Pharmacotherapy of Depression - A Critical Review THOMAS
A.
BAN,
M.D.
INTRODUCTION
The tcrm "depression" applies to a state of lowered affect, a mood of prevailing sadness. It may refer to a symptom, a syndrome or a nosological category (Lehmann 1959). While depressive symptoms, or the depression syndrome, are a common secondary feature of various physical and psychiatric conditions, in the primary mood disorders, the fundamental feature is the mood change, and usually there are no other associated illnesses. As far as the primary mood disorders are concerned, Kraepelin's (1921) original concept of an endogenous disorder (e.g. manic depressive psychosis) which is independent of external influences was later to be confirmed. Similarly, Ross' (1926) concept of reactive (secondary) depression which is the result of external influences has also been further substantiated. More recentlv however, there is increasing evidence, that Leonh;;d's (1959) distinction, between the bipolar and thc unipolar forms of recurrent depression, is the most meaningful, at least from a clinical psychopharmacological point of view. PHARMACOTHERAPY WITH TRICYCLIC ANTIDEPRESSANTS
Therapy with tricyclic antidepressants is the most frequently employed treatment modaJity in depression. The history of tricyclic antidepressants began in 1956 with the administration of imipramine (G 22,355) for the first time to depressed psychiatric patients by Roland Kuhn (1970) at the Cantonal Psychiatric Clinic in Munsterlingen. In his first article Kuhn (1957) described the antidepressant effect of imipramine so carefully and elucidated it so thoroughly, that according to Angst (1970), "later research has added nothing of radical importance to the findings published in this first account". In the seventeen years following the introduction of imipramine, a large number of tricyclic antidepressant drugs have been synthesized. By 1974, there were ten chemical classes of tricyclic antidepressants known; at least 38 tricyclic antidepressants had been clinically investigated; and almost one quarter of those which had been studied were used in clinical practice (Table I) (Usdin and Efron 1972). In the United Dr. Ban is Director, Division of Psychopharmacology and Associate Professor of Psychiatry, McGill University, Montreal, Canada. Presented at a meeting of the Department of Psychiatry. Vanderbilt University, Nashville, Tennessee on June 6th, 1974. January /February/March, 1975
Table I
The ten different classes of tricyclic antidepressants.
I II III IV V VI VII VIII IX X
I. 2. 3. 4. 5. 6. 7. It
9. 10.
Class Dibenzazepines Dibenzocycloheptenes Dibenzoxepines Acridanes Anthracenes Anthridines Dibenzodiazepines Dibenzothiepines Dibenzoxazepines Dibenzothiazepines
Prototype Number of Drugs Drug Investigated Imipramine 11 Amitriptyline 13 Doxepin 2 Dimethacrine 2 Melitracene 2 Propazepine 1 Dibenzepin 1 Prothiadene 4 Amoxapine 1 SQ 10,368
States and/ or Canada, there are eight tricyclic antidepressants in clinical use. These include four dibenzazepines (Le. clomipramine, desipramine, imipramine and trimipramine), three dibenzocycloheptenes (i.e. amitriptyline, nortriptyline and protriptyline) and one dibenzoxepine (doxepin) (Table II). With the rapidly growing number of tricyclic antidepressants it becomes increasingly important that every new tricyclic antidepressant should have a better therapeutic index or a different therapeutic profile than imipramine or any of the other already clinically used tricyclic antidepressant drugs. These expectations have not been fulfilled. Of six double-blind comparative studies with amitriptyline and imipramine, in two amitriptyline was found to be superior, in three equal, and in one inferior to imipramine (Ban 1974). Furthermore, in one of the two studies, in which amitriptyline was found to be significantly superior to imipramine within the first six months of treatment, there was no significant difference between the two treatment regimes at the time of the 18 months