Melancholia: A History of Diagnosis and Treatment
Jakarta, Indonesia, July 1, 1996
Thomas A. Ban
 

Table 1             

                 DESCRIPTION OF MELANCHOLIA

OLD TESTAMENT        BOOK OF JOB                  HOMER'S  ILLIAD       

 "IF WE DON'T KNOW WHAT WE ARE TALKING ABOUT WE CAN STILL

TALK AND MOST LIKELY TALK VOLUBLY BUT THERE IS SMALL CHANCE    THAT WE ARE TALKING TO A DEFINITE POINT" (Wilson 1932:Amer J Cancer)

Table 2            

                   EPIDEMIOLOGICAL FINDINGS

        COHEN & FAIRBANK        1938           0.80%

        LEMKAU & AL             1941           0.90%

        LIN                     1952           0.40%

        EATON & WEIL            1955           0.80%

                    Imipramine-Kuhn-1957

        LEIGHTON & AL           1963           7.50%

        BLUMENTHAL & DIELMAN    1975          13.00%

        VAISANEN                1975           7.50%

        WEISSMAN & MYERS        1978           6.50%

               Point Prevalence (DSM-IVTM 1999)

        MDD                     1999           4.75%

        DYSTHYMIA               1999           3.00%

Table 3                                     

                       MELANCHOLIA

                    RECURRENT EPISODIC     

                     30%-35$ CHRONIC

                         SYMPTOMS

   Manifestations                 Depth of Depression

   Clinical Features        None    Mild    Moderate    Severe

                              %       %         %         %

   STOOPED POSTURE            6      32        70        98

   DIURNAL VARIATION          6      13        37        37

   SUICIDAL IDEAS            12      47        73        94

   SADNESS                   16      72        94        94

   LOSS OF APPETITE          17      33        61        88

   INDECISIVENESS            18      42        68        83

   FEELING INADEQUATE        25      56        75        90

   SLOWED SPEECH             25      53        72        75

   GUILT FEELINGS            27      46        64        60

   LOSS OF LIBIDO            27      38        58        61

   SLEEP DISTURBANCE         31      55        73        88

   LOW SELF-ESTEEM           38      60        78        81

   FATIGABILITY              39      62        89        84

   SELF-BLAME                43      67        80        80

Table 4                  

        1957 - 1999 UK POPULATION ON ANTIDEPRESSANTS       3%

        1996 - 2000 CANADA: PRESCRIPTION OF ADS INCREASED +62%

        1999    5TH LEADING CAUSE OF DISABILITY

        2020    2ND LEADING CAUSE OF DISABILITY

        UNDERTREATED        INCREASE OF PRESCRIPTIONS OF ADS

                            Canada              1994-1999

                            Point prevalence   2.4% -  1.9%

                            Antidepressants    18.2% - 32.6%

        1 OF 3 RESPONDS TO ADS

Table 5         

            HISTORICAL DEVELOPMENT OF DIAGNOSES

            HISTORICAL DEVELOPMENT OF TREATMENTS

            COMPOSITE DIAGNOSTIC EVALUATION OF DD

Table 6          

  HIPPOCRATES 4th BC. MANIA          ACUTE MENTAL DISTURBANCES

                      MELANCHOLIA    CHRONIC MENTAL DISTURBANCES

  CELSUS      1st AC. MELANCHOLIA    SADNESS-MELANCHOLIA

  ARETAEUS    1st AC. MELANCHOLIA    EPISODIC: ALTERNATES WITH  

                                     MANIA

  GALEN       2nd AC. ON MELANCHOLY ILLNESS vs TEMPERAMENT

         SYMPTOMS FOLLOW ILLNESS LIKE SHADOW ITS SUBSTANCE

         Forms: General M Brain M Hypochondriacal M

         Causes: Black bile, Yellow bile, Dietary, Emotional

                 Suppression of hemorrhoidal flux

Suppression of menstrual flux

Table 7         

   AURELIANUS     5th    Melancholia    MENTAL ANGUISH & DISTRESS

                                        WITH DEJECTION, SILENCE,

                                        ANIMOSITY, LONGING FOR

                                        DEATH, SUSPICION &  

                                        WEEPING

   TIMOTHY BRIGHT 16th    TREATISE

                             of

                          MELANCHOLIA

           NATURAL M                        UNNATURAL M

Galenic temperament              Severe mental disorder

 Sad and gloomy disposition, vague            Insanity

 feelings of sulliness, irritabilty   Violent disorderly passions

 moodiness, and oddities of conduct

Table 8           

SYDENHAM              17th From syndromes to disease

