CLIN.CHEM.

40/2, 303-308 (1994)

Brain Mechanisms in Manic Depression

Bernard J. Carroll

Manic depressive illness (bipolar disorder) is the mood facts” about manic depression and to emphasize the prob-
disorder classically considered to have a strong biological lems of accurate nosology that have probably impeded
basis. During manic depressive cycles, patients show progress to date. The correlation of clinical symptom clus-
dramatic fluctuations of mood, energy, activity, informa- ters with the likely brain mechanisms that are dysregu-
tion processing, and behaviors. Theories of brain function lated to produce those symptoms is presented, and I sug-
and mood disorders must deal with the case of bipolar gest areas where new insights may be expected from
disorder, not simply unipolar depression. Shifts in the current research. For more complete discussions of these

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nosologicconcepts of how manic depression is related to areas, readers should consult previous reviews (2,3) and
other mood disorders are discussed in this overview, and the comprehensive text of Goodwin and Jamison (4).
the renewed adoption of the Kraepelinian “spectrum”
concept is recommended. The variable clinical presenta- Present Concepts of Manic Depression
tions of manic depressive illness are emphasized. New Variable Presentations
genetic mechanisms that must be considered as candi- To understand our present concepts of manic depres-
date factors in relation to this phenotypic heterogeneity sion, it is essential to recognize their origins in the work
are discussed. Finally, the correlation of clinical symptom of Emil Kraepelin. Between 1880 and 1920, Kraepelin
clusters with brain systems is considered in the context of first clearly proposed the separation of mood disorders
a three-component model of manic depression. from schizophrenia (dementia praecox). He introduced
the term “manic depressive insanity,” which he recog-
IndexIng Terms: mood disorders/genetics/Tourelte syndrome/ nized as a familial condition, and he emphasized the
CreuWeldt-Jakob disease/fragile X syndrome/heritabledisorders multiple clinical presentations of this disorder, which he
regarded as varied expressions of “a single morbid pro-
Manic depressive illness is the classic example of a cess.” These presentations covered a wide spectrum of
biological mood disorder. Manic depression is closely severity, from mild, temperamental forms to severe psy-
related to the familial form of recurrent umpolar de- chotic disorders. Included were cases that today we
pression, and it reflects even more strongly all the asso- would call dysthymia, cyclothymia, minor depression,
ciations noted between some mood disorders and biolog- recurrent unipolar depression, bipolar disorder, simple
ical factors. Manic depression is a more homogeneous mania, and some psychotic or catatonic states. Kraepe-
syndrome than unipolar depression, so it is more infor- lin noted that these various forms of the basic disorder
mative in biological and pharmacological research stud- could substitute for each other over time within individ-
ies. Patients experiencing this condition (also termed ual patients and also within affected pedigrees. These
bipolar disorder) go through cycles of mood and behav- observations remain true today, and they are important
ior. These cycles have three phases: depressed, or dys- for current thinking about the genetic components of
thymic; normal, or euthymic; and manic, or hyperthy- the “single morbid process.”
mic. The cycles vary in amplitude (severity), and the Contrary to the original formulation of Kraepelin,
euthymic intervals between episodes of mania and de- however, these varied presentations of a single condi-
pression tend to shorten over the years. During the tion are defined as separate entities in contemporary
phases of each cycle, patients show dramatic bipolar classifications of mood disorders, such as the third edi-
fluctuations in mood, energy, activity, information pro- tion of Diagnostic and Statistical Manual of Mental Dis-
cessing, psychological functioning, and interpersonal re- orders (DSM III) (5). This deliberately agnostic position
lationships. In either the manic or the depressed phase, about the relatedness of the various mood disorders was
psychotic features (delusions, hallucinations) also may adopted mainly for administrative purposes. Family
appear. Manic depression, therefore, represents the history and longitudinal course, two cardinal validating
most extreme case of mood instability. As Donald Klein features of any medical classification, were ignored in
has observed, “... any theory of brain function and DSM III. That position has not been scientifically pro-
affect must deal with this striking phenomenon” (1). ductive, and the field is likely soon to return to a view
This review is not meant to be an extensive survey of more in line with Kraepelin’s. The same point has been
the many studies of biological factors in manic depres- made very strongly by Goodwin and Jamison (4). Cer-
sion. My purpose, rather, is to point out some of the “big tainly, the phenomena of patients switching from minor
depression to major depression, from unipolar to bipolar
Department of Psychiatry, Duke University Medical Center, disorder, and from nonpsychotic to psychotic presenta-
Durham, NC. Address for correspondence: Geropsychiatiy Insti.
tions are frequently observed, and in genetic studies the
tute, Box 31, John Umstead Hospital, Butner, NC 27509. Fax
919-575-4069; E-mail bcarroll@acpub.duke.edu. most common disorder among relatives of bipolar
Received August 9, 1993; accepted September 22, 1993. probands is unipolar depression. The relationship of

