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et al., 1978), and particularly in mixed mania (Swann et al., 1987, 1994), and
correlated with levels of dysphoria, anger, and anxiety in dysphoric mania (Post
et al., 1989). Blockade of norepinephrine receptors by haloperidol may be part of the
mechanism of the drug™s antimanic effect, and may be particularly important in
dysphoric mania. Certain atypical antipsychotics such as olanzapine and risperidone
337 The treatment of bipolar mixed states

are also antagonists at 5-HT-2 receptors and norepinephrine alpha2-receptors,
actions that may endow them with antidepressant properties.

Antipsychotics, depression in mania, and switch into depression
The response to treatment of depressive symptoms in mania has two aspects. First,
there is the response of depressive symptoms that occur during the presenting
manic phase. Second, there are the depressive symptoms that emerge as the manic
phase resolves; these may be regarded as postmanic depression or “ especially if
they appear suddenly “ as resulting from a switch from mania to depression.
In placebo-controlled studies of olanzapine in mania, 27% of patients had high
depression scores at the start (Hamilton-D > 20). Depressive symptoms improved
along with the mania ratings within 1 week (Baker et al., 2000). This improvement
in moderately severe depressive symptoms in a large proportion of bipolar patients
is compatible with model 4 (characterological response).
Olanzapine and haloperidol brought about similar degrees of improvement, not
only in ratings of mania, but also of depressive symptoms in patients with high
depression scores (Hamilton-D > 20) at the start (Tohen et al., 2003). However
the remission rates in patients with mixed mania (n ¼ 25, with full DSM-IV
syndromes) tended to be less than in pure mania (n ¼ 428), whether to olanzapine
(39% versus 53%) or haloperidol (17% versus 48%) (Tohen et al., 2003). This is in
keeping with model 1 (mixture of elements) applying to the small proportion of
patients with more severe depressive symptoms accompanying mania.
In the placebo-controlled studies, worsening of depression was not more com-
mon on olanzapine (3/33) than with placebo (7/35) (Baker et al., 2000). On the
other hand, the risk of switching from mania to depression within 6 weeks was
found to be less with olanzapine (6/128 or 4.7%) than with haloperidol (16/131 or
12.2%) (Tohen et al., 2003; Baker et al., 2004). This suggests that certain atypical
antipsychotics may have an advantage over classical antipsychotics in preventing
the development of mixed states and depression.
Combining olanzapine with lithium or valproate in manic patients (nearly all
outpatients) who had already been on the mood stabilizer for at least 2 weeks led to
greater improvement than mood stabilizer with placebo in the subset (48%)
of mixed mania (Tohen et al., 2002a). Depression scores also improved more
with olanzapine combination, and the proportion of patients gaining 50%
improvement in depression scores was greater for olanzapine (43.1%) than for
mood stabilizer with placebo (9.5%).

˜˜Manic defense,™™ transitions, and treatment of mania
Thus there is little evidence that treatment of mania or mixed states with antimanic
drugs worsens depressive symptoms as model 5 (manic defense) predicts. Another
338 J. Cookson and S. Ghalib

prediction of this model is that more prolonged mania would lead to greater
subsequent depression, as reparation has eventually to be made. This dynamic
interpretation is in keeping with a biological view that compensatory changes
occurring during mania might predispose to subsequent depression. In support of
these views, the high switch rate into depression among outpatients recovering
from mania on mood stabilizers in the study of Tohen et al. (2002a) was reduced
by additional treatment with olanzapine, which hastened the recovery from mania.
Evidence from prophylactic studies supports the view that intervening with a drug
that treats one phase may prevent recurrences of that phase and also, to a lesser
extent, the opposite phase.

Antipsychotics in prophylaxis of bipolar disorder
Antipsychotics are widely prescribed in the follow-up of patients after discharge
from hospital for mania; the majority are on antipsychotics at the time of dis-
charge, and a large proportion are still on antipsychotics 3“6 months later
(Cookson, 2001). In the large clinics run by community psychiatric nurses for
patients on depot medication, most patients have a diagnosis of schizophrenia or
paranoid states; however, there is a proportion of patients with a bipolar disorder.
Two retrospective studies, using a ˜˜mirror image™™ design, have examined the
effects of depot treatment in bipolar patients in such clinics. One study reported
an improvement in the frequency only of manic episodes (White et al., 1993).
The other study found an improvement in manic, depressive, and mixed episodes
(Littlejohn et al., 1994). Long-term treatment with antipsychotic drugs may enable
a proportion of bipolar patients to experience periods of greater stability.
The mechanisms involved may be primarily antimanic, but resulting in less
subsequent depression, as is argued for lithium (Koukopoulos et al., 1980).
These drugs are mostly prescribed for those with frequently recurring episodes,
who either do not benefit from or do not adhere to oral medication. For rapid-
cycling bipolar patients, depot antipsychotics such as haloperidol decanoate sta-
bilize mood swings (Lowe and Batchelor, 1990). Ketter and Calabrese (2002) have
described such action as ˜˜stabilizing mood from above.™™
The atypical antipsychotic clozapine is generally reserved for treatment-resistant
schizophrenia, because of its side-effects, which include agranulocytosis. However,
it is also of value in some cases of resistant bipolar disorder, including patients
with rapid-cycling and mixed states (Suppes et al., 1999). An open randomized
controlled trial of clozapine as an adjunct to previous medication versus continuing
treatment as usual included 38 patients with BP-I or schizoaffective disorder. Ten
had mixed bipolar states and 21 had a history of rapid cycling. With the criterion
for improvement being a 30% reduction in scores on the Brief Psychiatric Rating
Scale, by 6 months 82% on clozapine and 57% on treatment as usual had
339 The treatment of bipolar mixed states

