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unfavourable form of manic-depressive insanity.™™

Severe stage of mania
The mixed state may represent a qualitatively distinct presentation of mania, with
classical manic symptoms accompanied by marked anxiety, depression, or anger.
These symptoms tend to emerge in more severe stages of the illness and then to be
correlated in severity; thus Carlson and Goodwin (1973) described three stages of
mania through which an episode may develop, corresponding to mild, moderate,
and severe levels of symptoms. At moderate severity, the euphoric mood is
increasingly interrupted by periods of irritability and depression, and thinking
becomes delusional. In the severe stage, there is frenzied overactivity, mood is
Cambridge University Press, 2005.
325 The treatment of bipolar mixed states

Table 15.1 Concepts of mixed states

Model Authors

1. Mixture of elements (mood, activity, thinking) Kraepelin
2. Severe stage of mania Carlson and Goodwin
3. Dysphoric mania Post
4. Depression as characterological response to mania Akiskal, Bourgeois
5. Manic defense in depression Klein, Winnicott
6. Transition state during a cycle (MDI/DMI) Falret, Koukopoulos
7. Predominantly depressed (BP-II, Dm) Dunner, Angst
8. Mania modified by substance misuse Himmelhoch
9. Modified by organic brain disease Himmelhoch and Garfinkel
10. Ultrarapid cycling DSM-IV
11. With mood-incongruent psychotic features Dell™Osso
12. Mixed schizoaffective disorder Marneros

See text for definition of abbrevations.

experienced by the patients as unpleasant or even terrifying, delusional thinking
becomes bizarre and they have hallucinations, and in some cases disorientation.

Dysphoric mania
The term ˜˜dysphoric mania™™ has been used to describe patients in whom classical
manic symptoms are accompanied by marked anxiety, depression, or anger (Post
et al., 1989). Some patients present with these symptoms throughout an episode
and might be described as having dysphoric, mixed, irritable“paranoid or even
paranoid“destructive mania. Thus, Beigel and Murphy (1971) studied, prior to
treatment, 12 consecutive patients admitted to the National Institute of Mental
Health (NIMH). Eight were characterized as ˜˜elated“grandiose™™ and four as
˜˜paranoid“destructive,™™ on the basis of their scores on the nurses™ Manic State
rating scales. Patients with repeated manic attacks tended to exhibit similar
behavior and mood patterns during subsequent episodes and the pattern seemed
to persist independently of the overall severity of mania. These authors found
depressive symptoms in 11 of the 12 patients with mania. A similar division was
found in a later factor analysis of 30 patients (Murphy and Beigel, 1974). The
severity of dysphoria has been found to correlate with the level of norepinephrine
(noradrenaline) in the lumbar cerebro-spinal fluid (CSF) (Post et al., 1989).
Likewise, levels of the norepinephrine metabolite methoxy-hydroxy phenylglycol
were more elevated in mixed mania than in depression (Swann et al., 1994).
326 J. Cookson and S. Ghalib

Whether there is a sharp separation between pure and dysphoric mania is
doubtful. Bauer et al. (1994b) assessed 37 outpatients with mania or hypomania
(65% bipolar II and 92% rapid cycling) using five different definitions of dys-
phoric mania (all based upon the number of depressive symptoms). In this group
no bimodality was found in the depression scores that would allow a separation
into dysphoric and pure mania, and dysphoria was not found consistently in
successive episodes.

Depression as characterological response to mania
The manic state may predominate while depressive elements are present to a lesser
degree, perhaps fleetingly. The depressive symptoms may then be viewed as a
characterological response to the occurrence of mania (Akiskal, et al., 1998a).
Treatment of mania would be predicted to improve the depressive symptoms.
The development of the concept of temperament in relation to bipolar disorder
was reviewed by Angst (2000). There is as yet little direct evidence to link
temperament and mixed presentation, or indeed any particular personality type
with bipolar disorder. In the French national Epidemiology of Mania (EPIMAN)
study, mixed manic patients had a higher rate of depressive temperamental traits
compared with those with pure mania (Akiskal et al., 1998a). Bourgeois (2002)
reviewed the evidence that temperament, whether depressive or hyperthymic, may
color the acute episode (Akiskal and Akiskal, 1992; Cassano et al., 1992; Akiskal
et al., 1998b; Henry et al., 1999; Perugi et al., 2001). He also concluded that
two subtypes of bipolar type I disorder may be differentiated: on the one hand,
a subtype ˜˜with a predominance of manic psychopathology™™ and on the other
a ˜˜preponderantly depressed™™ (Angst, 1978) or ˜˜depression-prone™™ type (Quitkin
et al., 1986) or a ˜˜poor prognosis subtype marked by a relative persistence of
depressive symptoms™™ (Coryell et al., 1998).