CLINICAL CHEMISTRY, Vol. 40, No.2, 1994 303

these umpolar cases to unipolar depression in nonbipo- both phases of manic depressive illness. For the most
lar pedigrees is not clear at present. What is clear is that severe, especially psychotic episodes of both depression
unipolar depression and dysthymia, as currently defined and mania, electroconvulsive therapy is the most effec-
by DSM III, are extremely heterogeneous. They include tive and rapid means of terminating the episode. Drug
cases within the Kraepelinian spectrum but also cases effects also are very clear, both for precipitating as well
that may be of quite different etiology (6, 7). That is the as treating depressions and manias. For example, de-
essential problem with purely syndromal definitions of pressive episodes may be induced by reserpine or
clinical disorders. a-methyl DOPA (4). Antidepressant drugs and cortico-
steroids may precipitate manic episodes. Lithium, car-
Biological Associations baniazepine, and valproic acid are effective in treating
In addition to the genetic pattern, there are several mania, whereas depressive episodes may respond to the
powerful reasons to propose a biological basis of manic classical tricycic drugs, monoamine oxidase inhibitors,
depressive disorder. The pattern of behaviors that accom- or the selective serotonin-reuptake inhibitors. Recur-
pany the mood shifts is highly suggestive. Patients ex- rences of mania and depression are reduced by lithium

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hibit altered sleep, appetite, activity level, and psycho- in bipolar cases, and by lithium or antidepressants in
motor speed that are sustained for weeks or months and patients with unipolar depression. Antidepressant drug-
go well beyond simple subjective mood swings. Once pre- induced rapid cycling also is now recognized. Another
cipitated, the episodes appear autonomous and largely powerful observation is the reversal of the antidepres-
unresponsive to environmental influence. Experimental sant action of tricycic antidepressants or monoamine
studies reveal that information processing is markedly oxidase inhibitors in depressed patients by preventing
affected by the manic and depressive phases (8). serotonin synthesis with use of p-chlorophenylalanine
The periodicity and seasonal pattern of episodes are or with dietary tryptophan restriction (12, 13). In bipo-
striking. Though episodes may occur at any time, for lar patients, a switch from mania to depression can also
certain patients they cluster into two seasonal peaks. be rapidly induced by the anticholinesterase agent phy-
This seasonal pattern is found in 13.5% of recurrent sostigmine (2). In sum, all these “big facts” strongly
umpolar depressions and in 21.7% of bipolar I patients. indicate major biological influences on manic depressive
The frequency of manic episodes reaches a major peak in disorder.
the spring and a minor peak in the autumn. For depres-
sive episodes the major peak is in the autumn, with a Genetics
minor peak in the spring (9). The pattern of recurrences The familial tendency of manic depressive and related
also tends to maintain a periodicity of 12 months or conditions has already been noted. Genetic researchers
multiples thereof (4). The natural history is one of re- now increasingly adopt a broad, Kraepelinian “spec-
current episodes with spontaneous remissions, even trum” approach rather than a narrow, DSM III ap-
without treatment. Recent longitudinal data from the proach to identifying affected cases within pedigrees,
National Institute of Mental Health National Collabo- and I have already noted that unipolar depression is the
rative Study reveal that, although manic depressives single most-common mood disorder among the relatives
experience more lifetime episodes overall than unipolar of bipolar probands. The genetic influence varies among
depressives, the excess of episodes is entirely accounted families but, on average, the morbid risk of manic de-
for by the manias: They have the same number of de- pression and severe recurrent unipolar depression is
pressive episodes as the unipolar cases (10). This obser- 15-20% for first-degree relatives of affected individu-
vation may prove important for understanding the fun- als, increasing to 70% for monozygotic twins; in dizy-
“-‘