assessment (Kessell and Holt 1965; Hordern et al 1964). Similarly, and in spite of the clinical impressions, that some of the tricyclic antidepressants are more potent in their anxiolytic properties (e.g. doxepin, amitriptyline), or more rapid in their therapeutic action (e.g. desipramine, nortriptyline), or more selective in counteracting motor retardation (e.g. protriptyline), or lifting mood (e.g. imipramine, clomipramine), conclusive evidence for their differentiaJ clinical therapeutic effects has been lacking to date. While efforts to supersede the therapeutic efficacy of imipramine - or to establish differential therapeutic indications for the new drugs - have failed, there is sufficient evidence to believe that the overaJl therapeutic 17
PSYCHOSOMATICS
Table II Commercially available tricyclic antidepressants in the United States and / or Canada. Imipramine Amitriptyline (TofraniI) (Elavil) Desipramine Nortriptyline (Pertofrane) (Aventyl) (Norpramin) Clomipramine Protriptyline (Anafranil ) (Vivactil) (Triptil) Trimipramine Doxepin (Surmontil ) (Sinequan)
effectiveness of tricyclic antidepressants is greater than that of individual psychotherapy (Klerman et al 1974), group therapy (Covi et al 1974) and treatment with monoamine oxidase inhibitors (Klein and Davis 1969); and that the time required to spend in hospital is equal or may even be somewhat shorter with tricyclic antidepressants, than with electro-convulsive treatment (Degkwitz 1961). On the other hand, the overall improvement rate with the tricyclic antidepressant, imipramine (65 to 70 percent), was found to be only 26 to 39 percent higher than with an inactive placebo (31 to 39 per-;ent) (Angst 1970; Klein and Davis 1969; Klerman and Cole 1965); and the overall improvement rate with placebo in a recent study was found to be 60 percent after 28 days of treatment, Le. only slightly below the generally accepted figure of overall improvement rate with the therapeutically most effective tricyclic antidepressant drugs (Blashki 1972). POTENTIATION OF THERAPEUTIC EFFECTS
Irrespective of these considerations, there is an impressive concensus of opinion that the primary treatment of choice for depression today is pharmacotherapy with tricyclic antidepressants. This is in spite of the fact, that the relationship between the various pharmacological actions of these drugs, e.g. potentiation of central catecholaminergic (Schildkraut 1965) and serotoninergic (Coppen 1972) functions, central anticholinergic effects (J anowsky et al 1972 ), decrease of rapid eye movement (REM) sleep (Kupfer and Foster 1972), delay of onset of first REM period (Schildkraut and Keeler 1973), and their antidepressant effects are far from being fully elucidated (Theobald 1970). On the other hand, the pharmacological actions of these drugs explain the therapeutic success with tricyclic antidepressants in Parkinson's disease (potentiation of central catacholaminergic functions; central anticholinergic effects), and narcolepsy (delay of onset of first REM period). Since the mechanism of action responsible for antidepressant effects is not known, various methods for the potentiation of the therapeutic effectiveness of tri18
cyclic antidepressants have been developed. Among these are the supplementation of tricyclic antidepressants with methylphenidate, i.e. by increasing free catecholamine levels in the brain (Perel et al 1969); with l'dopa or 5-hydroxytryptophan, i.e. by increasing free catecholamine or indoleamine levels in the brain (Goodwin and Gordon 1973); with a monoamine oxidase inhibitor or reserpine, i.e. by increasing free monoamine levels in the brain (Ban 1974); and with thyroid stimulating hormone or I'triiodothyronine, i.e. by sensitizing receptors to monoamines in the brain (Prange et al 1971). Nevertheless. the clinical usefulness of these methods remains to be seen. THERAPY BASED ON BIOCHEMICAL HYPOTHESES
