Thomas A. Ban
Neuropsychopharmacology in Historical Perspective

Psychopharmacology and the Classification of Functional Psychoses



10. Empirical and Pragmatic Classifications of Depression


        Kurt Schneider is considered by some  “the last classicist in psychiatry" (Kisker 1968). Yet, his classification of "depression" is not universally accepted. Recognition of his classification of depression  has remained by and large restricted to the German speaking countries.

        In the English-speaking world, Kraepelin’s “unitary concept” was perpetuated by Aubrey Lewis’ article published in 1934 which was based on a clinical survey of depressive states.

        For some time, Lewis' findings  dominated British psychiatry, but in the 1950s, almost a quarter of a century after the publication of the  original paper, a controversy arose whether all depressions are the same endogenous disease or the diagnosis of depression includes different disorders distributed on a continuum (Ban 1981). The controversy stimulated research  and the findings of this research led to some of the empiricistic classifications based on a wide range of descriptive data collected from depressed patients and submitted to multivariate statistical techniques, e.g., factor analysis, cluster analysis, multiple discriminant analysis.

        It was in the course of this research that  Kiloh and Garside (1963) identified a bipolar factor, splitting observations into positive and negative loadings. Based on their findings they separated “endogenous depression” (age over 30, depression worse in morning, weight loss 7 lbs. or more) from neurotic depression (responsive to environmental change, self-pity, initial insomnia). Similarly, Kendell (1968) identified at the fourth order of analysis, a bipolar factor contrasting psychotic depression and neurotic depression. By employing principal component analysis, he found that the three leading symptoms of neurotic depression were anxiety, tension and brief duration of illness. Pursuing a similar line of research, Hamilton and White (1959) concluded that depressed patients with retardation are made up of a different population than depressed patients with agitation.

        Other empirically derived classifications of depression include Grinker, Miller, Sabshin et al. (1961) who separated four types of depression: retarded, anxious, hypochondriacal and angry; Overall, Hollister, Johnson and Pennington  (1966) who distinguished three classes of depression: retarded, anxious and hostility; and Paykel  (1972) who described four categories of depression: psychotic, anxious, hostile and "depression in the young with personality disorder." Klein and Davis (1969) divided depression into three groups of disorders: endogenomorphic, chronic dysphoric and reactive; Raskin and Crook (1976) identified four classes of depression: agitated, neurotic, endogenous and "depression with poor premorbid personality”; Paul Kielholz (1972) differentiated among somatogenic, endogenous and psychogenic depressions;  and Robins and Guze (1972) distinguished between primary and secondary depression. Primary depression in Robins and Guze’s classification refers to a combination of signs and symptoms that involve psychomotor and vegetative dysfunctions, dysphoria, hopelessness, worthlessness, guilt and suicidal preoccupations occurring de novo as a primary disorder of mood, whereas “secondary depression refers to a depression with similar manifestations that occur during the course of a preexisting nonaffective psychiatric disorder or is associated with medical illness. Secondary affective disorder implies an antecedent disease. In contrast to “primary depressions,” “secondary depressions” may show considerable heterogeneity in manifestations  (Andreasen and Winokur 1979). Even primary depression, however, has some heterogeneous features with regard to the course of the disease and the prevailing psychopathologic symptoms (Perris 1974). When compared with patients suffering from primary depression, patients with secondary depression tend to have a lifelong coping style, make more but less serious suicide attempts and complain more of hostility, anxiety, somatization and difficulties in falling asleep (Andreasen and Winokur 1979).      


Genetic and Experimental Classifications of Depression


        Antecedent-etiologic factors are of pivotal importance in genetic classifications in which the concept of "endogenous" translates into familial incidence of the disease.

        The prototype, and one of the most frequently referred to genetic classification of depression, is that of Andreasen and Winokur’s (1979) who distinguish three distinct groups of depressions: pure depression, depression spectrum disease and non-familial depression. Nonfamilial or sporadic  depression  refers to a depression which occurs in a person who has a family history of other than affective psychiatric disease,  such as alcoholism or antisocial personality (Baker, Dorzab, Winokur and Cadoret 1971).

        An entirely new approach to the classification of depression involves the employment of biochemical measures, such as plasma cortisol levels, urinary MHPG (the final metabolic end product of NE), cerebrospinal fluid HVA (the final metabolic end product of DA) and 5HIAA (the final metabolic end product of serotonin) concentrations, free plasma tryptophan levels and platelet MAO activity. Supplementing these measures are neuroendocrine tests, such as  the dexamethasone-cortisol suppression (DST) test,  the clonidine-growth hormone release (Ban 1974).