Manic defense in depression
The depressive state may predominate, but with elements of manic thinking, as
implied in the concept of ˜˜manic defense™™ against depression, described by Donald
Winnicott (1935) and Melanie Klein (1935), who had herself been psychoanalyzed
by Karl Abraham, one of the first in 1924 to apply psychoanalytical ideas to manic-
depressive illness. The manic defenses (omnipotent control, triumph, and con-
tempt) protect the ego against despair, but interrupt the process of reparation, and
produce a vicious circle by further attacks upon the ˜˜object.™™ However, a manic
form of reparation can occur and some of the identifications made in mania can be
seen as potential advances in individual development. This psychoanalytically
327 The treatment of bipolar mixed states

derived formulation of manic or hypomanic responses can be helpful in under-
standing the personal and interpersonal dynamics or relationships in which the
bipolar person may become involved. However their etiological significance is less
clear, a fact recognized by Freud, who referred to the ˜˜economic problem™™ of the
libido in mania and depression.
In Winston Churchill™s case, Storr (1969) emphasized the creative use of words
and ideas; his writing, painting, and oratory were ˜˜manic defenses™™ against the
depressive tendencies which could be traced in the family to the first Duke
of Marlborough. His daughter, however, has stated that her mother ˜˜very largely
kennelled the black dog™™ of Churchill™s melancholia except in his old age
(Soames, 1993).
Specific issues to be addressed with manic patients are the alienation of family
members, the progressive testing of limits by the patient, the over involvement
with other patients, and the tendency to dominate the ward. Janowsky et al. (1974)
described these tendencies as ˜˜the manic game™™ and implied that the manic patient
demands care without having to admit a need for it. Staff need to understand these
maneuvers in order to avoid becoming too personally involved, for instance in
angry exchanges. Community meetings are helpful as they allow the responses of
other patients to the manic™s behavior to be recognized and guided.

Transition state during a cycle: MDI/DMI
Kraepelin (1899) suggested that a distinction should be made between ˜˜transi-
tional forms™™ (mixed episodes representing a transitional point or interval during
the switch from depression to mania or vice versa) and ˜˜autonomous forms™™
(mixed episodes as a separate disorder) of mixed episodes (Marneros and Angst,
2000). Thus the opposite affective state may emerge during recovery from the first
state, as in postmanic depression, and the mixed state may occur during the
transition. In some patients the ˜˜switch ™™ occurs rapidly (in 24 h or overnight)
but in others it is much slower (Sitaram et al., 1978; Post et al., 1981). Such cycles
or periods of illness were first clearly recognized by Falret, in what he called folie
circulaire (1854), and less clearly by Baillarger as folie a double forme (1854).
Koukopoulos (2002) has emphasized the importance of these early ideas of
Falret to contemporary clinical diagnosis and treatment.
The emergence of the second state may be due to adaptations occurring during
the former. In this view the order of the sequence of mood states is important.
Koukopoulos has used the sequence of mood changes to distinguish patients in
whom an episode of mania is followed immediately by depression, followed by a
well interval (MDI), from those with depression followed by mania or hypomania
(DMI), those with a continuously circular (CC) pattern, and those with completely
328 J. Cookson and S. Ghalib

separate affective swings. In an investigation of the course of manic-depressive
cycles, involving 434 bipolar patients, Koukopoulos et al. (1980) found the
following patterns. A total of 119 patients (28%) had a pattern of MDI and
106 (25%) of DMI; there were 87 (20%) with rapid cycling, 83 (19%) with a CC
course, and 39 (9%) with irregular patterns. Thus 28% had a depressive phase
immediately following a manic phase, and may therefore have experienced a
transitional mixed stage.
Earlier intervention to treat or prevent the former state might prevent or reduce
the subsequent severity of the later state. On the other hand, prompt treatment of
the initial state might lead to earlier transition into the subsequent state than
would occur without treatment, as in the apparent ˜˜triggering™™ of mania by
treatment of bipolar depression with tricyclic antidepressant drugs. Thus,
Kukopulos and Reginaldi (1973) proposed that such a mechanism might account
for the finding that lithium reduces the frequency and severity of depressive
episodes in the prophylaxis of MDI disorder. The same could be applied to the
use of antipsychotic drugs in this condition. Drugs such as lithium and lamotrigine
may have the advantage of treating or preventing the depressed phase of bipolar
disorder with less risk of triggering secondary mania and may be particularly useful
in DMI (bipolar: BP-II) disorder.
Faedda et al. (1991) analyzed the findings of five studies in which the response to
lithium was considered in relation to clinical predictors of efficacy. They found
that the MDI or hypomania with severe depression (mDI) pattern of episodes
predicted better response to lithium than the other patterns. The sequence of
declining responsiveness was from this MDI pattern to irregular through CC,
DMI, or severe depression with hypomania (DmI) to rapid cycling, which was the
least responsive pattern. The odds ratio for responding between MDI and DMI
patterns was 4.4, with 95% confidence intervals of 2.8“7.0.