damental difference between bipolar and unipolar gotic twins, however, the risk is only “-‘20% (4). The
disorders. In other words, manic depressive patients are overall population incidence is 1-2%.
not just more unstable than unipolar patients in mood Why do most affected members of a pedigree manifest
regulation in both directions. unipolar depression or some milder variant within the
The pattern of recurrent episodes suggests an ongoing affective disorders spectrum, while others manifest the
process with progressive deterioration over time. manic depressive syndrome? A good example is the fam-
Kraepelln and others since his time noted a marked ily tree of Virginia Woolf. In this example, displayed in
tendency for the euthymic intervals to grow shorter Jamison’s recent text (14), there are 10 affected individ-
with the passage of years. Eventually, a significant uals, only 2 of whom are definitely bipolar. The others
number of patients enter a clinically malignant phase of have unipolar depressions, cyclothymia, or unspecified
rapid cycling. Apparently, as the brain ages, mood-sta- psychosis.
bilizing mechanisms that prevent frequent recurrences
begin to fail (3). We should further note the occurrence Relationshipof Unipolarto BipolarDepression
of “secondary” manias and depressions caused by phys- To answer the question just stated, one must clarify
ical disorders (11), especially lesions of the right cere- the relationship of recurrent unipolar depression to bi-
bral hemisphere for mania and of the left hemisphere polar disorder. GOOdWin and Jamison (4) argue for the
for depression (3). Kraepelinian spectrum view. The longitudinal data
Finally, in this listing of biological associations we mentioned above (10) tend to support the proposal that
must note the dramatic effects of somatic treatments on bipolar subjects have a second genetic vulnerability for

304 CLINICALCHEMISTRY,Vol.40, No.2, 1994

manias superimposed on their general genetic loading and earlier onset. Thus, a common allelic polymorphism
for recurrent depressions. This suggestion is strength- separate from the major mutation can radically alter
ened by the finding that the risk factors for mamas the clinical expression of the major mutation.
differ from those for depressions (10). Though the two- Another recently recognized exception to the classical
gene model for manic depression has not been promi- Mendelian patterns of inheritance is the trinucleotide
nent recently, we must also note that no single-gene repeat type of mutation now identified in several condi-
models involving chromosome 11 or chromosome X have tions to date, including Huntington disease, myotonic
been replicated in recent linkage studies (15, 16). The dystrophy, and fragile X syndrome. These triplet re-
sex ratios of unipolar and bipolar disorders also are peats direct the synthesis of repeating units of single
intriguing. For unipolar depression, the female:male ra- ampio acids (20) and they show great variation in
tio is 2-3:1, whereas this ratio is 1:1 for bipolar disorder. length of expansion. In the case of fragile X syndrome,
This difference again suggests that mamas and depres- for example, the length of the trinucleotide repeat at
sions are caused by separate factors. Xq27.3 is highly polymorphic in the normal population
(from 6 to “42 triplets); asymptomatic carriers have