Nosology Derived Classifications of Depression


        After being dormant for several decades  some interest in nosology-derived classification of depression and  in Kurt Schneider’s concept of vital depression re-emerged (Schneider 1920). By combining structural analysis with a holistic approach (i.e., perceiving the patient in his totality and not just as an aggregate of psychopathological symptoms) and with consideration of all four developmental stages of depressive illness, Leonhard (1957) recognized that “depression” consists of a number of different clinical syndromes. From these syndromes one, “pure melancholia,” is characterized by the triad  of cardinal symptoms: motiveless (incomprehensible) dysthymic mood, psychomotor retardation and thought retardation. He perceived the indecisiveness and feeling of inadequacy (insufficiency) as secondary phenomena to the cardinal primary manifestations.

        By shifting  emphasis from cross-sectional psychopathology to the unipolar-bipolar dimension of the course, Leonhard separated the melancholic syndrome of bipolar manic melancholic illness from unipolar pure melancholia, a concept introduced by Lange (1897) and Schou (1927) (Pedersen, Poort and Schou 1947). Similarly, by recognizing the importance of the overall (holistic) clinical picture, whether simple (monomorphous) or multiform (polymorphous), he separated unipolar pure melancholia from the unipolar pure depressions, i.e., nonparticipatory, harried, hypochondriacal, self-torturing and suspicious. These unipolar pure depressions are prevailingly affective, systematic diseases from a structural point of view, while pure melancholia is a nonsystematic disease in which thought and desire are also obligatorily disturbed. Furthermore, Leonhard called attention to cross-sectional features distinguishing between the bipolar and unipolar forms of depression. He suggested that bipolar – nonsystematic – forms display a more colorful appearance. Also, they vary not only between the two poles, but in each phase offer different clinical pictures. The same does not apply to the unipolar – systematic – forms in which each individual form is characterized by a syndrome not associated or even transiently related to any other form and recur in patients with a periodic course with the same symptomatology.

        The five distinct subtypes of pure depression are named on the basis of their prevailing clinical features. Although they are prevailingly affective mood disorders, in two of them (harried and nonparticipatory) motor-adaptive structures, and in three others (hypochondriacal, suspicious and self-torturing) perceptual-cognitive structures, are also involved. Of the five subtypes, “harried” depression is characterized by motor restlessness associated with marked tension and anxiety with driven (but meager) complaintiveness and poor thematization, while hypochondriacal depression by hypochondriasis and corporization (feeling sick or diseased) with hopeless complaintiveness and homonom bodily hallucinations (bodily misperceptions). Self-torturing depression is characterized by self-condemnation and guilt feelings with loss of self-esteem and lamentativeness, while suspicious depression by suspiciousness, ideas of reference and auditory hallucinations. Nonparticipatory depression is characterized by lack of affective participation and feelings of alienation with abulia and the feeling of loss of feelings referred to as anhedonia. In contradistinction to pure melancholia which usually ends within a limited period of time, in pure depressions there is a tendency for chronicity. On the other hand, similar to pure melancholia, pure depressions yield to complete remission between episodes, even if the duration of the episodes is prolonged.

        Irrespective of the nosological classifications described, ICD-9 distinguishes three subtypes of depression and DSM-III five subtypes. The three subtypes of the ICD-9 include manic-depressive psychosis depressed type, manic depressive psychosis circular type but currently depressed and other nonorganic psychoses depressive type. Corresponding subtypes in DSM-III are bipolar disorder depressed, major depressive disorder single episode, major depressive disorder recurrent, cyclothymic disorder and atypical depression. There is no correspondence between Leonhard's depressive subtypes, adopted in the KDK, and depressive diagnoses in ICD-9 or DSM-III.


Psychopharmacology and the Depressions


        The two major groups of drugs primarily used in the treatment of depressive disorders are cyclic antidepressants and MAOI antidepressants.


Cyclic Antidepressants


        Differential responsiveness to therapeutically effective cyclic (tricyclic) antidepressants brought to attention the heterogeneity within the depressive population.        