BOISSIER DE SAUVAGES  18th  M: Disorders of Intellect

CULLEN                18th         VESANIAS

                              Disorders of Judgement

                        AMENTIA Inbeciltiy of Judgement

                        MELANCHOLIA Partial distortion of reality

                        MANIA Universal distortion of reality

CHIARUGI              18th     MELANCHOLIA    MANIA       AMENTIA

                               True (sad)

                               False (happy)

                               Violent

PINEL                 18th     MELANCHOLIA    MANIA       AMENTIA

Table 9         

                REID (1764) FACULTY PSYCHOLOGY

                 Intellect, Emotion, Volition

                       HEINROTH  (1818)           

                MELANCHOLIA: PARTIAL INSANITY

 FACULTIES      EXALTATIONS       DEPRESSIONS      MIXED        

 Intellect      Paranoia          Dementia         Confusion

 EMOTION        Insanity          MELANCHOLIA      DELUSIONAL M

 Volition       Manai             Abulia           Angst

Table 10           

         PINEL (1798, 1801)           ESQUIROL (1838)

         MELANCHOLIA                  LYPEMANIA                               

         Delirium about              Sad mood affects

         one subject                 thinking,feeling

         exclusively                 & will

    MANIA WITHOUT DELIRIUM      MONOMANIA

                                     Intellectual

                                     Affective

                                     Instinctual

         MANIA WITH DELIRIUM         MANIA

         DEMENTIA                    DEMENTIA

         IDIOTISM                    IMBECILITY

Table 11         

                 GRIESINGER (1845, 1861)

STATES OF MENTAL DEPRESSIONS

Hypochondriasis

Melancholia in a limited sense

Melancholia with stupor                                        

Melancholia with destructive tendencies

   Murderous homicidal

   Murderous suicidal

   Melancholia with persistent excitement of the will           STATES OF MENTAL EXALTATION

   Monomania

   Mania

STATES OF MENTAL WEAKNESS

Table 12           

            KAHLBAUM   1863   VECORDIA        DYSTHYMIA

            KRAEPELIN  1891   MELANCHOLIA     MELANCHOLIA

                              Periodic P      Depressive

                              Delusional P    Depressive

                       1896   INVOLUTIONAL P  INVOLUTIONAL M

                              Periodic P      Depressive

                       1899   INVOLUTIONAL P  INVOLUTIONAL M

                              MD Insanity     Depressive States

                       1904   MD Insanity

                       1904   MD Insanity

Table 13            

              UNITARY CONCEPT OF MELANCHOLIA

          Kraepelin 1891 Mapother 1926 Lewis 1934

     AUTHOR       YEAR                 SYNDROMES

Hamilton&White    1959   RETARDED   AGITATED

Kiloh&Garside     1963   ENDOGENOUS NEUROTIC

Plowsky et al     1969   ENDOGENOUS NEUROTIC

Foulds            1976   PSYCHOTIC  NEUROTIC  DYSTHYMIC

Overall et al     1966   ANXIOUS    HOSTILE   RETARDED

Wing et al        1974   PSYCHOTIC  ANXIOUS   HOSTILE

Paykel           1971   PSYCHOTIC  NEUROTIC  ENDOGENOUS

YOUNGWITH PERSONALITY

DISORDER

Raskin et al      1976   ENDOGENOUSAGINOUS      POOR PREMORBID

                                              PERSONALITY

Table 14          

               KRAEPELIN'S UNITARY CONCEPT 1904

    SYMPTOMATIC               ENDOGENOUS            PSYCHOGENIC

    Bonnhoeffer                 Moebius               Wimmer

      1910                       1900                  1916

DEPRESSIVE PSYCHOPATHY    VITAL DEPRESSION    REACTIVE DEPRESSION                          Schneider 1920, 1958

                               LEONHARD

                                 1957

UNIPOLAR                                                    BIPOLAR

Pure Melancholia

Pure Depressions

   Non-participatory

   Harried

   Hypochondriacal

   Self-torturing

   Suspicious

Table 15            

                KKRAEPELIN   1891    THOUGHT RETARDATION

                                     DECREASED DRIVE

                SCHNEIDER    1920    CORPORISATION

                                     FEELING OF LOSS OF VITALITY

                BERNER ET AL 1983    DIURNAL VARIATION

                                     SLEEP DISTURBANCE

Table 16                  

                    ADOLF MEYER 1908 (1952)

