Thomas A. Ban
Neuropsychopharmacology in Historical Perspective

Psychopharmacology and the Classification of Functional Psychoses


9. Affective Psychosis


       The origin of the concept of affective psychosis is in the 1850s when Falret stated that a predictable "natural course" of an illness "presupposes the existence of a natural species of disease with a pattern of development." It was the application of this notion to the description of a "natural species" ("endogenous") of disease, that presents with two specific cross-sectional psychopathological syndromes (i.e., manic and melancholic) and follows a predictable "natural course" that led to the recognition of manic-depressive illness.

       Falret in his lectures at Salpetriere (Lecons a l'Hospice de l’Salpetriere) during 1850-1851, was first to describe folie circulaire, the disorder later to become known as manic-depressive psychosis. In the same year, 1854,  that Falret published his thesis De la folie circulaire, Baillarger (1854) presented  a somewhat similar diagnostic concept, he referred to it as folie a double forme to the French Academy of Medicine (Pichot 1983). There has been some controversy regarding priority.


Manic-Depressive Illness


       In spite of the early recognition by Falret and Baillarger, folie circulaire, a three-dimensional diagnosis which takes into consideration onset, cross-sectional psychopathology and course, was not recognized worldwide until the publication of the 5th edition of Kraepelin's textbook of psychiatry in 1896.

       In the first edition of his textbook, published in 1883, Kraepelin described six different forms of melancholia: simplex, gravis, stuporous, paranoid, fantastic and delirious, and four different forms of mixed states: depressed mania, agitated depression, depression with flight of ideas and depression with partial inhibition. In the 5th edition of his text, published in 1896, he contended that all of these different forms of disease were manifestations of one and the same nosological entity, manic-depressive insanity (Hippius, Peters and Ploog 1983).

       Kraepelin's original definition of manic-depressive insanity included "the whole domain of the so-called periodic or circular insanities" as well as "simple mania, most of the morbid states referred to as melancholia, and also a considerable proportion of the amentias.” This already broad definition was expanded later to include "all cases of affective excess." Ultimately, on the basis of findings by Dreyfus (1905), it included also “involutional melancholia,” a disorder regarded at the time as a separate diagnostic entity because of its prolonged course.

       Although the unitary concept of manic-depressive insanity had already been questioned by Jaspers (1913a), it was not until Leonhard's publication of his text on the Classification of Endogenous Psychoses in 1957 that a consistent attempt to break the unitary concept of manic-depressive psychosis began (Perris 1974). First with consideration of the end-states of the illness, Leonhard separated a number of distinct disorders within manic-depressive illness.

       By introducing the concept of "polarity" he distinguished within the affective psychoses bipolar and unipolar forms. In the "bipolar" both manic and depressive episodes occurred in the same patient. In the “unipolar”  form, he originally referred to as “monopolar,” there were only "depressive" or only “manic” episodes.

       Stimulated by Leonhard's work, two independent investigations were carried out, one by Jules Angst (1966) in Switzerland and the other by Carlo Perris (1966) in Sweden. Results of these studies favored the distinctiveness of bipolar and unipolar affective psychoses on the basis of "heredofamilial factors" (Angst and Perris 1968). Similar conclusions were reached by Winokur and Clayton (1967) in the United States. Furthermore, in bipolar patients urinary 3-methoxy-4-hydroxy-phenyl-glycol (MHPG) concentrations (Beckman and Goodwin 1975) and platelet monoamine oxidase (MAO) activity (Murphy and Weiss 1972) were found to be significantly lower than in unipolar patients.

       In the DAS of the KDK (Pethö, Ban, Kelemen et al. 1984) the diagnosis of affective psychosis is based on the evaluation of 27 variables. They include variables relevant to mood (hyperthymic, dysthymic, irritable); variables relevant to onset (acute, subacute); and variables relevant to the overall (Gestalt) disease picture (simple, multiform).    Other, cross-sectional psychopathological manifestations included distractibility and/or concentration difficulties with disturbance of sleep, appetite and/or sexual behavior. There is no split among cognitive, relational-affective and motor-adaptive psychopathological structures. Perceptions, relations and actions are congruent with mood. Accordingly, with a shift in the mood state from depression towards elation (hyperthymia) or from elation to depression (dysthymia), there is an increase or decrease of speed of thought and an increase or decrease of psychomotor activity. As a rule, affective psychoses don’t have an insidious onset and follow a unipolar or bipolar course with periodically or even rhythmically recurring episodes, with full remission between them.