        Tricyclic antidepressants exert a therapeutic effect in 65-70% of depressed patients during acute and maintenance phases of treatment. Response rates have remained essentially the same with the new generation of cyclic antidepressants. Included among these substances are drugs with specificity towards the NE system, such as maprotiline, the serotonin system, such as fluvoxamine, fluoxetine, citalopram and trazodone, or the DA system, such as nomifensine. Included also are antidepressants in which monoamine uptake inhibition (characteristic of antidepressants) is combined with DA receptor blockade (characteristic of antipsychotics), such as amoxapine. There are indications that response rate can be improved by adjusting the dose on the basis of monitored blood levels to attain a therapeutic range.

        Considering that the usefulness of cyclic antidepressants in prophylactic treatment is questionable, that approximately 25% of depressed patients respond to nonspecific-placebo treatment and another 25% spontaneously remit within three to four weeks, it is difficult to determine the actual percentage of depressed patients who are cyclic antidepressant responsive (Ban 1974). To identify this population numerous clinical studies have been designed. In a  comprehensive review of these studies Bielski and Friedel (1976) revealed that patients with endogenous depression, characterized by psychomotor retardation, anorexia, weight loss and sleep disturbance, are the ones with a favorable therapeutic response. Delusions and neurotic, hysterical and/or hypochondriacal traits, considerably decrease the response rate.

        In the absence of a well-identified biologically homogenous depressive population which is responsive to cyclic antidepressants, it is unlikely that valid inferences can be made about the biological substrate of depression from the action mechanism of these drugs. Regardless of their clinical relevance, however, research designed to elucidate the action mechanism of cyclic antidepressants has contributed to the development of modern neuropharmacology and to a better understanding of the neurochemistry of the brain.

        By now there is substantial evidence that the therapeutic action of cyclic antidepressants cannot simply be attributed to monoamine reuptake inhibition, alpha-adrenergic receptor blockade and/or immediate increase in available monoamine concentrations at the synaptic cleft (Carlsson Fuxe, Hamburger and Lindqvist 1966; Carlsson, Corrodi, Fuxe and Hökfelt 1969; Snyder and Yamamura 1977; Voigtlender 1976). It is more likely that therapeutic changes result from the decrease in sensitivity of the noradrenergic receptor system associated with a decrease in NE turnover rate and activity (firing rate) of noradrenergic neurons in the locus coeruleus and/or the increase in serotonin (5HT) receptor sensitivity in the hippocampus and geniculate bodies (Karobath 1975). In spite of the blocking effect of muscarinic acetylcholine and histamine receptors (Kolata 1979; Richelson 1979), it is commonly held that the crucial mechanism in the action of cyclic antidepressants is the "down regulation" of the e2-receptor coupled NE-sensitive adenylate cyclase system in specific brain regions. A frequently used argument in favor of this contention is that the time course of this down-regulation in both human and animal studies parallels the delayed onset of therapeutic effect. Another frequently used argument in favor of the "down regulation" hypothesis is that it is a common feature of all effective treatment modalities, including electroconvulsive therapy (ECT), of depressive states. Nevertheless, because the therapeutic indications for ECT are not restricted to depression and they include some of the schizophrenias and manias (Small, Small, Milstein et a1. 1985), super sensitivity of e2-receptors cannot be considered a valid hypothesis for the pathomechanism of depression even if down regulation of e2-receptors is an important step in the action mechanism of cyclic antidepressants.

        While attention is focused on the NE system in relationship to the action mechanism of cyclic antidepressants, clinical neurophysiological studies revealed a significant relationship between the changes in the tonic components of rapid eye movement (REM) sleep (i.e., latency time and number of periods), regulated by cholinergic mechanisms, and therapeutic response (Kupfer and Foster 1972). Furthermore, an increase in REM latency and REM suppression after a loading dose of 50 mg of amitriptyline was predictive of a favorable outcome with a high level of probability (Kupfer, Hanin, Spiker et al. 1979). Considering that there is no habituation of changes seen in the tonic components of REM sleep while there is habituation to changes seen in the phasic components, one may speculate that in the antidepressant effect of amitriptyline, cholinergic mechanisms play a more important role than catecholaminergic mechanisms (responsible for the regulation of the phasic components of REM sleep). In favor of this is the correlation between amitriptyline blood levels and the tonic components (but not the phasic components) of REM sleep and the significantly greater sensitivity to arecoline, a muscarinic cholinergic agent to increase REM latency in depressed patients than in normal controls (Ban 1981).