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New Genetic Mechanisms from “50 to 200 copies, whereas affected cases have
Despite the clear familial inheritance patterns, the expansions as great as 2000 or more copies. In other
yield of genetic linkage studies in unipolar and manic words, the mutation is not the same for each member of
depressions over the past 30 years has been disappoint- the pedigree. The reasons for this variability are not
ing. For that reason, newly identified genetic mecha- known. However, such a mechanism can explain the
nisms in neurological disorders are being closely studied clinical facts of these disorders such as incomplete pen-
for their applicability to psychiatric conditions such as etrance and variability of symptoms from one individual
the mood disorders. to another. Patients with the longer repeat segments
A first example is Gilles de la Tourette’s disease. In presumably have more severe symptoms than those
this condition, characterized by motor tics and coprola- with shorter ones. These aspects and others, such as
ha, recent studies of large pedigrees strongly support “anticipation,” are discussed by Ross et al. (20). [“An-
the disease spectrum concept (17). Three disorders pre- ticipation” refers to the tendency of a genetic disorder to
viously thought to be quite separate according to con- be more severe and to present with an earlier age of
ventional classifications were identified a alternative onset in succeeding generations. Ross et al. (20) sum-
expressions of the genotype. These three were classical marize the evidence for anticipation in manic depressive
Tourette disease, simple motor tics (without the vocal pedigrees.] The potential applicability of all these new
tics), and, most surprisingly, obsessive compulsive dis- genetic concepts to manic depression and to the Kraepe-
order. A gender effect was noted as well, with Tourette linian spectrum of mood disorders is obvious.
disease predominating among males and obsessive com-
pulsive disorder among females. All three conditions are ClInical Symptoms and Brain MechanIsms
now known to be associated with dysfunction of the Whatever the genetic locus eventually identified for
basal ganglia (18). This example well ifiustrates the the familial mood disorders, we stifi need to consider the
potential power of genetic studies to force revisions of brain systems involved in the expression of clinical
standard disease classifications that are based solely on symptoms. Only then may the steps between the gene
clinical features. mutation and the clinical disorder be clarified. In the
A completely new genetic mechanism of pleomorphic case of Huntington disease, for example, we already
disease expression was described in 1992 (19). In this know from correlative neuroanatomy and neuropathol-
example, two phenotypically distinct disorders have ogy that the primary affected site is the caudate nu-
been associated with an identical point mutation in cleus. For the familial mood disorders, we can likewise
codon 178 of the prion protein gene located on the short examine the symptoms in reference to the brain mech-
arm of chromosome 20. The two disorders are a type of anisms through which they are expressed. Several mod-
familial Creutzfeldt,-Jakob disease and fatal familial els have been proposed over the years to correlate mood
insomnia. The first condition is a diffuse spongiform symptoms with brain mechanisms (see refs. 3, 4). A
encephalopathy that presents with a subacute demen- recent formulation of one such neurobiological model (3)
tia, whereas the clinical features of fatal familial insom- is outlined below.
nia are subacute intractable insomnia, dysautonomia, The signs and symptoms of depression and mania are
and selective destruction of thalainic nuclei. Whether at first confusing because not all patients express exactly
familial Creutzfeldt-Jakob or fatal familial insomnia is the same features, and because psychological symptoms
expressed depends on a common allelic polymorphism at are so prominent in addition to behavioral and physio-
codon 129 of the same gene. The frequencies of the logical changes. Current diagnostic criteria such as DSM
methionine and valine alleles at this position are 0.62 III (5) do not clarify matters by simply giving a catalog of
and 0.38, respectively. Familial Creutzfeldt-Jakob dis- the possible features without any attempt to consider
ease occurs when the valine allele is present; fatal fa- how they are linked through underlying constructs. It is
milial insomnia is associated with the methionine al- possible, however, to view the manifold signs and symp-
lele. Furthermore, patients homozygous for the toms of manic depression as related to dysregulation of
respective alleles at codon 129 had more severe disease three major neurobiological systems: those that involve