               Spectrum of Affective Reactions

             Replaced Melancholia with Depression

           Assigned Depressions to Hypothermergasias 

                     ROBINS & GUZE 1972

           PRIMARY                          SECONDARY

                     SPITZER ET AL 1978

             MAJOR                            MINOR

                DSM-III (1980) - DSM-IV (1994)

        MAJOR DEPRESSION                    DYSTHYMIA

        LOSS OF PLEASURE                    DEPRESSSED MOOD               Disturbance of Concentration        Feelings of Guilt

        Suicidal Ideation                   Disturbed Sleep

        Loss of Appetite                 Retardation/ Agitation                

                         Covered Up

  Component diagnoses & Treatment responsive forms of illness

TABLE 17        

                        DEPRESSED MOOD

                LOSS OF INTEREST/ENJOYMENT/PLEASURE

              (INCREASED FATIGABILITY/LOSS OF ENERGY)

             REDUCED CONCENTRATION/ATTENTION/THINKING

                    IDEAS OF GUILT/UNWORTHINESS

              IDEAS OR ACTS OF SELF-HARM OR SUICIDE

                        DISTURBED SLEEP

                      DIMINISHED APPETITE

              Reduced Self-esteem Confidence (ICD-10)

          Bleak Pessimistic Views of the Future (ICD-10)

           Psychomotor Retardation or Agitation (DSM-IV)

     ICD-10= 2+ typical & at least 2 of 3 other; 5 specifiers

   DSM-IV= 5+ other with at least 1 of 2 typical; 15 specifiers

TABLE 18         

                    FROM DSM-III TO DSM-IV

                       MAJOR DEPRESSION    

                          More Severe

                         Less Prolonged

                          DYSTHYMIA           

                         Less Severe

                        More Prolonged

                   CONSENSUS BASED DIAGNOSES

         Component Diagnoses Covered Up (Vital Depression)                  Treatment Responsive Forms of Illness Covered Up

Table 19      

                     SAMUEL TUKE 1813

                 York Retreat 30 Patients

  MEDICAL & MORAL TREATMENT                     70% Response Rate

  Warm Bath & Physical Exercise                  (65% recovery)

                     RAVINDRAN & AL  1999

  Sertraline & Gognitive Therapy           71% Response Rate

                     KELLER ET AL 2000

  Nefazodone & Cognitive Behavioral Analysis  85% Response Rate

Table 20       

                           POPPY

                     Papaver Somniforum

 PARACELSUS          1493-1541     LAUDANUM (elixir-arcanum)

 ALBRECHT von HALLER  1708-1777    OPIUM (analgesic & soporofic)

                   OPIUM CURE: 1890-1957          

            3 Weeks: 3-25 Minims= 50% Discharged

                            ECT

        Dinitrile Succinate (Gillis and Salfield 1953)

               Hematoprophyrin (Bruel 1957)

           Reserpine (Davies and Shepherd 1955)

Table 21           

                        CHLORPROMAZINE

               Anticholinergic Phenothiazines

               Levomepromazine (Ban & Schwarz 1963)

               Thioridazine (Overall et al 1966) 