        These new findings revived interest in Selbach's (1961) contention about the action mechanism of the prototypical cyclic antidepressant, imipramine. According to Selbach, imipramine exerts its effect in three successive stages. The first, is characterized by trophotropic actions (feeling of tiredness, decrease of blood pressure), the second by lability (tremor, fluctuation in blood pressure) and the third by ergotropic effects (elation increased interest). Or in other words, imipramine has an effect on autonomic regulation and produces an imbalance in which the parasympathetic (trophotropic)-cholinergic system is more strongly inhibited than the sympathetic (ergotropic)-catecholaminergic system as reflected in the ergotropic manifestations. The finding that there is a fall in plasma cortisol level with all forms of effective treatment of depressive states (Ban 1974) is in keeping with the importance of anticholinergic effects in the action mechanism of cyclic antidepressants, since anticholinergic substances, such as atropine, block the circadian rise in plasma cortisol (that is commonly seen in depression). In keeping also are the findings of some of the original reports with the DST. According to these reports, patients whose morning rise of cortisol can be suppressed by atropine-like substances, have a favorable response to cyclic antidepressants (McLeod, Carroll and Davies 1970), while "non-suppressors” have not (Mcleod 1972).


Monoamine Oxidase Inhibitors


        The second most frequently employed group of drugs used to treat depressed psychiatric patients are the MAOIs. They comprise a structurally heterogenous group of drugs with the common characteristics of inhibiting the activity of the intracellular (mitochondrial) enzyme, MAO, responsible for the oxidative deamination of biogenic amines, such as NE, DA and 5HT, to pharmacologically inactive acidic derivatives. Because a prerequisite for the therapeutic effect of these drugs is a minimum of 80% inhibition of MAO activity, it is assumed that this action is intrinsically linked to their therapeutic effect in depression.

        The origin of MAOIs was in substances used to treat tuberculosis. Substitution of one of the hydrogen atoms in the hydrazine moiety of isoniazid by an isopropyl group resulted in iproniazid, the first clinically employed MAOI antidepressant. Both isoniazid and iproniazid, used as tuberculostatic agents, produced euphoria. Nevertheless, only with iproniazid was the "euphoria" associated with MAO inhibiting properties (Flaherty 1952; Zeller, Barsky, Fouts et al. 1952). However, it was not until the late 1950s that three independent teams of psychiatrists were able to demonstrate the anti-depressant effects of the drug (Crane 1957; Scherbel 1960). While Brodie, Pletscher and Shore (1956) revealed an actual rise in brain monoamines after iproniazid administration and an actual decrease in brain monoamines after reserpine administration, Loomer, Saunders and Kline (1957) contrasted the iproniazid-induced elevation of mood with the reserpine-induced depression.

        Iproniazid  was  withdrawn  from  clinical  use  because  of  hepatotoxic effects. It was replaced by various MAOI hydrazine preparations such as isocarboxazid, mebanazine, nialamide and phenelzine and by various non-hydrazine compounds, such as tranylcypromine, a phenylcyclopropylamine, and pargyline, a propargylamine used primarily to treat hypertension (Biel, Horita and Drukker 1964).

        Considerable difficulties have been encountered in establishing the therapeutic indications for MAOIs in depressive states. Some clinicians regard MAOI antidepressants as the secondary choice of treatment in depression and prescribe them only when a cyclic antidepressant has failed. There is sufficient clinical experience, however, for using a MAOI as primary therapy for patients with at least two cross-sectional depressive syndromes. One, referred to as “atypical” depression (Sargant 1961), is characterized by hyperphagia, hypersomnolence, waves of lethargy, reversed diurnal variation and hyperactivity (Quitkin, Rifkin and Klein 1979). Another is characterized by anxiety, fatigue, phobia and numerous somatic complaints (Robinson, Nies, Ravaris and Lamborn 1973). It remains to be determined whether these cross-sectional clinical syndromes, delineated by careful clinical observations, represent nosologically meaningful diagnostic categories.

        The recent upsurge of interest in MAOI antidepressants is probably the result of purification and characterization of the enzyme MAO from the brains of animals and man (Youdim 1975) and the evidence that mitochondrial MAO in the CNS exists in more than one form (Johnstone 1968). It is probably also related to the advent of new drugs, such as clorgyline (Barbeau 1978) and deprenyl (Knoll 1978), which are selective inhibitors of enzyme forms referred to as Type A and Type B (Gershon 1978). Of the two enzymes, Type A is primarily responsible for the deamination of 5-hydroxytryptamine (Tripton and Mantle 1978) frequently implicated in the pathomechanism of depression, and Type B for the deamination of benzylamine and phenylethylamine (Magyar and Knoll 1977). It is the activity of the Type B enzyme that is measured in the platelet and that is predominant in the primate brain. In spite of extensive research, the only tangible result is an increased Type B enzyme activity in premenopausal woman with depression (Klaiber, Brovennan, Vogel and Kobayashi 1979). It is not known, however, to what extent this patient population is therapeutically responsive to the administration of MAOI antidepressants. Furthermore, because some clinical manifestations seen in patients with hysteroid dysphoria (Klein 1974b), a population characterized by increased appetite and need for sleep, correspond with manifestations of amphetamine withdrawal (the result of derangement in the regulation of phenylethylamine structures), the possibility has been raised that hysteroid dysphoric patients may show a favorable therapeutic response to deprenyl or other Type B MAOIs.