       In the DCR the diagnosis of manic melancholic psychosis is based on the presence of the manic or the melancholic syndrome with a history of the opposite syndrome in the past. Bipolar manic melancholic psychosis is subdivided into four subtypes on the basis of their course: manic melancholic psychosis with mania (Bipolar I), manic melancholic psychosis with hypomania (Bipolar II), manic melancholia psychosis with melancholia (Bipolar III) and manic melancholic psychosis with subclinical melancholia (Bipolar IV).

       Corresponding diagnoses to affective psychoses in the DCR are affective psychoses in the ICD-9 and major affective disorders and cyclothymic disorder in the DSM-III. Corresponding diagnoses to DCR’s  manic melancholic psychosis are manic-depressive psychosis circular types (currently manic, currently depressed, mixed or current condition not specified) in the ICD-9 and bipolar disorders (mixed, manic or depressed) and cyclothymic disorder in the DSM-III.

       In the ICD-9, similar to the DCR, the diagnosis of affective psychosis is not restricted to manic-depressive illness with alternating manic and depressive episodes. The diagnosis is not made, however, unless there is evidence for mood-congruent evaluations. In contradistinction to the DCR, in the ICD-9 there is a considerable emphasis on accompanying psychopathological symptoms, such as delusions, perplexity, disturbed attitude to self and disordered behavior. Also, greater emphasis is placed on suicidal tendency.

       DSM-III criteria for major affective disorders correspond to DCR  diagnoses. In certain respects, however, the DSM-III diagnosis is more restrictive. Continuous signs of the disorder must be present to a significant degree for at least one week. Patients whose illness does not meet criteria for duration and severity are diagnosed as cyclothymic disorder in DSM-III.

       Psychopharmacological contributions favor the distinctness of bipolar and unipolar affective psychoses. The therapeutic effect of lithium salts is superior to other treatment modalities in the prophylactic treatment of bipolar manic-depressive patients. The prophylactic effect of lithium salts in bipolar patients has been demonstrated in at least seven placebo-controlled clinical studies involving a total of 400 manic-depressive patients. In these studies, lithium, in the daily dosage range of 600 to 1200 mg with serum lithium levels from 0.6 to 1.2 mEq/1, was consistently more effective than placebo in reducing the occurrence of both manic and depressive episodes. The evidence for lithium prophylaxis in depressive episodes is less conclusive than in manic episodes. However, Schou (1979) found that the relapse rate in tricyclic antidepressant-treated bipolar depressed patients was significantly higher (59%) than in lithium-treated bipolar patients (35%).

       In spite of the superiority of lithium salts over other treatments, studies on the action mechanism of lithium salts have contributed little to the understanding of manic-depressive psychosis. This may be related to the fact that the mechanism of action of lithium salts has not been fully elucidated as yet (Baldessarini and Lipinski 1975; Schou 1979). By now there is sufficient evidence to believe that lithium interferes with the release and increases  in the reuptake of catecholamines at the site of presynaptic neurons (Baldessarini and Yorke 1970); decreases the sensitivity of postsynaptic catecholamine receptors (Hollister 1978); inhibits the release of the NE and/or prostaglandin (PG) E-stimulated cyclic 3,5 adenosine monophosphate (cAMP) (Forrest 1975; Murphy, Donnelly and Moskowitz 1973); stimulates stimulation of choline transport (Millington, McCall and Wurtman 1979) with enhancement of the synthesis of acetylcholine, glutamate and y-aminobutyrate (Gottesfield, Epstein and Samuel 1971; Jape and Jenden 1978); differentially  activates phospholipase; and reestablishes the resting electrolyte balance across the cell membrane (Coppen, Shaw and Mangoni 1962). Yet, it is not known which of these actions are responsible for its therapeutic effects in bipolar patients. Some attribute its therapeutic effect in bipolar patients to its action on the central catecholamine system  (Ahluwalia and Singhal 1984).