                     ANTIDEPRESSANTS 1957

            IMIPRAMINE                Kuhn TA-MAUI

            IPRONIAZID                Loomers et al -MAOI

                   SPECTROPHOTOFLUORIMETER

            RESERPINE     Decr.NE/5-HT      DYSPHORIA

            IPONIAZID     Incr.NE/5-HT      EUPHORIA

TABLE 22          

                          MAOIs

 ESSENTIAL            HYDROXYLATION           CEREBRAL

AMINO ACIDS          DECARBOXYLATION         MONOAMINES

Phenylalanine                                   NE

Tryptophan                                    5-HT

       MONOAMINES         MAO            OXIDATIVE DEAMINATION

              Pugh&Quastel,Blaschko et al 1937

IPRONIAZID MAOI

                   Zeller et al 1952

SPECTROPHOTOFLUORIMETER

Pletscher, Brodie, Carlsson, Shore, Beckmann           

       RESERPINE       Hollister          DYSPHORIA

       IPRONIAZID      Selikoff et al     EUPHORIA           

Table 23            

IPRONIAZID MAOI    isopropyl derivative       Crane 1957

                                              Loomers et al 1957

ISONIAZID Non-MAOI                            Delay et al 1952

                                              Salzer&Lurie 1953

IPRONIAZID                                    hepatotoxicity

PHENIPRAZINE                                  hepatotoxicity

TRANYLCYPROMINE                               hypertensive crises

                   Atypical Depression

  Hysteroid features, hypersomnia, excessive appetite

Type A                Clorgylene              Youdim

Type B                Deprenyl                Knoll 

   PHENELZINE       TRANYLCYPROMINE         MOCLOBEMIDE

Table 24             

                          MAUIs

                        IMIPRAMINE

              Kuhn 1957; Klerman & Cole 1965

  23STS   1009PTS   550IMI   459PBO   65%IMI2of3    PBO35%1of2

                  Domenjoz & Theobald 1959

  Antihistaminic  Anticholinergic  Noradrenergic  Serotonergic

                     Costa et al 1960

           IMIPRAMINE REVERSED RESERPINE INDUCED

          sedation, hypothermia, ptosis, diarrhea  

                    AMPT - DESIPRAMINE

                      CONFOUNDING

       RESERPINE REVERSAL WITH ANTIDEPRESSANT EFFECT

 ACTION MECHANISM OF THE DRUG WITH PATHOMECHANISM OF THE ILLNESS

Table 25          

                          SSRIs

VETULANI   1975     intact 5-HT system   Beta-adrenergic receptor

 down-regulation

SHOPSIN    1976     PCPA                 Reverses effects of IMI

LANGER     1980     IMI & 5-HT binding    Hypothalamus of rat

                               sites

PAUL       1980     IMI & 5-HT binding    Human platelet

     STIMULATION of 5-HT2A COMPENSATORY DECLINE OF DA

Imduce insomnia, reduce appetite, interfere with sexual functioning irritability,    anxiety          akathisia with suicidal/homicidal

                      NEW DRUGS

VENLAFAXINE SNRI-SE  

(NEFAZODONE SeSSA)   

(MIRTAZEPINE NaSSA)

SNRI-NA/SE   NARI  SSRI   NaSSA/SeSSA   MAOI/MAOI-A   SePr

TABLE 26

                   22 ANTIDEPRESSANTS IN CANADA

               SNRI-NA       AMITRIPTYLINE/IMIPRAMINE/AMOXEPINE/

                             DOXEPIN

               SNRI-SE       CLOMIPRAMINE/VENLAFAXINE

               NARI         DESIPRAMINE/MAPROTILINE/NORTRIPTYLINE

               SSRI          FLUOXETINE/PAROXETINE/FLUVOXAMINE/                                 SERTRALINE

               NaSSA         TRIMEPRAMINE/(MIRTAZEPINE)

               SeSSA         TRAZODONE/(NEFAZODONE)

               MAOI          PHENELZINE/TRANYLCYPROMINE

               MAOI-A        MOCLOBEMIDE

               NDRI          BUPROPION

               SePr          L'TRYPTOPHAN

Table 27            

       DRUGS                               RESPONSE RATES %

 NAME         CLASS                        DRUG     PLACEBO

Sertraline    SSRI                          79         48

Imipramine    NSRI-NA                       68         40

Fluvoxamine   SSRI                          67         39

Amoxapine     NSRI-NA                       67         49

Phenelzine    MAOI                          64         30

Moclobemide   MAOI-A                        64         24

Fluoxetine    SSRI                          60         33

Amitriptyline NSRI-NA                       60         25

(Mirtazepine   NaSSA                        48         20)