CUNICAL CHEMISTRY, Vol. 40, No. 2, 1994 305

reinforcement-reward functions, central pain mecha- The brain system that mediates reinforcement-reward
nisms, and psychomotor activity. is known from animal studies of intracranial self-stimu-
lation. Although stimulation of electrodes implanted in
Reinlorcement-Reward Dysregulation most areas of the brain does not induce self-stimulation,
An essential feature of the depressed phase of manic in certain areas it is highly rewarding. These areas in-
depression is anhedonia, the inability to obtain pleasure dude noradrenergic and dopaminergic cell bodies in the
or satisfaction from sources that previously did give brain stem, and their limbic forebrain projection areas
pleasure. These sources are both external stimuli and such as hypothalamus and septal nuclei. In recent years
internal stimuli (cognitions). The experience of pleasure there has been increasing recognition that the basal gan-
in response to stimuli is an evolved function of the brain glia also are involved in hedonic behaviors, especially
termed consummatory reward. In animal studies the incentive reward functions that involve foresight and
hedonic experience is inferred from stimulus-seeking motivated planning of activity to obtain consummatory
behavior (termed incentive reward). Humans can report rewards. Reports of profound anhedonia and disinterest
the hedonic experience directly. The classical animal without dysphoria after localized lesions of the basal gan-

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paradigms to study hedonic functions are intracranial glia are especially instructive (see ref. 3). Acetylcholine is
self-stimulation, self-administration of drugs, and food regarded as an inhibitory neurotransmitter in this sys-
or place preferences. tem. Neuropeptides such as enkephalins and Substance
In the depressed phase of manic depression, the re- P also modulate self-stimulation.
ward system of the brain may be viewed as inhibited. Thus, one distinct group of classical symptoms in
The patient is unable to experience the normal reinforc- manic depression can be viewed as mediated by this
ing properties of stimuli. On this basis, the patient re- particular neurobiological system. It is also clear that
ports lack of pleasure in relationships and activities that more than one neurotransmitter may be involved in the
previously were engaging, such as social settings, work, expression of those symptoms through this system.
and avocations. Loss of enjoyment of basic drives such as
sex and food intake are viewed in the same light. Cog- Central Pain Dysregulation
nitions or internally derived stimuli also hose their re- Another group of signs and symptoms in manic de-
warding property. On this basis, the depressed patient’s pression is viewed as being mediated by dysregulation
self-image changes from competent and valued to in- of a separate brain system, for which the term “central
competent and devalued. Cognitions of the future pain mechanism” is used (1-3). In the depressed phase
change from the expectation of pleasure and success to this system is seen as disinhibited, whereas in mania it
anticipation of emptiness and failure. The important is inhibited. The essential distinction between central
point here is that some of the specifically human, psy- pain and anhedonia is that between bad (or aversive)
chological aspects of depressive anhedonia can be un- and not-good (or nonrewarding).
derstood in the same way as the more simple anhedonic In the depressed phase, stimuli that previously were
symptoms and behaviors. nonaversive are experienced as distressing. Again,
In the manic phase, the reward system is viewed as these stimuli are both external and internal (cognitive).
disinhibited, i.e., dysregulated in the opposite direction. On this basis, the depressed patient perceives neutral
Manic patients over-attend to stimuli with excessive events as catastrophic. For example, one patient whose
eagerness. From being anhedonic and withdrawn, they spouse was 30 min late visiting him in the hospital
switch to exaggerated seeking of social contact and sen- became convinced she had been killed in a road accident
sory stimulation. Their mood switches from boredom en route, and proceeded agitatedly to call the police to
and disinterest to pathological satisfaction and intru- conilrm this belief. Changes in self-image due to central
sive overinterest, with marked distractibility as new pain dysregulation go beyond feelings of incompetence
stimuli present to them, either from their environment and devaluation. The depressed patient perceives him-
or in the form of cognitions from within. The self-image self as bad, unworthy, and guilty.
is grandiose and omnipotent rather than devalued and When manic, however, the same person displays a
incompetent, and the manic’s perception of the future is cognitive blindness to the aversive or negative proper-
unrealistically optimistic rather than pessimistic. ties of stimuli. Hence the characteristic denial of illness
In summary, the affective information processing of and the disregard of the manic for the painful conse-
the positive (reinforcing, rewarding) properties of both quences of his own behavior. That is why manic patients
internal cognitions and external stimuli is dysregulated will behave out of character in such ways as reckless
in the manic depressive patient. The salient fact to keep driving, foolish investments, spending sprees, embar-
in mind when contemplating these switches of hedonic rassing sexual indiscretions, and risk-taking of all
capacity is that it is the same person, with the same kinds. The self-image of the manic shifts from painful
developmental history and a constant environment, who self-deprecation to euphoric self-esteem.
cycles between, e.g., incompetent vs omnipotent self- The brain system that interprets the negative emo-
perceptions. The critical factor, then, is the ability of the tional significance of cognitions and external stimuli
reinforcement-reward system to detect the positive comprises the central pain pathways, in which intracra-
qualities of self-cognitions, no less than of external stim- nial self-stimulation is aversive rather than reinforcing
uli or of cognitions about the future. or neutral. The sites thus identified include the mid-