Systematic pharmacological studies brought to attention the possible role of neurotransmitter monoamines, i.e. the indoleamine serotonin, and the catecholamine dopamine and norepinephrine in the pathogenesis of depression. Indoleamine Hypothesis The indoleamine hypothesis of affective disorder is based on the generalization of the findings, that certain drugs which cause depletion and inactivation of serotonin (5HT) centrally, produce sedation in animal and/ or depression in man, while certain drugs which cause an increase or potentiate 5HT centrally produce stimulation in animal and/ or elation in man and may have antidepressant effects (Bain 1953; Pletscher, Shore and Brodie 1956). On the basis of these observations it was suggested that depression might be associated with a relative deficiency of 5HT, whereas elevation of mood might be associated with an excess of 5HT. at functionally important receptor sites in the brain (Richter 1967). In favor of the indoleamine hypothesis of affective disorder are the findings of low 5HT (and 5-hydroxyindo1eacetic acid) concentrations in suicide brain tissues; the antidepressant effects of clomipramine, a selective blocker of serotonin reuptake into the neuron; and the clinical observations on the antimanic effects of antiserotonin agents, such as methysergide and cinanserin (Ban 1974). Nevertheless, the finding that administration of parachlorophenylalanine, a specific blocker of tryptophan-5-hydroxylase activity which produces an 80 to 90 percent reduction of serotonin concentration in the brain, does not induce depressionand may even produce hypersexuality with increased responsiveness to the environment in animals - is the most important argument against the indoleamine hypothesis of affective disorder to date (Mendels and Frazer 1974). While the indoleamine hypothesis of affective disorder could not be fully substantiated by experimental findings, the possibility was raised that there might be a subgroup within the depressed patient population Volum~
XVl
PHARMACOTHERAPY OF DEPRESSION-BAN
which is characterized by low 5-hydroxyindoleacetic acid (5HIAA) concentration, the major metabolite of 5HT, in the cerebrospinal fluid. While in the course of systematic studies, Ashcroft et aI (1974) were able to demonstrate that unipolar, but not bipolar, depressed patients were characterized by low 5HIAA concentration in the cerebrospinal fluid, they found no change (increase) in the concentration of this acid metabolite in the course of successive treatment with psychoactive drugs. Even more, in Post and Goodwin's (I974) study. treatment with tricyclic antidepressant drugs, produced a decrease, instead of an increase, of 5HIAA. Nevertheless, Van Praag and his associates ( 1972) reported on favourable therapeutic effects with 5-hydroxytryptophan - the precursor of 5HT - in a group of patients with low concentration of serotonin metabolites in their cerebrospinal fluid. These findings, however, need to be further substantiated in appropriately controlled clinical studies.
findings, the possibility was raised, that there might be a subgroup within the depressed patient population which is characterized by low homovanillic acid (HVA) concentration, the major metabolite of OM in the cerebrospinal fluid. While in the course of systematic studies Ashcroft et al (1974) were able to demonstrate that unipolar, but not bipolar, depressed patients were characterized by low HVA concentrations in the cerebrospinal fluid, they found no change (increase) in the concentration of this acid metabolite in the course of successive treatment with psychoactive drugs. Similarly, Post and Goodwin (1974) found no significant change of HVA in the course of treatment with tricyclic antidepressant drugs, i.e. imipramine and amitriptyline. Nevertheless, Van Praag and Korf (1971) reported on favorable therapeutic effects with I'dopa the precursor of OM and NE - in a group of patients with low concentration of HVA in their cerebrospinal fluid. These findings, however, need to be further substantiated in appropriately controlIed clinical studies.
