the 16 patients with mixed mania.
The prophylactic phase of the study involved 25 mixed bipolar states (16 with mild
depression, nine with moderate to severe depression). A total of 5/8 on lithium, 7/7
on imipramine, and 9/10 on the combination experienced a recurrence.
Imipramine treatment was thus associated with a greater risk of recurrence. The
combination of lithium with imipramine provided no apparent advantage to
lithium alone in prevention in this small group of patients after mixed mania.
Similarly, a double-blind study comparing the prophylactic use of lithium
carbonate with and without imipramine for BP-I patients (Quitkin et al., 1981)
found that the use of antidepressants contributed to some instability of mood.
This mood instability was only partially ameliorated by the concurrent use of
mood stabilizer.


Suicide risk
Long-term treatment with lithium has been associated with a reduction in the risk
of suicide. The mechanisms involved may be separate from the benefits of lithium
in preventing depression or hypomania (Muller-Oerlinghausen et al., 1992). Such
findings are of particular interest considering the especially high suicidal ideation
in people with mixed as opposed to pure mania (Dilsaver et al., 1994; Strakowski
et al., 1996).


Conclusions
The diagnosis of mixed affective states can be applied to many different clinical
presentations of bipolar disorder. Twelve different formulations of the condition
are discussed here. The literature concerning prognosis and treatment of mixed
states is controversial and inconsistent. Recent clinical trials using standard diag-
nostic criteria have clarified some of the issues about response to medication.
The majority of patients with mania display some depressive symptoms and a
substantial minority meets the more stringent criteria for a mixed state according
to DSM-IV, having additional symptomatology of a major depressive episode.
In most such patients depressive symptoms improve, along with manic symptoms
during treatment. However a minority of patients respond less fully to drugs,
344 J. Cookson and S. Ghalib


including antipsychotics and lithium. Some of these respond more fully to valpro-
ate and perhaps to carbamazepine than to lithium. Electroconvulsive treatment is
also considered an effective option for such patients. Factors other than mixity that
may contribute to treatment resistance in mania include substance misuse and
organic brain pathology, but it has not been established that these factors increase
the mixity of mania.
Predominantly depressed patients with mixed states are likely to require anti-
depressant medication, but most guidelines recommend that monoamine reup-
take inhibitor or monoamine oxidase inhibitor treatment should be accompanied
by a mood stabilizer, such as lithium or valproate, or by the antidepressant anti-
convulsant lamotrigine, in order to reduce the risk of subsequent switch into mania
and that the antidepressant should be stopped if manic symptoms appear or worsen
(Hirschfeld et al., 2002; Grunze et al., 2003). The combination of an antidepressant
with an antipsychotic is widely used and may also avoid worsening mania.
For long-term treatment it is important to consider not only the distinction
between BP-I and BP-II mixed types, but also the history of sequences of mood
transitions, including the MDI and Md concepts of classification. Lithium may be
preferable for patients with primarily manic sequences (BP-I, MDI, or Md), while
lamotrigine may be useful for those with initial or preponderant depressive phases
(BP-II, DMI, Dm, and dM).


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