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Brain Mechanisms in Manic Depression

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  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
  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
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  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
  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

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  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
  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

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  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-
  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-

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  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.
  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,

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                                                                                                        CHEMISTRY, ol.40, No.2, 1994                     307
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                                                                           9. Faedda      GL, Tondo L, Teicher MH, Baldessarini RJ, Gelbard
  over the next 2 h, the patient will return to his previous               HA, Floris      GF. Seasonal mood disorders: patterns of seasonal
  manic state.                                                             recurrence     in mania and depression. Arch Gen Psychiatry 1993;
      In each of these clinical examples,           the neurotrans-        50:17-23.
                                                                           10. Winokur     G, Coryell W, Keller M, Endicott J, Akiskal H. A
  mitter basis of the specific shifts can be inferred (see ref.            prospective follow-up of patients with bipolar and primary unipo-
  2). Other examples also could be given. The importance                   lar affective disorder. Arch Gen Psychiatry   1993;50:457-65.
  of these clinical ifiustrations        is to emphasize    that anal-     11. Krauthammer        C, Kierman GL. Secondary mania. Arch Gen
                                                                           Psychiatry     1978;35:1333-9.
  ysis of the signs and symptoms in terms of specific brain                12. Shopsin B, Gershon       5, Goldstein M, Friedman E, Wilk S. Use
  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-
  to assume a prominent place in these connections                  (3).   depressant action. Arch Gen Psychiatry 1990;47:411-8.
  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
  sion is still speculative,      as is our understanding       of how     Psychiatry 1991;148:1683-7.
                                                                           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.
  genetic influence in manic depression or of the major                    17. Pauls DL, Leckman           JF. The inheritance      of Gilles de la
                                                                           Tourette’s syndrome and associated behaviors: evidence for auto-
  importance       of biological     factors in the etiology and           somal dominant transmission.        N Engi J Med 1986;315:993-7.
  treatment     of this disorder.                                          18. Baxter L. Brain imaging as a tool in establishing          a theory of
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    This work was supported by NIH grant MH40159, CRC/PR for               try 1990;51(Suppl 2):22-5.
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