Catecholamine Hypothesis The catecholamine hypothesis of affective disorder is based on the generalization of the findings, that certain drugs which cause depletion or inactivation of dopamine (OM) and norepinephrine (NE) centrally produce sedation in animal and/ or depression in man, while certain drugs which cause an increase or potentiate OM and NE centrally produce stimulation in animal and/ or elation in man and may have antidepressant effects. On the basis of these observations, it was suggested, that depression might be associated with a relative deficiency of catecholamines whereas mania might be associated with an excess of OM and NE, at functionally important receptor sites (Schildkraut 1965; Van Praag and Korf 1971). In favour of the catecholamine hypothesis of affective disorder are the findings of low urinary concentrations of 3-methoxy-4-hydroxy-phenyl-glycol (MHPG), the major urinary metabolite of NE from the brain pool, in depressed patients (Maas, FawcelI and Oekirmenjian 1968; Schildkraut 1973); the antidepressant effects of desipramine, a selective blocker of norepinephrine reuptake into the neuron; and the antimanic effects of lithium salts which facilitate the intracelIular deamination of NE and thereby decrease the urinary excretion of normetanephrine and increase the urinary excretion of vanylmandelic acid. Nevertheless, the finding, that administration of alpha-methylparatyrosine, a specific blocker of tyrosine hydroxylase activity which selectively depletes the brain of OM and NE, does not produce depression, is the most important argument against the catecholamine hypothesis of affective disorder to date (Mendels and Frazer 1974). While the catecholamine hypothesis of affective disorder could not be fuIIy substantiated by experimental January /February /March, 1975
CONCLUSIONS
In a recent report, based on the findings in two multihospital studies, Raskin (1974) confirms the notion, that depression is a self-limiting illness with a high spontaneous recovery and high placebo response rate. He noted, that neurotic depressed patients did as well or better with placebo as with active treatment within the seven week experimental period. Anergia and motor retardation responded best to tricyclic antidepressants, while hostility became not infrequently aggravated by the same drugs. In the control of anxiety and sleep disturbance the effectiveness of anxiolytic sedatives, tricyclic antidepressants and neuroleptics was approximately the same. As far as psychotic depressions are concerned, there is now sufficient evidence to believe that there is a genetic and biochemical difference between bipolar and unipolar depressions; and that the primary choice of maintenance therapy in bipolar depression is with lithium salts and in unipolar depression with tricyclic antidepressants (Prien 1974). While none of the hypotheses of affective disorder, based on one or another pharmacological actions of tricyclic antidepressants, could be fully substantiated to date, systematic psychopharmacological studies with tricyclic antidepressants have provided sufficient data to hypothesize, that in psychomotor retardation catecholamines, and in sleep disturbance indoleamines, may play an important role. Nevertheless, the fact remains, that there is no evidence that clomipramine, a drug with a great specificity to interfere with serotonin reuptake, is therapeutically superior to desipramine, a drug with a great specificity to interfere with catecholamine reuptake, in unipolar depressed patients with prevailing sleep disturbance; nor is there evidence, 19
PSYCHOSOMATICS