       The therapeutic indication of lithium is not restricted to bipolar manic-depressive patients. It is indicated also for the treatment of impulse disorders, episodic violence, emotionally unstable character disorders, premenstrual syndrome and borderline patients (Bernstein 1983).

       Lithium  salts have remained the primary treatment modality for a well-identified diagnostic population within the endogenous psychoses. Many patients stabilized on lithium therapy exhibited rapid relapse which may manifest  as severe mania  after their treatment with lithium was stopped (Klein, Broucek and Greil 1981; Lapierre, Gagnon and Kokkinidis 1980; Small, Small and Moore 1971; Wilkinson 1979). Yet not all patients stabilized on lithium relapse rapidly following cessation of therapy and not all bipolar manic-depressive patients respond favorably to lithium.

       The finding that only approximately 65% of bipolar patients respond to lithium prophylaxis  indicates that bipolar affective psychosis is a biologically heterogeneous diagnostic group. It remains to be seen whether the separation of Bipolar I (depression with mania) from Bipolar II (depression with hypomania) and from Bipolar III (depression with hypomania or mania precipitated by the administration of an antidepressant or electroconvulsive therapy) will improve homogeneity (Spitzer, Endicott and Robins 1978a,b).

       Recognition of the pharmacological heterogeneity of the bipolar population could explain why some patients who remain refractory to lithium treatment respond favorably to carbamazepine, while others respond favorably to valproic acid (Lerer 1985). It remains to be seen whether a relatively high pre-treatment plasma calcium/magnesium ratio (more than 2.62) could separate a biologically homogenous and/or nosologically meaningful lithium-responsive bipolar group which is distinct from the carbamazepine and/or valproic acid responders (Carman, Post, Teplitz and Goodwin 1974). In favor of the  possibility that it will is the rise in plasma magnesium levels in lithium-responsive depressed patients during the initial five days of treatment (Crammer 1975).

       Independent from clinical psychopharmacologic research, genetic psychiatric research has indicated that the density of muscarinic cholinergic (quinuclidinyl benzilate) binding sites in the skin fibroblasts of patients with manic-depressive psychosis and in their manic-depressive relatives is significantly higher than in normal subjects. Also, incubation of cells with lithium resulted in a decrease of binding sites into the normal range in treatment responsive patients (Nadi, Nurnberger and Gershon 1984). Attempts to replicate these findings, however invariably failed (Lenox, Hertzmann, Richelson and Kelsoe 1985; Kelsoe, Gillin, Janoswky et al. 1985; Gershon, Nadi, Nurnberger and Berrettini 1985). Should they be supported by further evidence the question still remains whether this alleged genetic-biological marker could be linked to a subpopulation within manic-depressive psychosis.


Melancholia and Depressions


       From the two cross-sectional psychopathologic syndromes encountered in manic-depressive psychosis, depression is the more frequent. It is estimated that 100 million people worldwide suffer from a recognizable depression (Ban, Gonzalez, Jablensky et al. 1981). A survey carried out from 1967 to 1976 in a community in the United States revealed that 6.8% of the respondents were experiencing depression at the time of the survey (period prevalence) and 26.7% (one of four respondents) had experienced symptoms of depression earlier in their lives (lifetime prevalence) (Weissman and Klerman 1978; Weissman and Myers 1978a,b). However, not all persons who have experienced depression suffer from a clinically verifiable depressive illness. If those cases that are not depressive illnesses are excluded, the prevalence figures are considerably lower.