Paroxetine    SSRI                          45         23

       Response rates (HAMD 50%). Meta analyses of

       Davis et al 1993

TABLE 28

    SIDE EFFECTS                      WEIGHTED EVENT RATE

                                        SSRI       TCA

                                          %         %

   Agitation                             14         8

   Anxiety                               13         7

   Constipation                          10        22

   Diarrhea                              13         5

   Dizziness                             13        23

   Dry mouth                             21        55

   Headache                              17        14

   Insomnia                              12         7

   Nausea                                22        12

   Nervousness                           15        11

             Based on Trinade and Menon 1997

   RESPONSIVENESS TO A SECOND STRUCTURALLY & PHARMACOLOGICALLY

   DIFFERENT ANTIDEPESSANT IS ENCOUNTEED MORE FREQUENTLY THAN

   IT COULD BE ACCOUNTED FOR BY CHANCE/PLACEBO EFFECT

TABLE 29          

              EACH DRUG HAS ITS OWN IDENTITY

                   Chemical Structure

                Pharmacological Profile

                  THERAPEUTIC PROFILE

                    No Information

           RESPONSIVENESS TO A SECOND STRUCTURALLY &

           PHARMACOLOGICALLY DIFFERENT ANTIDEPRESSANT

           IS ENCOUNTERED MORE FREQUENTLY THAN IT

           COULD BE ACCOUNTED FOR BY CHANCE/PLACEBO

           EFFECT

TABLE 30         

   PHARMACOTHERAPY WITH ADs FOCUSSED ATTENTION ON THE

   PHARMACOLOGICAL HETREOGENEITY OF DEPRESSIVE ILLNESS

  ATTEMPTSTO RESOLVE HETEROGENEITY INCONSISTENT RESULTS

                Linear Regression Equation

                Biological Markers

                Pharmacological Load Tests

                Biochemical Indicators

  KIELHOLZ 1968   Secondary Amines      Motor Retardation

                  Tertiary Amines      

  POTTER   1985   MHPG                   NARI     

                  5-HIAA                 SSRI

                  Desipramine/Zimelidine Lowers Both

TABLE 31   

     DRUGS            RESPONSE RATES        IC50 Value (nM)