306 CUNICALCHEMISTRY,Vol.40, No.2, 1994

brain tegmentum, the periaqueductal gray area of the bradykinesia. In agreement with this emphasis on the
midbrain, and periventricular areas of the thalamus striatum in psychomotor function are reports of “pure
more rostrally. The classical sensory projection systems psychic akinesia” after bilateral lesions of the basal
involving intralaminar thalanuc relay nuclei, primary ganglia (24).
sensory neocortex, and cortical association areas have
descending connections to the subcortical pain areas Clinical IllustratIons
mentioned above. The amygdala, in particular, occupies The three neurobiological systems described above in
a central position in appraising stimulus input to yield association with specific groups of signs and symptoms
a “value transformation.. that encodes the adaptive in manic depression display bipolar dysregulation ac-
value or affective significance of the stimulus” (21). cording to the phase of illness. They are also to some
There is also experimental evidence linking the basal extent independent or orthogonal components of manic
ganglia to pain perception and regulation (see ref. 3). An depression because change can be seen at times in one
emerging concept is that the basal ganglia exert a sen- system independent of changes in the others. Several
sory gating function in the process of stimulus appraisal clinical examples illustrate this point.

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by modulating the thalamus, which up to now has been The occurrence of mixed states is the primary exam-
regarded as the major site of selective attention to sen- ple. About 30% of manic episodes are of this type, where
sory input and its affective significance. dysphoric (central pain) features coexist with psychomo-
Of the classical neurotransmitters, serotonin and ace- tor acceleration and increased incentive drive. This
tylcholine are known to be important in the perception of state is not the same as agitated depression (3, 25), a
pain. Reduction of serotonergic activity, as with p-chlo- point on which today we disagree with Kraepelin. An-
rophenylalanine, increases responses to aversive stimuli; other mixed state well described by Kraepelin is manic
increasing choilnergic activity has a similar effect. Brain stupor, in which the patient has grandiose thoughts and
enkephalins and other neuropeptides also are involved in elated mood but diminished psychomotor drive. These
mediating pain-responding. Thus, this second fundamen- instances tell us clearly that the three dimensions of
tal brain system is viewed in contemporary models as manic depression can be dissociated at times.
responsible for the expression of a distinct set of signs and As a depressive episode develops, a prodromal change
symptoms characteristic of manic depression. These clin- in the reinforcement-reward system frequently appears
ical features are different from those mediated by the before psychomotor slowing, and central pain symptoms
reinforcement-reward system. may be the last to appear. The patient will become
quiet, withdrawn, and anergic for days or weeks before
PsychomotorRegulation dysphoric symptoms develop. Family members often are
The clinical changes seen in manic depression include aware of the developing episode of depression before the
a third group of signs and symptoms termed “psychomo- patient is.
tor function.” Included here are speed of thought pro- In the early phase of response to a tricycic antide-
cess, cognitive associations, speech volume, speech la- pressant drug such as imipramine, improvement is seen
tency, speech quantity, nonverbal communicative in psychomotor and hedonic function before the dyspho-
gestures, and physical energy. Overall, psychomotor ric symptoms begin to abate. Ward staff will report that
function is accelerated during mania and decelerated the patient is spending more time out of his room, seek-
during depression. In extreme forms, the psychomotor ing social contact, eating better, and is less psychomo-
dysregulation can progress to depressive stupor on the tor-retarded, though at this transitional time the pa-
one hand, and to manic frenzy on the other. tient reports feeling unchanged in his dysphoric
The anatomic substrate of these functions is viewed as thoughts. For these reasons, this early response to a
the “distributed processing system,” which includes tricycic is recognized clinically as a time of increased
frontal cortex, basal ganglia, cerebellum, and thalamus risk of suicide attempt.
(22). For the executive control of motor programming by In the treatment of mania, use of a neuroleptic drug
this system, Shepherd (22) has emphasized the central such as haloperidol will control the dopamine-driven
programming role played by the subcortical striatal sys- psychomotor acceleration and incentive drive but does
tem, as opposed to the primacy previously accorded to not modify the inhibited central pain features. Thus,
the motor and premotor cortex. Nauta (23) stresses the manic patients continue to express grandiose thoughts
equivalent functions of the ventral striatum (nucleus and convictions of special powers despite the psychomo-
accumbens) and ventral pallidum, with their corre- tor slowing produced by the drug. Basically, use of a
sponding connections to ventral tegmental dopamine neuroleptic drug by itself in treating a manic episode
nuclei (A9 area), dorsomedial thalamus, and limbic cor- simply provides behavioral control of the patient until
tex, including amygdala, in the executive control of cog- the mania resolves of its own course.
nitive processes and emotional expression. Of the clas- As a final example, the acetylcholinesterase inhibitor
sical neurotransmitters, dopanune has a facilitatory physostigmine will rapidly produce dramatic change in
(accelerating) role, and acetylcholine has the opposite a manic subject. Within 10 min of starting an infusion of
effect. In the depressed phase of manic depression, the physostigmine, the patient will display psychomotor
psychomotor deceleration resembles the bradyphrenia slowing, decreased hedonic activity, and reduced incen-
seen in Parkinson disease, at times separately from tive drive. Only later will dysphoric symptoms appear,