       The incidence of affective illness in the general population is estimated to be approximately 2% (l of 50) with a slightly higher incidence in females (2.5%) than in males (1.8%). Among the relatives of unipolar and bipolar patients, however, the risk for all mood disorders jumps to between 10-20 times the rate of the general population rate (Tsuang and Vandermey 1980). Accordingly, Winokur and Clayton (1967) found that the risk of brothers and sisters of a person with mood disorder rises from 12% if neither parent is ill, through 26% if one parent is ill, to 43% if both parents are ill. Although the mode of inheritance remains hidden the significant increase in the rate of occurrence of affective disorder among the biological relatives of patients indicate that biological-genetic factors play an important role in the etiology of these illnesses.


Vital Depression


       The most important contribution to the clarification of the confounding situation created by the all-embracing diagnostic concept of manic-depressive psychosis (which includes all depressions) was made by Schneider (1920, 1959). By separating "vital depression," which he considered a medical illness, from the other ("non-psychotic") depressive disorders, Schneider opened the path to a more discriminate use of the term, depression.

       The crucial step in the separation of depressive illness from other depressive disorders was the recognition   and introduction of the concept of "depressive personality." Distinct from "vital depression," which is the result of a disease process, depressive personality is a developmental abnormality. As such, it is ill-defined in psychopathological terms (Chodoff 1972). In general, however, people with depressive personality lack self-confidence, are susceptible to fatigue and dread the unknown. Unlike those with depressive illness they have been feeling sad, experiencing guilt and complaining of concentration difficulties over a long period of time.

       Vital depression is an endogenous affective illness which embraces all three psychopathological structures, the perceptual-cognitive, the relational-affective and the motor-adaptive. It is characterized by “passive-unmotivated” dysphoria and disturbance of   vital feelings with the explicit experience of displeasure and discontent leading to a disturbed time sense, poverty of thought, reduced emotional susceptibility and psychomotor retardation. There are also vegetative symptoms, accompanied by hypochondriasis, corporization and feelings of motor and sensory disturbances.

       The concept of vital depression described by Kurt Schneider in 1920 differs considerably from Kraepelin's (1921) concept of "depressive states” which are characterized by the triad of sad or anxious mood, thought retardation and decreased drive.

       Another related concept, "psychogenic depressive reaction," was perceived at first as a reaction  of subjects with abnormal personalities to  moderate  or  mild  stress,  or as a reaction  of normal personalities to severe stress (corresponding to Schneider's concept of neurosis). By this definition "psychogenic depressive reaction" was positioned between "developmental anomalies" and sui generis "depressive illnesses."     

       More recently, with the contributions of Strömgren (1958, 1968), it has been recognized that psychogenic depressive reactions are illnesses that may occur in psychotic and non-psychotic forms. Common characteristics of both are a clearly identifiable precipitating factor, thematic continuity between the trauma and the content of the illness, lack of depressive evaluation and preoccupation with the traumatic life events. Other common characteristics include reactive mood changes and feelings of passivity (Jaspers 1963,1974).

       Within Strömgren’s frame of reference "psychogenic depressive reactions" are perceived as disorders (illnesses), regardless whether psychotic or not, in which activation of an endogenous factor depends on a precipitating factor.



Ahluwalia P, Singhal RL. Comparison of the changes in central catecholamine systems following short- and long-term lithium treatment and the consequences of lithium withdrawal. Neuropsychobiology, 1984;12:217-23.  

Angst J. Zur  Atiologie und Nosologie endogener Psychosen. Springer, Berlin; 1966. 

Angst J, Perris C. Zur Nosologie endogener Depressionen. Vergleich der Ergebnisse zwier Untzersuchungen. Arch Psychiat Z Neurol, 1968;210:373-86. 

Baillarger J: De la folie a double forme. Ann Med Psychol, 1854;6:369-84. 

Baldessarini RJ, Lipinski JF. Lithium salts 1970-1975. Ann Intern Med, 1975;83:527-33. 

Baldessarini RJ, Yorke C. Effect of lithium and of pH on synaptosomal metabolism and noradrenaline. Nature, 1970;288:1301-3. 

Ban TA, Gonzalez R, Jablensky A, Sartorius N, Vartanian FE, editors. Prevention and Treatment of Depression. University Park Press, Baltimore; 1981. 