                                            5-HT        NE

    AMITRIPTYLINE           60              100         25

    AMOXAPINE               67              600         25

    FLUOXETINE              60               15        200

    FLUVOXAMINE             67                5        500

    IMIPRAMINE              68               50         25

    PAROXETINE              45                1         70

    SERTRALINE              79                4        300

                   Adopted from Ban 1999

           THE SAME PATIENT TEND TO RESPOND IN

           DIFFERENT EPISODES TO THE SAME DRUG

TABLE 32           

     THE INFORMATION GENERATED WITH THE METHODOLOGY

           FOCUSSED ON THERAPEUTIC EFFICACY  COVERED UP THE

           POSSIBLE DIFFERENCES BETWEEN ANTIDEPRESSANTS

     DIFFICULTIES ENCOUNTERED IN THE DEMONSTRATION

           OF THE THERAPEUTIC EFFECTIVENESS OF IMIPRAMINE

           DUE TO LACK OF SENSITIVE INSTRUMENTS

     IN EFFICACY THE INVERSE RELATIONSHIP BETWEEN THE

           HETEROGENEITY OF THE DEPRESSIVE POPULATION

           AND RESPONSIVENESS TO TREATMENT IS EXPRESSED

     TO DEVELOP INSTRUMENTS WHICH ARE SENSITIVE FOR

           CHANGES IN SEVERITY OF SYMPTOMS & RELIABLE

     CLINICAL DIAGNOSTIC END-POINTS

          Pharmaceutical Industry

          Practicing Psychiatrists

     COUNTERPRODUCTIVE FOR IDENTIFYING THE TREATMENT

         RESPONSIVE FORMS OF ILLNESS IN THE VAST DATA BASES

TABLE 33     

                      OBSTACLES

   Consensus Based Classifications                            

   THE PRIMARY PURPOSE OF THE DSM-III WAS THE CREATION OF A

   COMMON LANGUAGE AND NOT THE PROVISION OF DIAGNOSTIC END-

   POINTS FOR CLINICAL INVESTIGATIONS

   TO ACCOMODATE THE DIFFERENT ORIENTATIONS IN PSYCHIATRY THE

   DIAGNOSTIC CATEGORIES ARE BROAD AND BY ACCOMODATING THE DIF-

   FERENT FORMS OF DISEASE IN A LIMITED NUMBER OF DIAGNOSES THE

   DIAGNOSTIC CATEGORIES ARE HETEROGENOUS AND THEIR PREDICTIVE

   VALIDITY IS LOW

   RAPID SUCCESS: RELIABLE CLINICAL END-POINTS FOR CLINICAL DRUG

                  DEVELOPMENT & FOR THE COMMUNICATION OF APPROVED

   INDICATIONS OF ANTIDEPRESSANTS

Sensitised Rating Scales

   RATING SCALES CAN BE SENSITISED BY THE OMISSION OF SYMPTOMS

   WHICH ARE NOT INFLUENCED BY TREATMENT OR RETAINING ONLY ITEMS

   WHICH SHOW THE LARGEST CHANGES                

   SENSITIVE SCALES HELP TO DEMONSTRATE THERAPEUTIC EFFECTIVENESS

   IN THE SHORTEST POSSIBLE TIME IN THE SMALLEST NUMBER OF

   PATIENTS BUT PRECLUDES THE POSSIBILITY OF FINDING ANY RELEVANT    INFORMAT-ION IN THE VAST DATA BASES BY META-ANALYSES

TABLE 34           

    TO BREAK THE IMPASSE IN IMPROVING THERAPEUTIC EFFECTIVENESS

    THERE IS A NEED FOR A SHIFT IN EMPHASIS IN CLINICAL RESEARCH

    FROM THE DEMONSTRATION OF THERAPEUTIC EFFICACY TO THE IDEN-

    TIFICATION OF THE TREATMENT RESPONSIVE FORMS OF ILLNESS

    CONSENSUS-BASED DIAGNOSTIC END-POINTS AND SENSITIVE SCALES

    NEED TO BE SUPPLEMENTED/REPLACED BY COMPOSITE DIAGNOSTIC         EVALUATIONS & COMPREHENSIVE PSYCHOPATHOLOGIC CHECK LISTS

Table 35      

  SHIFT EMPHASIS FROM EFFICACY TO IDENTIFICATION OF TREATMENT

             RESPONSIVE FORMS OF ILLNESS

                     CODE SYSTEM

   SET OF DIAGNOSTIC INSTRUMENTS WHICH BY SPECIALLY DEVISED

   ALGORITHMS CAN ASSIGN A DIAGNOSIS FROM SEVERAL DIAGNOSTIC

   SYSTEMS SIMULTANOUSLY

                                                      CODE-DD

   EACH CODE CONSISTS OF: SET OF SYMPTOMS               90

                          SEMI-STRUCTURED INTERVIEW

                          DIAGNOSTIC DECISION TREES     25

TABLE 36       

                         CODE-DD

      RATING SCALE FOR DEPRESSIVE DIAGNOSES      90 ITEMS

      RS F ASSESSMENT OF SEVERITY OF DD          40 ITEMS

      SEMI-STRUCTURED INTERVIEW                  90

      DECISION TREES                             25

                    1.  KRAEPELIN 1891

                    2.  SCHNEIDER 1920

                    3.  LEONHARD  1957

                   15.  PAYKEL    1971

                   23.  BERNER    1983

                   25.  CDC       1989

      COMPLETED: 30-40 MINUTES WITH OR WITHOUT COMPUTER PROMPTING

      RELIABILITY-MEDIAN ITEM AGREEMENT: 87.8%  1st Study

                                        100.0%  2nd Sudy

                                        100.0%  3rd Study

      Overall Kappa coefficient of 1.00

Table 37         

DSM-III-R MAJOR DEPRESSION IS A BROAD & HETEROGENOUS DG CATEGORY

  1. Number and % of 230 patients with the dg. of MD who could        not be classified as depressed

          VRC                  77       33.5%

          KDS                  54       23.5%

          LEONHARD             41       17.8%

          HAMILTTON            36       15.7%

          RDC                  31       13.5%

          OVERALL              31       13.5%

  2. Depressive illness: unmotivated depressed mood, depressive         evaluations and lack of reactive mood changes (N=322)

     DEFINITE: 119 (37%) PROBABLE: 91 (28.2%) POSSIBLE: 61 (19%)

               15.8%-63.0% iatrogenic

  3. KDS: depressed mood, motor retardation & thought retardation

     SVD: unmotivated depr mood, corporization, loss of vitality

     Less than 50% overlap between 2 diagnoesgs in 2 studies

Table 38       

       NOSOLOGIC HETEROGENEITY=PHARMACOLOGICAL HETEREOGENEITY

       NEUROPSYCHOPHARMACOLOGY LINKS EFECT ONMENTAL ILLNESS &           BRAIN STRUCTURES PROVIDES ANDBRIDGES GAP BETWEEN GENES &         PSYCHIATRIC NDOSOLOGY