Pharmacotherapy of Depression


        While there is substantial evidence for a differential therapeutic response within the depressive population to both cyclic and MAOI antidepressants, there is little information, based on well-designed studies, on the effect of either cyclic or MAOI antidepressants in the different  depressive subpopulations. Consequently, there is no convincing evidence that cyclic or MAOI antidepressants, or any of the other treatment modalities, psychological, behavioral, physical and/or  pharmacological,  can  produce  favorable  changes  in patients with "depressive personality" (Schneider 1959). The same applies to “hostile depression” and “depression in the young with personality disorder” (Paykel 1972); "chronic dysphoria" (Klein 1974b); "depression with poor premorbid personality" (Raskin and Crook 1976); and possibly also to the "hostile depression syndrome" of Overall,  Hollister, Johnson and Pennington (1966). For psychogenic depressive reactions, a number of different treatment modalities, psychological and pharmacological, have been tried, but because of the usually short duration of these disorders and their high susceptibility to placebo treatment, it is difficult to decide whether anyone of the treatment modalities is superior to the others.

        Included among these disorders are neurotic depression (Kiloh and Garside 1963; Kendell 1968; Raskin and Crook 1976), also referred to as anxious depression (Overall,  Hollister, Johnson and Pennington 1966; Paykel 1972), psychogenic depression (Kielholz 1972) and reactive depression (Klein 1974b). The same does not apply to psychogenic affective (depressive) psychosis in which psychotherapy, behavior therapy and treatment with anxiolytic sedatives or MAOI antidepressants are not indicated, while treatment with cyclic antidepressants alone usually does not suffice and needs to be combined with the administration of an antipsychotic. In a considerable proportion of patients not even this is sufficient and pharmacotherapy needs to be replaced by electroconvulsive treatment. To some extent the same applies to depression spectrum disease in which treatment with cyclic antidepressants usually does not suffice and needs to be supplemented or replaced by an antipsychotic to attain a favorable therapeutic response (Andreasen and Winokur 1979).

        In the treatment of vital depression, Schneider (1920) also referred to as endogenous depression (Kiloh and Garside 1963; Kielholz 1972; Raskin and Crook 1976), psychotic depression (Kendell 1968; Paykel 1972), primary depression (Robins and Guze 1972), endogenomorphic depression (Klein 1974a) and pure depression (Andreasen and Winokur 1972), a number of different antidepressants have been tried. While there is reason to believe that there is a differential therapeutic response to antidepressants within the vital-endogenous depressive population, indicating that endogenous depression consists of a biologically heterogenous population, there is little information based on properly designed studies on the effect of different treatment modalities in the different subpopulations. Consequently, there are indications but no convincing evidence that in Leonhard's (1979) nonsystematic depressive population (i.e., bipolar depression and unipolar pure melancholia), cyclic antidepressants alone are usually not sufficient and need to be supplemented with lithium salts. Further, there are indications that among the five subtypes of pure (systematic) depressions only two – nonparticipatory (usually referred to as retarded) and self-torturing (may be referred to as suicidal) – show a favorable therapeutic response to treatment with cyclic antidepressants. But one of these two subtypes, suicidal depression, seems to respond more consistently and reliably to ECT.