Beckman H, Goodwin FK. Antidepressant response to tricyclics and urinary MHPG in unipolar patients. Arch Gen Psychiatry, 1975;32:17-21. 

Bernstein JG. Handbook of Drug Therapy in Psychiatry. John Wright, Boston, Bristol, London; 1983. 

Carman JS, Post RM, Teplitz TA, Goodwin FK. Divalent cations in predicting antidepressant response to lithium. Lancet, 1974;2(7894):1454. 

Chodoff P. The depressive personality. A critical review. Arch Gen Psychiatry, 1972;27:666-73. 

Coppen AJ, Shaw, OM and Mangoni A: Total exchangeable sodium in depressive illness. Br Med J, 1962;5300:295-8. 

Crammer J. Lithium, calcium and mental illness. Lancet, 1975;1:215-6.  

Dreyfus GL. Die Melancholie, ein Zustandsbild daes manisch-depressiven  Irreseins. Jena: Gustav Fischer; 1905. 

Falret  JP. Memoir  sur la folie circulaire ;forme de maladie mentale  caracterisee par la reproduction  successive et regiliere de l’etat  maniaque,, de l’etat melancolique  et d’ une intervale lucide plus ou moins prolongee. Bulletin de la Academie de Medicine, 1854;19:382:415.  

Forrest  JN  Jr. Lithium inhibition and cAMP mediated hormones. A case history. N Engl J Med, 1975;292:423-4. 

Gershon ES, Nadi NS, Nurnberger JI, Berrettini WH. Failure to confirm muscarinic receptors on skin fibroblasts. N Engl J Med, 1985;312:861-2. 

Gottesfield Z, Epstein BS, Samuel D. Effects of lithium on concentrations of glutamate and GABA on amygdala and hypothalamus of rat. Nat New Biol, 1971;234(47):124-5. 

Hippius H, Peters G, Ploog D. Emil Kraepelin Lebenserinnerungen. Springer, Berlin, Heidelberg, New York, Tokyo; 1983. 

Hollister LE. Clinical Pharmacology of Psychotherapeutic Drugs. Churchill Livingstone, New York; 1978. 

Jape RS,  Jenden DJ. Lithium and cholinergic function in rat brains. Presented at the 7th International Congress of Pharmacology, Paris; 1978. 

Jaspers  K. Allgemeine  Psychopathologie. 1.  Aufl. Springer, Berlin, Heidelberg; 1913a. 

Jaspers K. Allgemeine Psychopathologie. 7 Aufl. Springer, Berlin, 1959. Translated by Hoenig J, Hamilton MW, under the title “General Psychopathology.” Manchster:  Manchester University Press; 1963.  

Jaspers K. Kausale und “verstandliche" zusammenhange Zwischen schicksal und  Psychose  bei  der  Dementia  praecox (Schizophrenie). Zschr fd gesamte  Neurol u Psychiat, 1913;14:158-263. Translated  by J. Hoenig under the title “Causal and ‘meaningful’ connections between life history and psychosis.” In: Hirsch SR, Shepherd M, editors. Themes and Variations in European Psychiatry. University Press of Virginia, Charlottesville; 1974. 

Klein HE, Broucek B, Greil W. Lithium withdrawal triggers psychotic states. Br J Psychiatry, 1981;139:255-6. 

Kraepelin E. Psychiatrie. 1st Edition. Abel, Leipzig; 1883. 

Kraepelin E. Psychiatrie. 5 Aufl. Barth, Leipzig; 1896.  

Kraepelin E. Manic Depressive  Insanity and  Paranoia. Translated by RM Barclay, Livingstone, Edinburgh; 1921. 

Lapierre YD, Gagnon A, Kokkinidis L. Rapid recurrence of mania following lithium withdrawal. Biol Psychiatry, 1980;15:859-64. 

Lenox RH, Hertzmann RJ, Richelson E, Kelsoe JR. Failure to confirm muscarinic receptors on skin fibroblasts. N Engl J Med, 1985;312:861-2. 