  PRIMARY TARGETS OF ADS MOLECULAR STRUCTURES INVOLVED IN     NEURONAL TRANSMISSION ENCODED BY GENESHICH HAVE BEEN        IDENTIFIED TREATMENT RESPONSIVE POPULATION IS SUITABLE FOR   THE GENERATION OF GENETIC HYPOTHESES WITH CANDIDATE GENE    APPROACH

Table 39          

  1970 DEVELOPMENT OF RECEPTOR BINDING ASSAYS

  1980 IDENTIFICATION OF RECEPTOR SUBTYPES

       DELINEATION OF RECEPTOR PROFILES

  1990 GENETIC TECHNOLOGY

       TAILORING DRUGS TO RECEPTOR AFFINITIES

       BY USING CELL LINES TRANSFECTED  WITH CLONED RECEPTORS

       FOR FINDING CHEMICALS WHICH FIT SPECIFIC RECEPTORS &

       DESIGNING ADS WHICH COULD FIT DISEASES LIKE KEYS THEIR

       LOCKS

  2000 IF CURRENT CAPABILITY OF NEUROPHARMACOLOGICAL RESEARCH

       WOULD BE COMPLEMENTED WITH CLINICAL PSYCHOPHARMACOL-

       OGICAL RESEARCH (CODE-DD) IT WOULD OPEN UP A NEW PER-

       SPECTIVE IN THE TR OF THE DIFFERENT FORMS OF DISEASE             COVERED UP BY THE DG CATEGORY OF MAJOR DEPRESSION

Table 40 

                        CONCLUSIONS

1. IN SPITE OF THE GROWING USE OF ADS D IS EXPECTED TO BECOME THE    2ND LEADING CAUSE OF DISABILITY BY 2020

2. IDENTIFICATION OF THE TREATMENT RESPONSIVE FORMS OF D IS THE

   ESSENTIAL PREREQUISITE FOR REDUCING D-INDUCED DISABILIT

3. NPS PROVIDES A METHOD FOR RESOLVING THE HETEROGENEITY OF D &

   FOR BRIDGING THE GAP BETWEEN NOSOLOGY AND THE GENES

4. CONSIDERING WHAT PHAMACOGENOMICS CAN OFFER INDUSTRY IS

   PREPARING   FOR A CHANGE IN WHICH GENETIC INFORMATION WILL       DEFINE TREATMENT

5. IN THE NEW PERSPECTIVE EACH DIFFERENT FORM OF DISEASE SUBSUMED

  UNDER DEPRESSION WILL GET ITS OWN "MAGIC BULLET"

Thomas A. Ban

July 21, 2016

MARTIN KATZ: ONSET OF ANTIDEPRESSANT EFFECT

Reply by Donald Klein on Comment by Elemer Szabadi

The debate between Martin Katz and myself centers on the question of how soon after antidepressant treatment is initiated does specific treatment benefit become manifest. The relevant measures used were weekly psychiatric scales, in placebo controlled clinical trials.

Dr. Szabadi (Szabadi et al., 1976) proposes an alternative measure: decreases in the speech pause time during automatic counting. His pilot study of four subjects during antidepressant treatment was promising. The article does not refer to the “small group” that showed effects during the first treatment week. Since there were only 4 subjects, one wonders at the size of this subgroup.

However, several studies found similar findings relating decreased speech pause time to improvement in depression. One mentioned that agitated depressions showed opposite effects. I was unable to find any placebo controlled clinical trial that used speech pause time as a dependent measure and I would appreciate such references.

Dr. Szabadi's simple, objective observation has been neglected. Any contribution to the Katz-Klein disagreement depends on its relative value to the usual scales for detecting clinical improvement. Conceivably, it might be measuring the degree of retardation, which is clinically difficult to evaluate but is an important component of remission.

If it were shown that only those drug treated patients with marked decreases in pause time during the first treatment week went on to substantial clinical improvement, this would be in harmony with Marty's views. Contrariwise, if many patients showed a later onset of substantial maintained improvement that would argue against the stand that early improvement can serve as a surrogate for eventual improvement.

I think the data generated by scales have already invalidated Katz's hypotheses. Nevertheless, such promising alternative measures are, in principle, welcome. Funding their evaluation is another issue.

Donald F. Klein

October 22, 2015