responded, a 25% advantage for clozapine, corresponding to a ˜˜number needed to
treat™™ of four.
Long-term studies of olanzapine are discussed in Chapter 16, and suggest that
this atypical antipsychotic and antimanic drug may reduce not only manic but also
a proportion of depressive recurrences.

Results from an open-label study of lamotrigine for treatment of BP-I disorder
suggested that lamotrigine was effective in the treatment of depressive and manic
symptoms (Calabrese et al., 1999a). Subsequently, a 7-week double-blind, placebo-
controlled study demonstrated that lamotrigine monotherapy was effective for
depressive episodes in 159 patients with BP-I disorder as early as 3 weeks after
initiating therapy (Calabrese et al., 1999b). More recently, the efficacy and toler-
ability of lamotrigine monotherapy for BP-I disorder were established in two
18-month placebo-controlled maintenance studies (Bowden et al., 2002; Calabrese
et al., 2002) and a meta-analysis of these two trials, where lamotrigine was found
to reduce significantly mean Hamilton-D and Clinical Global Impression (70)
scores across 76 weeks of treatment in 638 patients (Goodwin et al., 2002). These
results suggest that lamotrigine is effective for the acute treatment and long-term
management of BP-I depression. Acute effectiveness has also been demonstrated in
patients with treatment-refractory (Bowden et al., 2000) and rapid-cycling BP-II
disorder (Bowden et al., 2001), as well as a cohort of recently manic patients with
BP-I disorder (Frye et al., 2000). It would appear important to examine further
whether these responses were related to the patterns of mood cycles in the patients,
using the classifications of Angst and of Koukopoulos.

Treatment of mixed states with antidepressants
The predictions of responses to antidepressants in different models of mixed states
are shown in Table 15.4

Antidepressants in bipolar mixed states
The use of antidepressants in bipolar depression is controversial, because of the
suspected risk of triggering mania; their use in mixed states is also controversial.
Akiskal and Mallya (1987) described 25 patients referred for treatment-resistant
depression who displayed subacute or chronic mixed states apparently induced by
tricyclic antidepressants. They improved with discontinuation of antidepressants
and treatment with lithium or carbamazepine, with or without antipsychotics.
Akiskal (2002) has argued that failure to recognize such a depressive mixed state as
being bipolar is a serious clinical lapse, as antidepressants are likely to aggravate it.
340 J. Cookson and S. Ghalib

Table 15.4 Prediction of response to antidepressant drug in models

Model Prediction

1. Mixture of elements (mood,
Partial response (in depressive elements)
activity, thinking)
2. Severe stage of mania No response
3. Dysphoric mania No prediction
4. Depression as characterological
No response
response to mania
5. Manic defense in depression Improved
6. Transition state during a cycle DMI: shortened depression, mania or hypomania
(MDI/DMI) occur sooner; stabilize mood ˜˜from below™™
7. Predominantly depressed (BP-II,
Depression improved, mania more evident
8. Mania modified by substance
Resistance while comorbidity persists
9. Modified by organic brain disease Resistance while comorbidity persists

See text for definition of abbrevations.

Similarly, Koukopoulos et al. (1992) reported 45 patients with bipolar dis-
order who experienced a mixed depressive syndrome, meeting DSM-IIIR criteria
for major depression but not for mania, who deteriorated when treated with
antidepressants, displaying increased agitation, insomnia, and, in some cases,
suicidal impulses. The continuation of antidepressants may eventually result
in rapid cycling (Koukopoulos et al., 1983). On the other hand, a substantial
proportion of depressed patients with mild bipolar features may show satisfac-
tory and stable long-term outcome with antidepressants not necessarily com-
bined with mood stabilizers (Cassano, 2002).
Monoamine oxidase inhibitors may be effective in bipolar depressed states.
Himmelhoch et al., (1991) conducted a double-blind randomized study com-
paring imipramine (100“300 mg/day) with the stimulant monoamine oxidase
inhibitor tranylcypromine (20“60 mg/day) in 56 outpatients with anergic bipolar
depression. Tranylcypromine was superior to imipramine with greater sympto-
matic improvement and a higher global response rate, with no greater risk of
treatment-induced hypomania or mania (14% and 20%). The 12 non-responders
to imipramine were then crossed over to tranylcypromine and nine responded
(Thase et al., 1992).
It is unclear whether mixed states are more or less likely to deteriorate than
pure manias when exposed to antidepressants. For example, in a study by Altshuler
et al. (1995) of 51 patients with BP-I and BP-II, 85% switched to mania while
341 The treatment of bipolar mixed states

on antidepressants, of which 35% were antidepressant-induced. However, in a
randomized, double-blind, prospective trial (Altshuler et al., 2003), the risk of
depressive relapse was significantly lower in patients continuing the antidepres-
sants compared to those discontinuing after remission, with no statistically sig-
nificant difference for breakthrough manic episodes. Generally, clinical practice
favors protecting the bipolar patient from manic switches and cycle acceleration by
the preferred use of mood stabilizers over antidepressants, or their combination.
This approach is not necessarily supported by the literature, but a recent review
concluded that patients taking an antidepressant without a mood stabilizer are
more likely to develop a manic or hypomanic episode than patients who are also
taking a mood stabilizer (Ghaemi and Goodwin, 1999).