Lerer B. Alternative therapies for bipolar disorder. J Clin Psychiatry, 1985;46:309-16

Kelsoe, Gillin, Janoswky et al. 1985. 

Millington WR, McCall AL, Wurtman RJ. Lithium and brain choline levels. N Engl J Med, 1979;300:196-7. 

Murphy DL, Weiss R. Reduced monoamine oxidase activity in blood platelets from bipolar depressed patients. Am J Psychiatry, 1972;128:1351-7. 

Murphy DC, Donnelly C, Moskowitz J. Inhibition by lithium of prostaglandin E1 and norepinephrine effects on cyclic adenosine monophosphate production in human platelets. Clin Pharmacol Ther, 1973;14(5):810-4. 

Nadi NS, Nurnberger JI, Gershon ES. Muscarinic cholinergic receptors on skin fibroblasts in familial affective disorder. N Engl J Med, 1984;311:225-30. 

Perris C. A study of bipolar (manic-depressive) and unipolar recurrent depressive psychoses. Introduction. Acta Psychiatr. Acta Psychiatr Scand Suppl, 1966;194:9-14. 

Perris C. A  study  of cycloid  psychoses. Acta Psychiatr Scand Suppl, 1974;253:1-77. 

Pethö B, Ban T, Kelemen A, Ungvari  G,  Karczag I, Bitter I, Tolna J. KDK Budapest. Kutatasi   Diagnosztikai Kriteriumok functionalis psychosisok korismezesehez. Ideggyogyaszati Szemle, 1984;37:102-31. 

Pichot P. A  Century of Psychiatry. Paris: Roger Dacosta; 1983.  

Schneider K. Die Schichtung des emotionalen Lebens und der Aufbaue der Depressionszustande. J ges Neural Psychiatry, 1920;59:281-5. 

Schneider K. Clinical Psychopathology. Translated from 3rd edition by MW Hamilton and EW Anderson. Grune and Stratton, New York; 1959. 

Schou M. Biography on the biology and pharmacology of lithium. Neuropsychobiol, 1979;5:241-65. 

Small JG, Small IF, Moore DF. Experimental withdrawal of lithium in recovered manic-depressive patients: a report of five cases. Am J Psychiatry, 1971;127(11):1555-8. 

Spitzer RL, Endicott J, Robins E. Research Diagnostic Criteria (RDC) for a Selected Group of Functional Disorders. 3rd Edition. New York Psychiatric Institute, New York; 1978a. 

Spitzer RL, Endicott J, Robins E. Research Diagnostic Criteria: Rationale and Reliability. Arch Gen Psychiatry, 1978b;35:773-82. 

Strömgren E. Pathogenese der verschiedenen Formen von psychogenen Psychosen. (Memorial Volume to Ernst Kretsctmer on his seventieth birthday.) In: Winkler WT, editor. Mehrdimensionale Diagnostik und Therapie, Thieme, Stuttgart; 1958. 

Strömgren E. Contributions to Psychiatric Epidemiology and Genetics. Universitatsforlaget, Aarhus; 1968. 

Tsuang MT, Vandermey R. Genes and the Mind. Oxford University Press, Oxford, New York, Toronto; 1980. 

Weissman MM, Klerman GL. Epidemiology of mental disorders: Emerging trends in the United States.            Arch Gen Psychiatry, 1978;35:705-12. 

Weissman MM, Myers JK. Affective disorders in a US urban community. Arch Gen Psychiatry, 1978a;35:1304-11. 

Weissman MM, Myers JK. Rates and risks of depressive symptoms in United States urban community. Acta Psychiatr Scand, 1978b;57:219-31. 

Wilkinson DG. Difficulty in stopping lithium prophylaxis? Br Med J, 1979;1:235-6. 

Winokur G, Clayton P. Family history studies: two types of affective disorders separated according to genetic and clinical factors. In: J. Wortis, editor. Recent Advances in Biological Psychiatry. Vol. 9. Press, New York; 1967.


June 3, 2021