        Therapeutic responsiveness to cyclic antidepressants in the other three subtypes of pure depression is more questionable. In harried (usually referred to as agitated) depression, treatment with cyclic antidepressants usually does not suffice and needs to be combined with antipsychotics to attain behavioral control. Hypochondriacal traits decrease therapeutic responsiveness and the administration of a cyclic antidepressant may even increase the complaints of patients with hypochondriacal depression. On the other hand, anxiolytic sedatives seem to alleviate suffering and are frequently combined with cyclic antidepressants in the treatment of hypochondriacal depression. Similar to hypochondriacal traits, suspiciousness decreases therapeutic responsiveness and the administration of a cyclic antidepressant may even aggravate the content disorder of thought and psychotic symptomatology of patients with suspicious (usually referred to as psychotic or delusional) depression. On the other hand, anti-psychotics effectively control psychotic symptomatology and are frequently combined with cyclic antidepressants in the treatment of suspicious depression. Considering the dopamine receptor blocking properties of 7-OH amoxapine, one of the hydroxylated metabolites of amoxapine, and the distinct possibility that dopaminergic structures play a role in psychotic symptomatology, amoxapine has been tried in a limited number of patients with suspicious-delusional (psychotic) depression and in a limited number of patients with harried-agitated depression. In both subtypes the therapeutic response was favorable in the majority of patients (Anton and Sexauer 1983; Ragheb and Ban 1984).

        Although diagnostic classifications based exclusively on biochemical measures are of questionable value, there are indications that some of the biochemical data become meaningful and interpretable within a four-dimensional classification of depressive states. Thus, both platelet MAO activity and urinary MHPG concentrations have been found to be significantly lower in bipolar than in unipolar depression (Schildkraut, Orsulak, LaBrie et al. 1978; Schildkraut, Orsulak, Schatzberg et al. 1978; Murphy and Weiss 1972). This is in line with the findings that cyclic antidepressants are superior to MAOI antidepressants in their therapeutic effect in patients with bipolar depression. It is also consistent with the clinical impression that treatment with imipramine is superior to treatment with amitriptyline in the same patients. On the other hand, there is sufficient evidence that patients with relatively higher urinary MHPG concentrations respond more favorably to amitriptyline than to imipramine (Maas, Fawcett and Dekimenjian 1972; Schildkraut 1973).

It remains to be seen whether hysteroid dysphoria (Klein 1974b) is characterized by high platelet MAO activity. Also, whether premenopausal women with high platelet MAO activity (Klaiber, Brovennan, Vogel and Kobayashi 1979) show a more favorable therapeutic response to MAOI than cyclic antidepressants. Similarly, it remains to be seen whether the high MAO group, consisting of patients with depressive anxiety states, which has been found to be responsive to treatment with monoamine oxidase inhibitors would correspond with neurotic depression, referred to as dysthymic disorders in the DSM-III (Robinson, Nies, Ravaris and Lamborn 1973). Recent findings indicating a linear relationships between 24-hour urinary free cortisol excretion and high MAO activity and high MAO activity and DST non-suppression (Schatzberg, Rothschild, Bond et al. 1983) are at variance with this contention.

        There is no evidence that low CSF-HVA concentrations (signifying a low dopamine turnover rate in the CNS) will identify patients with "vital depression," but there are indications that it might correspond with the diagnostic subtype of unipolar depression referred to as retarded or nonparticipatory (Van Praag 1977). Similarly, although there is no evidence that low CSF-5HIAA concentrations (signifying low serotonin turnover rate in the CNS) will identify patients with "endogenous depression,” there are indications that low 5HIAA concentrations especially if associated with low CSF magnesium levels (Banki, Vojnik, Papp et al. 1985), may correspond with the diagnostic subtype of unipolar depression referred to as suicidal or self-torturing (Asberg, Thorén, Träskman 1976; Lidberg, Tuck, Asberg et al. 1985). It remains to be seen whether these new diagnostic end points can be translated into differential therapeutic responsiveness to antidepressants accessible for clinical use. If they are valid, nomifensine, a dopaminergic substance, should be more efficacious than other cyclic antidepressants in nonparticipatory depression. Also, fluoxetine, fluvoxarnine, trazodone and citalopram, all serotoninergic substances, should be more efficacious than other cyclic antidepressants in the treatment of self-torturing depression.

        Finally, and more recently, there are indications that DST non-suppression might correspond with the diagnostic subtype of unipolar depression, referred to as psychotic (delusional) or suspicious (Rothschild, Schatzberg, Langlais et al. 1983). The delusional-psychotic symptoms in these patients are attributed to the hypercortisolemia induced increase in dopaminergic activity. Hypercortisolemia was found to be associated with DST non-suppression (Schatzberg, Rothschild,  Bond et al. 1983) and dexamethasone, similar to other steroids, was found to produce pronounced increases of unconjugated DA levels in human plasma as well as specific areas (such as the nucleus accumbens) in the rat brain (Rothschild, Schatzberg, Langlais et al. 1983). This is in line with the findings that patients with suspicious depression require a combination of a cyclic antidepressant and an antipsychotic or a dibenzoxazepine, such as amoxapine, which through its hydroxylated metabolite combines antidepressant with antipsychotic effects.