that desipramine is therapeutically superior to clomipramine in unipolar depressed patients with prevailing motor disturbance. This corresponds with the finding that there is decreased concentration of both 5HIAA and HVA in the spinal fluid of unipolar depressed patients. REFERENCES Angst, J.: Clinical aspects of imipramine. In: Tofrani/, Verlag Stampfli & Cie, AG Berne 1970. Ashcroft, G.W., Blackburn, Ivy. Eccleston, D., Glen, A, Hartley. W., Kinloch, Nancy, Lonergan, Mary, Murray, L.G. and Pullar, I.A: Changes on recovery in the concentrations of tryptophan and the biogenic amine metabolites in the cerebrospinal fluid of patients with affective illness. Psychol. Med. 3: 319-325. 1973. Ban, T.A.: Depression and the Tricyclic Antidepressants. Ronaids Federated Graphics, Ltd .. Montreal 1974. Bein, H.J.: Zur Pharmakologie des Reserpin, eines neuen Alkaloids aus Rauwolfia serpentia benth. Experiell/ia 9: 107110, 1953. Blashki, T.G.: A controlled trial of an antidepressant (amitriptyline) in general practice. In: Davies, B., Carroll, B.J. an.j Mowbray, R.M. (eds.): Depressil'e Illness. Charles C. Thomas. Springfield 1972. Coppen. A.: Indoleamines and affective disorders. J. Psychiat. Res. 9: 167-171,1972. Covi. L., Lipman, R., Derogatis, L., Smith, J .E. and Pattison, J.: Drugs and group psychotherapy in neurotic depression. Amer. J. Psychiat. 131: 191-198,1974. Degkwitz, R.: The effect of imipramine (Tofranil) in different kinds of depressions in comparison with electro-shock treatment. A report on 600 cases. In: Proceedings of the 3rd World Congress of Psychiatry, Montreal 1961. University of Toronto Press. Toronto 1961. Goodwin, F.K. and Gordon, E.K.: Cerebrospinal fluid amine metabolites in affective illness: the probenecid therapy. Amer. I. Psychiat. 130: 73-79, 1973. Hordern, A., Burt. e.G., Gordon, W.F. and Holt, N.F.: Amitriptyline in depressive states: six month treatment results. Brit. J. Psychiat. 110: 641-647, 1964. lanowsky, D.S., EI-Yousef, M.K., Davis, J.M. and Sekerke, H.J.: A cholinergic-adrenergic hypothesis of mania and depression. Lancet 2: 632-635, 1972. Kessell, A. and Holt, N. F.: Depression - an analysis of follOW-lip study. Brit. J. Psychiat. 3: 1143-1153, 1965. Klein, D.F. and Davis, J.M.: Diagnosis and Dmg Treatment of Psychiatric Disorders. Williams and Wilkins, Baltimore 1969. Klerman, G.L. and Cole, J.D.: Clinical pharmacology of imipramine and related antidepressant compounds. Pharmacol. Rei'. 17: 101-141,1965. Kraepelin, E.: Manic-Depressive Insanity and Paranoia. Livingstone, Edinburgh 1921. Kupfer, D.J. and Foster, F.G.: Interval between onset of sleep and rapid eye movement sleep as an indicator of depression. Lancet 2: 684-686, 1972. Lehmann, H.E.: Psychiatric concepts of depression: nomencla-
20
ture and classification. Canad. Psychiat. Ass. J. 4: SI-SIO, 1959. Leonhard, K.: Auftei/ung der Endogenen Psychosen. Akademie Verlag, Berlin 1959. Maas, J.E., Fawcett, J.A. and Dekirmenjian, H.: Catecholamine metabolism in depressive illness and drug response. Arch. Gen. Psychiat. 26: 252-262, 1968. Mendels, J. and Frazer, A: Brain biogenic amine depletion and mood. Arch. Gen. Psychiat. 30: 447-451, 1974. Mowbray, R.M.: The classification of depression. In: Davies, B., Carroll, B.J. and Mowbray, RM. (eds.): Depressi\'e J/lness. Charles C. Thomas, Springfield 1972. Perel, J.M., Black, N., Wharton, R N. and Marlitz, S.: Inhibition of imipramine metabolism by methylphenidate. Fed. Proc. 28: 418, 1969. Pletscher, A., Shore, P.A. and Brodie, B.B.: Serotonin as a mediator of reserpine action in brain. J. Pharmacal. Exp. Therap. 116: 84-89, 1956. Post, R.M. and Goodwin, F.K.: Effects of amitriptyline and imipramine on amine metabolites in the cerebrospinal fluid of depressed patients. Arch. Gen. Psychiat. 30: 234-239, 1974. Prange, AJ., Wilson, I.e., Knox, A., McClane, R.K. and Lipton, M.A.: Enhancement of imipramine by thyroid stimulating hormone: clinical and theoretical implications. Amer. J. Psychiat. 127: 191-195,1971. Prien, R.F.: Prophylactic treatment of recurrent depression: observations from a multihospital collaborative study. Veteran's Administration Central Neuropsychiatry Laboratory Research Report No. 98 March 1974. Raskin, A.: A guide for drug use in depressive disorders. Amer. J. Psychiat. 