Psychopharmacology and the Classification of Functional Psychoses 

By Thomas A. Ban and Bertalan Pethö

Four-Dimensional Classification

Affective Psychoses

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 as a nosological entity until the publication of the fifth edition of Kraepelin's textbook of psychiatry in 1896. In this edition Kraepelin replaced cross-sectional syndromatologic diagnosis with longitudinal-nosological diagnosis for the first time. In the first edition of his textbook (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 his 1896 presentation he contended that all of these different forms 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 termed melancholia, and also, a considerable proportion of the amentias." This broad definition was expanded later to include "all cases of affective excess" and ultimately, on the basis of the contributions of Dreyfus (1905) also "involutional melancholia," a disorder regarded at the beginning as a separate nosological 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 (1957) contributions that a consistent attempt to break down the unitary concept of MDP (manic-depressive psychosis) began (Perris, 1974). By employing a four-dimensional approach with consideration to the end-states of the illness, Leonhard separated a number of distinct disorders within manic- depressive illness. By introducing the concept of "polarity" regarding the formal pattern of the course he separated within the affective psychoses bipolar and unipolar forms. A "bipolar" form means that both manic and depressive episodes occur in the same patient. A "unipolar," originally referred to as "monopolar," form means that there are only "depressive" or only "manic" episodes.

Stimulated by Leonhard's work, two independent comprehensive investigations were carried out, one by Angst (1966) in Switzerland and another by Perris (1966) in Sweden. Results of these studies favored the distinctness 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 (Petho, 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 disease picture (simple, multiform). Other, cross-sectional psychopathological manifestations include distractibility and/or concentration difficulties with disturbance of sleep, appetite and/or sexual behavior. There is no split among percentual-cognitive, relational-affective and motor-adaptive psychopathological structures. Perceptions, relations and actions are congruent with mood. Accordingly with a shift in the mood state towards elation (hyperthymia) or depression (dsythmia), there is an increase or decrease of speed of thought and an increase or decrease of psychomotor activity. As a rule, affective psychoses do not have an insidious onset. On the other hand, they present with a unipolar or bipolar course with periodically or even rhythmically recurring episodes. There is full remission between episodes.

In the same classification the diagnosis of manic melancholic psychosis (a group of nonsystematic-bipolar disorders) is based on the presence of the manic (or hypomanic) or the melancholic (or subclinical melancholic) syndrome and respectively the melancholic or the manic syndrome in the past. Bipolar manic melancholic psychosis is subdivided into four subtypes on the basis of their course, i.e., manic melancholic psychosis with mania (bipolar I), manic melancholic psychosis with hypomania (bipolar II), manic melancholis 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 cyclothmic disorder in the DSM-III. Similarly corresponding diagnoses to DCR 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.

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In spite of the superiority of lithium salts over other modalities in the treatment of bipolar, manic-depressive patients, 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 explained (Baldessarini and Lipinski, 1975; Schou, 1979a). However, there is sufficient evidence to believe that lithium interferes with the release and increases the reuptake of catecholamines at the site of presynaptic neurons (Baldessarini and Yorke, 1970), decreases the sensitivity of postsynaptic catecholamine receptors (Hollister, 1978); and 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). Other effects of lithium include stimulation of choline transport (Millington, McCall and Wurtman, 1979) with enhancement of the synthesis of acetylcholine, glutamate and y-aminobutyrate (Gottesfeld, Epstein and Samuel, 1971; Jope and Jenden, 1978); differential activation of phospholipase, and reestablishment of the resting electrolyte balance across the cell membrane (Coppen, Shaw and Mangoni, 1962). It is not known which actions of lithium are responsible for its therapeutic effects in bipolar patients. Some believe that it is its action on the central catecholamine systems (Ahluwalia and Singhal, 1984).

Another possible reason that lithium salts have provided little if any clues for a better understanding of the nature of manic-depressive disorders is that they are far from being specific treatments and are indicated also in the treatment of impulse disorders, episodic violence, emotionally unstable character disorders, premenstrual syndrome and borderline patients (Bernstein, 1983). In spite of other indications lithium salts remain the specific treatment modality for a well identified diagnostic population within the endogenous psychoses. Many patients stabilized on lithium therapy exhibit rapid relapse into severe mania following cessation of drug treatment (Klein, Brovcek and Greil, 1981; Lapierre, Gagnon and Kokkinidis, 1980; Small, Small and Moore, 1971; Wilkinson, 1979). Nevertheless, not all patients stabilized on lithium therapy relapse rapidly following cessation of therapy and/or not all bipolar manic-depressive patients respond to lithium treatment. The finding that only approximately 65 percent of bipolar patients respond to lithium prophylaxis clearly 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 electroconvulsaive therapy) will improve homogeneity (Spitzer, Endicott and Robins, 1978a and b). On the other hand, recognition of the heterogeneity of the bipolar population could explain why some patients who remain refractory to lithium treatment respond favorably to carbamazepine, while others respond to valproic acid (Lerer, 1985). It remains to be seen whether a relatively high pretreatment plasma calcium/magnesium ratio (over 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 et al., 1974). In favor of this possibility is the rise in plasma magnesium level in lithium-responsive depressed patients during the initial five days of treatment (Crammer, 1975).

Independent of 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 ill relatives is significantly higher than in normal controls. Also, incubation of cells with lithium resulted in a decrease of binding sites into the normal range (Nadi, Nurnberger and Gershon, 1984). Attempts to replicate these findings, however, consistently failed (Lenox et al., 1985; Kelsoe et al., 1985; Gershon et al., 1985). Would they be supported by further evidence, the question remains whether this alleged genetic-biological marker could be linked to a nosologically meaningful subpopulation within manic-depressive psychosis and/or the genetically defined population would be homogenous in terms of responsiveness to lithium salts.