Resistance to treatment in mixed states
It has been thought that mixed states are less responsive to treatment than pure or
classical manic states. Himmelhoch et al. (1976) identified mixed states in 26/84
(31%) of manics in 143 consecutive admissions in Yale and Pittsburgh. Alcohol
and sedative misuse was more common in the mixed patients. Poor prognosis
(strongly influenced by poor response to lithium) was more common in mixed
patients, and this was only partially accounted for by the association with sub-
stance misuse. Paradoxically, 10/14 mixed patients with psychotic features showed
a good response to lithium, whereas only 1/12 mixed patients without psychotic
features did so. A total of 47/58 with pure mania responded well to treatment.
This suggested to Himmelhoch and Garfinkel (1986) that the non-psychotic
mixed patients had some other poor prognostic factor and, in a second series of
46 lithium-resistant bipolar patients, they identified a substantial frequency of
features of organic brain disease (developmental disorders, and electroencephalo-
graphic abnormalities). In all, 37/46 of these patients had mixed states and 31 of
these 37 had these neuropsychiatric factors (Himmelhoch and Garfinkel, 1986).
However, 23 out of the group of 46 were in adolescence, suggesting that factors
involved in the selection process may have produced a somewhat unrepresentative
sample. In the combined groups of 63 mixed manic presentations, only 1/45
with additional neuropsychiatric or substance misuse factors responded to
lithium“antidepressant combinations; by contrast, 10/18 with uncomplicated
mixed mania responded to this combination. Only 11 of the 45 showed psychotic
features. Perugi et al. (1997) found that mixed states took longer to recover.
Keller et al. (1986) also found mixed manic patients less responsive to lithium
than other manic patients. Secunda et al. (1987b) found a good response to
lithium in 10/11 patients with pure mania (91%) but in significantly fewer (2/7)
who had mixed mania (29%). Himmelhoch and Garfinkel (1986) reported that
342 J. Cookson and S. Ghalib

21/46 (46%) of lithium-resistant patients (80% had mixed mania) responded to
anticonvulsant therapy, which usually involved carbamazepine.
In the placebo-controlled study of Pope et al. (1991) of valproate in 23 patients
with lithium-resistant mania, the antimanic response was not associated with
measures of dysphoria. Valproate differs in its mechanism of action from anti-
psychotic drugs, reducing presynaptic dopamine release as opposed to blocking
postsynaptic receptors (Yatham et al., 2002). Freeman et al. (1992) conducted a 3-
week randomized controlled trial, comparing lithium and valproate in 27 patients
with mania, of whom eight had mixed mania and 19 pure mania. The response rate
on lithium (12/13) was non-significantly higher than on valproate (9/14), and
non-responders to valproate had significantly lower depression scores than the
Swann et al. (1997) had quite different findings. They investigated the relation-
ship between depressive symptoms and response to treatment with lithium or
valproate among 179 patients with mania in the trial of Bowden et al. (1994).
Mixed states were associated with poor response to lithium, compared with pure
mania. By contrast, the presence of depressive symptoms had no effect on the
response to valproate. A limitation of this study is that a proportion of patients
(75/179) admitted to the trial were already known to be non-responders to
lithium. Thus, a bias against lithium was introduced at the start of the trial, and
the validity of the concept of ˜˜lithium non-responder™™ was confirmed.
Nevertheless, among patients with pure mania there were fewer drop-outs for
lack of effect on lithium (29%) than on valproate (40%). Performing a multiple
regression analysis to identify factors that might predict response to lithium or
valproate, they found no correlation with gender, number of previous episodes,
psychotic features, or history of substance abuse.
Two studies have compared valproate with olanzapine in mania. One of these
has reported the response in mixed mania, which comprised 43% of the sample
(Tohen et al., 2002a, 2002b). Although the response to olanzapine was greater and
more rapid than that to valproate, each drug was effective in mixed mania to only a
slightly lesser extent than in pure mania. The improvement in depression scores
was similar in the two treatment groups.
Electroconvulsive therapy is potentially a useful option in mania, especially in
treatment-resistant cases (Okasha, 2002).

Combining lithium and antidepressants in prophylaxis of mixed mania
Prien et al. (1988) conducted a double-blind, prophylactic study of lithium,
imipramine, and the combination in three subgroups, including 34 with pure
mania, 46 with mixed mania with mild depression (Hamilton-D score 7“14), and 23


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