131: 181-185,1974. Richter, D.: Tryptophan metabolism in mental illness. In: Himwich, H.E., Kety, S.S. and Smythies, J.R. (eds): Ambles and Schizophrenia. Pergamon Press, London 1967. Ross, RA: Discussion on manic-depressive psychosis. Brit. Med. J. 2: 877, 1926. Schildkraut, J.J.: The catecholamine hypothesis of affective disorders: a review of supporting evidence. Amer. J. Psychiat. 122: 509-522, 1965. Schildkraut, J.J.: Norepinephrine metabolites as biochemical criteria for classifying depressive disorders and predicting response to treatment. Preliminary findings. Amer. J. Psychiat. 130: 695-699, 1973. Schildkraut, J J. and Keeler, Barbara A: MHPG excretion in depressive disorders: relation to clinical subtypes and desynchronized sleep. Science 181: 762-764, 1973. Theobald, W.: Experimental studies. In: Tofrani/. Verlag Stampfli et Cie. AG Berne 1970. Usdin, E. and Efron, D.: Psychotropic Dmgs and Related Compol/nds (Second Edition). DHEW Publication No. (HSM) 72-9074, Washington 1972. Van Praag, H.M. and Korf, J.: Retarded depressions and the dopamine metabolism. Psychopharmacologia 19: 199203, 1971. Van Praag. H.M., Korf, J., Dols, L.e.W. and Schut, T.: A pilot study of the predictive value of the probenecid test in application of 5-hydroxytryptophan as antidepressant. Psychopharmacologia 25: 14-21, 1972.
Volume XVI
A.
BAN,
M.D.
INTRODUCTION
The tcrm "depression" applies to a state of lowered affect, a mood of prevailing sadness. It may refer to a symptom, a syndrome or a nosological category (Lehmann 1959). While depressive symptoms, or the depression syndrome, are a common secondary feature of various physical and psychiatric conditions, in the primary mood disorders, the fundamental feature is the mood change, and usually there are no other associated illnesses. As far as the primary mood disorders are concerned, Kraepelin's (1921) original concept of an endogenous disorder (e.g. manic depressive psychosis) which is independent of external influences was later to be confirmed. Similarly, Ross' (1926) concept of reactive (secondary) depression which is the result of external influences has also been further substantiated. More recentlv however, there is increasing evidence, that Leonh;;d's (1959) distinction, between the bipolar and thc unipolar forms of recurrent depression, is the most meaningful, at least from a clinical psychopharmacological point of view. PHARMACOTHERAPY WITH TRICYCLIC ANTIDEPRESSANTS
Therapy with tricyclic antidepressants is the most frequently employed treatment modaJity in depression. The history of tricyclic antidepressants began in 1956 with the administration of imipramine (G 22,355) for the first time to depressed psychiatric patients by Roland Kuhn (1970) at the Cantonal Psychiatric Clinic in Munsterlingen. In his first article Kuhn (1957) described the antidepressant effect of imipramine so carefully and elucidated it so thoroughly, that according to Angst (1970), "later research has added nothing of radical importance to the findings published in this first account". In the seventeen years following the introduction of imipramine, a large number of tricyclic antidepressant drugs have been synthesized. By 1974, there were ten chemical classes of tricyclic antidepressants known; at least 38 tricyclic antidepressants had been clinically investigated; and almost one quarter of those which had been studied were used in clinical practice (Table I) (Usdin and Efron 1972). In the United Dr. Ban is Director, Division of Psychopharmacology and Associate Professor of Psychiatry, McGill University, Montreal, Canada. Presented at a meeting of the Department of Psychiatry. Vanderbilt University, Nashville, Tennessee on June 6th, 1974. January /February/March, 1975
Table I
The ten different classes of tricyclic antidepressants.
I II III IV V VI VII VIII IX X
I. 2. 3. 4. 5. 6. 7. It
9. 10.