Mixed states in predominantly depressed bipolar patients (BP-II, Dm)
Patients with recurrent depression who have hypomanic episodes (not requiring
hospitalization), especially on recovery from depression, were described as BP-II
and those with a history of mania as BP-I (Dunner et al., 1976). There is extensive
overlap between patients with the DMI pattern and those with BP-II, and between
those with the MDI pattern and BP-I. Koukopoulos (2002) reported that, of the
119 DMI bipolars described above, 101 (85%) were BP-I and represented almost
half of the total of 207 patients with BP-I. On the other hand, 80 (75%) of the
DMI patients could be classified as BP-II.
An average of 40% of BP-I patients develop a mixed state at some point during
the course of their illness (Akiskal et al., 2000). In two recent clinical trials, the
329 The treatment of bipolar mixed states

proportion of manic patients with mixed mania as defined by Diagnostic and
Statistical Manual of Mental Disorders, 4th edn (DSM-IV: American Psychatric
Association, 1994) was 17% (Tohen et al., 1999) and 43% (Tohen et al., 2000).
Another formulation of the predominantly depressed forms of bipolar disorder
was proposed by Angst (1978). Because of the different combinations of severity
of manic and depressive episodes, Angst proposed three categories of patients:
(1) MD (in whom both manic and depressive episodes are severe enough to
require hospitalization)
(2) Md (recurrent mania with only mild depression)
(3) Dm (BP-II) (hypomania with severe depression)
To these might be added:
(1) md (cyclothymia)
(2) M (unipolar mania)
The phenomenon of switching from depression to mania has been studied exten-
sively both in the era before antidepressant therapy (Angst, 1985) and recently
(Wehr and Goodwin, 1987). The switch from mania to depression has been
studied less. Angst (1978) examined the sequence of mood changes in 1176
separate episodes, in 95 consecutive bipolar admissions for the period
1959“1963. Ninety-nine percent of episodes entailed either one or two mood
phases. Of 378 episodes that began with mania or hypomania, 123 (32%) were
immediately followed by depressive states. In 27/378 (7%) cases the depression
that followed was severe, and in 96/378 (25%) it was mild. Severe depression
followed mania in 13/215 (6%) episodes, but followed hypomania in 14/67 (21%),
indicating that the severity of subsequent depression is not related simply to the
severity of the preceding mania. A recent trial in which switch rates into depression
were high (27%), despite mood stabilizers, was that of Tohen et al. (2002a), in
which outpatients with mild mania were recruited.
Severe agitated depression with associated hypomania was described by
Himmelhoch et al. (1976) as a variant of bipolar mixed states. Koukopoulos and
Koukopoulos (1999) have described intensely agitated depressions, which they
consider as forms of not unipolar, but bipolar depressive mixed states. Perugi et al.
(1997) also identified such a mixed depressive syndrome, with pressure of speech
and flight of ideas. Likewise, mild mixed states have been described among BP-II
patients, involving irritability, distractibility, and racing thoughts (Benazzi, 2000).
Koukopoulos (2002) has argued that this form of agitated depression may require
particular care in drug treatment.
Akiskal et al. (1998a) describe depressive mixed states related to BP-II disorder.
These patients satisfy the criteria for a major depressive episode, but also show
intense activation in the form of dramatic expressions of suffering; unrelenting
dysphoria, irritability, and lability; psychomotor agitation; extreme fatigue with
330 J. Cookson and S. Ghalib

racing thoughts; intense sexual excitement; free-floating anxiety, and panic
attacks; as well as suicidal obsessions. In some cases these appear to be brought
about by overzealous prescription of antidepressants (McElroy et al., 2000).
Swann et al. (1993) compared the clinical characteristics of mixed manics with
those of agitated depressed patients. The mixed manic patients had more severe
agitation, hostility, and cognitive impairment (disorganization and lack of insight)
than did the agitated depressed patients. However, they could not find sufficient
evidence to classify agitated depression as a mixed state. The term ˜˜hyperthymic
depression,™™ has been suggested as a preferable name for these mixed states
rather than ˜˜agitated depression,™™ which has other connotations (Marneros and
Angst, 2000).

Modified by substance misuse
The presentation of mania may be modified, leading to mixed forms, by the
comorbid misuse of alcohol, sedatives, or stimulant drugs. The combination of
mental illness and substance misuse is known as dual diagnosis or comorbidity.
Bipolar disorder is associated with an increased risk of comorbid conditions,
including personality disorder, alcohol or drug misuse, and anxiety states. Some
patients increase and some decrease alcohol or drug abuse when manic compared
to euthymic (Bernadt and Murray, 1986). Alcohol and stimulants such as amfeta-
mines and cocaine are misused by patients to restore hypomania during a dysphoric
phase or to heighten existing states of elation (Gawin and Kleber, 1986). These
drugs can alter the course of bipolar disorder by triggering mania; they diminish
impulse control and impair judgment and are serious risk factors for suicide.
Therefore the recognition and treatment of alcohol or drug abuse in recurrent
affective patients is a matter of urgency. Despite the earlier use of Cannabis indica
for mania in the nineteenth century, for example, by Clouston (1896), current
preparations of cannabis have been associated with an increase in psychotic
symptoms in mania (Harding and Knight, 1973), and with the induction of
mania (Rottanburg et al., 1982).
A manic episode may be triggered by amfetamine in predisposed individuals
(Gerner et al., 1976). Dopamine agonists with preferential presynaptic effects are
sedative and may improve mania, but dopamine agonists may also cause secondary


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