CLINICALCHEMISTRY,Vol.40, No.2, 1994 307

in the form of depressed mood, tearfulness, pathological visuospatial perception in mania, depression, and psychotropic
guilt, and suicidal ideation. As the drug is eliminated medication. Biol Psychiatry 1992;32:399-410.
9. Faedda GL, Tondo L, Teicher MH, Baldessarini RJ, Gelbard
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10. Winokur G, Coryell W, Keller M, Endicott J, Akiskal H. A
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of these clinical ifiustrations is to emphasize that anal- 11. Krauthammer C, Kierman GL. Secondary mania. Arch Gen
Psychiatry 1978;35:1333-9.
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systems is possible. The challenge for the future will be of synthesis inhibitors in defining a role for biogenic amines during
to understand more completely the anatomic and neu- iniipramine treatment in depressed patients. Psychopharmacol
rotransmitter connections among these three brain sys- Res Commun 1975;1:239-49.
13. Delgado PL, Charney DS, Price LH, Aghjanian GK, Landis
tems in manic depression. The basal ganglia are likely H, Heninger GR. Serotonin function and the mechanism of anti-
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From this review, one can see that single-neurotrans- 14. Jamison K. Touched with fire: manic-depressive illness and
the artistic temperament. New York: The Free Press, 1993:227.
mitter theories of the disorder are not likely to account 15. Mendlewicz J, Leboyer M, De Bruyn A, Malafosse A, Sevy S.
for the wide array of observed signs and symptoms. The Hirsch D, et al. Absence of linkage between chromosome llpl5
nature of the switch mechanism into mania or depres- markers and manic-depressive illness in a Belgian pedigree. Am J
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16. Hebebrand J. A critical appraisal of X-linked bipolar illness:
lithium protects against both manic and depressive evidence for the assumed mode of inheritance is lacking. Br J
switches. There is no longer any doubt, however, of the Psychiatry 1992;160:7-11.
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Tourette’s syndrome and associated behaviors: evidence for auto-
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This work was supported by NIH grant MH40159, CRC/PR for try 1990;51(Suppl 2):22-5.
the study of depression in late life. 19. Goldfarb LG, Petersen RB, Tabaton M, Brown P, LeBlanc AC,
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