        Simultaneously with the recognition of the possible underlying pathomechanism of suspicious-delusional depression, a family genetic study has provided support for the validity of this diagnostic subtype of unipolar depression. In a study of Porsolit and his associates carried out in the 1980s the relatives of delusional probands were 1.5 times more likely to have major depression than were the relatives of the non-delusional probands and 3.5 times more likely to have major depression than the relatives of normal controls. More importantly, there was some evidence for specificity of transmission; 37% of the depressed relatives of the delusionals had delusional depression themselves compared to 19% of the relatives of the non-delusionals (Porsolt 1990).


Mania and Euphorias


        The other cross-sectional syndrome encountered in manic-depressive illness is mania. It is considerably less frequent than depression, although there are no reliable figures on its incidence and/or prevalence.

        One of the best descriptions of the pure manic syndrome was given by Jaspers (1963). According to him the syndrome in its pure form is characterized by "a primary, unmotivated and superabundant hilarity and euphoria, by psychic changes towards a flight of ideas and an increase in possible associations." This superabundant hilarity or "feeling of delight in life" is accompanied by "an increase in instinctual activities; increased sexuality; increased desire to move about; pressure of talk; and pressure of activity." The massive associations at the patient's disposal make him look witty and sparkling but "render him at the same time superficial and confused." Furthermore, "physically and mentally patient feels that he is extremely healthy and strong. He thinks his abilities are outstanding. With unfailing optimism, he will contemplate all things around him, the whole world and his own future in the rosiest of lights. Everything is as bright and happy as can be. His ideas and thoughts all agree on this point most harmoniously; to any other idea he is wholly inaccessible."

        Pure mania in the ideal form is extremely rare. Therefore, as early as 1899 Weygandt separated a number of components, such as hilarity (affective), flight of ideas (cognitive) and pressure of movements (adaptive) which he considered the structural elements of mania. Integrating these structural elements in different possible constellations he identified a number of different syndromes, such as the syndrome of "unproductive mania," which consists of hilarity and pressure of movement with retardation of thought, and the syndrome of "manic stupor," which consists of hilarity and retardation of movement with retardation of thought.

        By combining structure analysis with a holistic approach, Leonhard (1979) recognized that the illness referred to as mania consists of a number of different clinical syndromes of which only one, pure mania corresponds to some extent with the original concept. However, and in contradistinction to Weygandt, he considered the triad of motiveless (incomprehensible) elated mood, psychomotor excitation and flight of ideas with pressured speech as the cardinal symptoms  of pure mania. The extreme decisiveness with premature decisions and exaggerated self-esteem with feelings of competence were perceived as secondary phenomena to the cardinal-primary symptoms. By shifting the emphasis to the unipolar-bipolar dimension Leonhard separated the manic syndrome of bipolar manic melancholic illness from unipolar pure mania. Similarly, by recognizing the importance of the overall clinical picture, whether simple (monomorphous) or multifold (polymorphous), he separated unipolar pure mania from unipolar pure euphorias, i.e., nonparticipatory, unproductive, hypochondriacal, enthusiastic and confabulatory. These unipolar pure euphorias are prevailingly affective diseases, while pure mania is a disease in which thought and desire are also obligatorily disturbed. Furthermore, Leonhard brought attention to cross-sectional distinguishing features between the bipolar and the unipolar forms of mania. He suggested that the bipolar forms display a more colorful appearance. They vary not only between the two poles, but in each phase offer different clinical pictures. The same does not apply to the unipolar form which is characterized by a syndrome not associated or even transiently related to any other forms and recurs in patients with a periodic course with the same symptomatology.

        The five distinct subtypes of pure euphoria are named for their prevailing clinical features. Affective-mood changes prevail in all subtypes. However, in two of them, i.e., in unproductive and nonparticipatory, motor-adaptive structures, and in three of them, i.e., enthusiastic, hypochondriacal and confabulatory, perceptual-cognitive structures are also affected. Of the five subtypes, unproductive euphoria is characterized by motiveless feeling of happiness with radiant facial expression and poor thematization; hypochondriacal euphoria by hypochondriasis with homonom bodily hallucinations and cheerful complaintiveness; enthusiastic euphoria by exaggerated self-esteem with excessive happiness and a desire to make others happy; confabulatory euphoria by confabulations with recounting happy experiences and lively talkativeness; and nonparticipatory euphoria by lack of feelings of sympathy with impoverishment of emotions and will. Pure mania usually ends within a brief period of time, but pure euphorias tend to be chronic. On the other hand, similar to pure mania, pure euphorias completely remiss between episodes, even if the duration of the episodes is prolonged.

        ICD-9 distinguishes three types of mania and DSM-III two types. The three types of the ICD-9 include manic depressive psychosis manic type, manic depressive psychosis circular type (but currently manic) and other non-organic psychosis excitative type. Corresponding types in the DSM-III are bipolar disorder manic and cyclothymic disorder. There is no correspondence between Leonhard's manic subtypes, adopted in the DCR, and manic diagnoses in the ICD-9 and DSM-III.

        In spite of substantial evidence that antipsychotics are equally as effective as lithium salts in controlling an acute manic episode, there is an increasing consensus that lithium salts are the treatment of choice in manic patients. Nevertheless, it is unwise to undertake treatment with lithium before some behavioral control and cooperation is attained by the parenteral administration of an antipsychotic drug because of the metabolic imbalance created by the frequently insufficient food, fluid and, in particular, salt intake (Ban and Hollender 1981; Shaw 1979). Another important observation is that a considerable proportion of patients with a manic syndrome do not respond to either lithium salts or antipsychotic drugs given within the therapeutic dosage range. Some of these patients remain refractory even to combined treatment.

        The differential therapeutic response to lithium salts and/or antipsychotics favors the contention that patients with a manic syndrome are a biologically heterogenous population. Nevertheless, no systematic attempt has been directed to identify the patient population showing a favorable response to lithium salts and/or antipsychotics. There are indications, however, that the lithium-responsive population is the one which displays a nonsystematic picture, i.e., pure mania, with prevailing manifestations in the perceptual-cognitive, relational-affective and motor-adaptive psychopathological structures simultaneously, while the lithium refractory population is the one which displays systematic pictures, i.e., pure euphorias with prevailing manifestations in two of three psychopatholog1cal structures. In view of the insufficient therapeutic response in a considerable proportion of patients several different experimental therapeutic approaches have been tried. Included among them are treatment with the serotonin agonist, fenfluramine (Murphy, Campbell and Costa 1978) and treatment with serotonin antagonists such as methylsergide, mianserin and p-chlorophenyl alanine (Ananth 1976). Included also are treatment with e-adrenergic blockers, such as oxprenolol and propranolol (Atsman  and  Blum 1978;  Volk, Bies, Bruan et al. 1972); treatment with anticonvulsants such as carbamazepine and valproic acid (Okuma, Kishimoto and Inone 1973); and treatment with methyl­dopa, a false norepinephrine neurotransmitter (Mosher, Klerman and Greavy 1966). All these experimental approaches are of questionable clinical value. None of them has been validated in properly designed clinical experiments.

        Substantial evidence indicates that reserpine, a Rawolfia alkaloid, is a therapeutically effective agent in a substantial proportion of patients. To attain optimal therapeutic effects dosages as high as 20 mg per day may need to be prescribed. There are some indications that the effectiveness of reserpine is restricted to bipolar patients and to patients with pure mania. However, in the course of reserpine treatment there might be a shift to depression from mania in bipolar patients (Ban 1969). Since the same does not apply to patients with pure mania, reserpine may be a useful agent for the separation of bipolar mania from pure unipolar mania.

        Because reserpine, with therapeutic effect in mania, has central cholinomimetic properties, while imipramine, with therapeutic effect in depression, exerts central anticholinergic effects, it is hypothesized that a given affective state may represent a balance between central cholinergic and adrenergic activity, with depression being a disease of cholinergic and mania a disease of adrenergic dominance (Janowsky, el-Yousef, Davis and Sekerke 1972). In favor of these contentions are the findings that physostigmine, a substance that interferes with the breakdown of acetylcholine via enzyme inhibition, has rapidly controlled mania in a clinical study and induced depression in marijuana intoxicated patients. In favor also is the finding that physostigmine-induced depression can be reversed by the administration of atropine, a standard anticholinergic drug (Ban 1974).

        In view of the differential therapeutic response to drugs in manic patients it seems that the manic syndrome consists of a biologically heterogenous population. Because drugs with different action mechanisms have been shown to produce favorable therapeutic effects in some patients, there is no good reason to believe that studying the action mechanism of these drugs will provide clues for a better understanding of the pathomechanism of "mania."



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