Class Dibenzazepines Dibenzocycloheptenes Dibenzoxepines Acridanes Anthracenes Anthridines Dibenzodiazepines Dibenzothiepines Dibenzoxazepines Dibenzothiazepines
Prototype Number of Drugs Drug Investigated Imipramine 11 Amitriptyline 13 Doxepin 2 Dimethacrine 2 Melitracene 2 Propazepine 1 Dibenzepin 1 Prothiadene 4 Amoxapine 1 SQ 10,368
States and/ or Canada, there are eight tricyclic antidepressants in clinical use. These include four dibenzazepines (Le. clomipramine, desipramine, imipramine and trimipramine), three dibenzocycloheptenes (i.e. amitriptyline, nortriptyline and protriptyline) and one dibenzoxepine (doxepin) (Table II). With the rapidly growing number of tricyclic antidepressants it becomes increasingly important that every new tricyclic antidepressant should have a better therapeutic index or a different therapeutic profile than imipramine or any of the other already clinically used tricyclic antidepressant drugs. These expectations have not been fulfilled. Of six double-blind comparative studies with amitriptyline and imipramine, in two amitriptyline was found to be superior, in three equal, and in one inferior to imipramine (Ban 1974). Furthermore, in one of the two studies, in which amitriptyline was found to be significantly superior to imipramine within the first six months of treatment, there was no significant difference between the two treatment regimes at the time of the 18 months assessment (Kessell and Holt 1965; Hordern et al 1964). Similarly, and in spite of the clinical impressions, that some of the tricyclic antidepressants are more potent in their anxiolytic properties (e.g. doxepin, amitriptyline), or more rapid in their therapeutic action (e.g. desipramine, nortriptyline), or more selective in counteracting motor retardation (e.g. protriptyline), or lifting mood (e.g. imipramine, clomipramine), conclusive evidence for their differentiaJ clinical therapeutic effects has been lacking to date. While efforts to supersede the therapeutic efficacy of imipramine - or to establish differential therapeutic indications for the new drugs - have failed, there is sufficient evidence to believe that the overaJl therapeutic 17
PSYCHOSOMATICS
Table II Commercially available tricyclic antidepressants in the United States and / or Canada. Imipramine Amitriptyline (TofraniI) (Elavil) Desipramine Nortriptyline (Pertofrane) (Aventyl) (Norpramin) Clomipramine Protriptyline (Anafranil ) (Vivactil) (Triptil) Trimipramine Doxepin (Surmontil ) (Sinequan)
effectiveness of tricyclic antidepressants is greater than that of individual psychotherapy (Klerman et al 1974), group therapy (Covi et al 1974) and treatment with monoamine oxidase inhibitors (Klein and Davis 1969); and that the time required to spend in hospital is equal or may even be somewhat shorter with tricyclic antidepressants, than with electro-convulsive treatment (Degkwitz 1961). On the other hand, the overall improvement rate with the tricyclic antidepressant, imipramine (65 to 70 percent), was found to be only 26 to 39 percent higher than with an inactive placebo (31 to 39 per-;ent) (Angst 1970; Klein and Davis 1969; Klerman and Cole 1965); and the overall improvement rate with placebo in a recent study was found to be 60 percent after 28 days of treatment, Le. only slightly below the generally accepted figure of overall improvement rate with the therapeutically most effective tricyclic antidepressant drugs (Blashki 1972). POTENTIATION OF THERAPEUTIC EFFECTS
Irrespective of these considerations, there is an impressive concensus of opinion that the primary treatment of choice for depression today is pharmacotherapy with tricyclic antidepressants. This is in spite of the fact, that the relationship between the various pharmacological actions of these drugs, e.g. potentiation of central catecholaminergic (Schildkraut 1965) and serotoninergic (Coppen 1972) functions, central anticholinergic effects (J anowsky et al 1972 ), decrease of rapid eye movement (REM) sleep (Kupfer and Foster 1972), delay of onset of first REM period (Schildkraut and Keeler 1973), and their antidepressant effects are far from being fully elucidated (Theobald 1970). On the other hand, the pharmacological actions of these drugs explain the therapeutic success with tricyclic antidepressants in Parkinson's disease (potentiation of central catacholaminergic functions; central anticholinergic effects), and narcolepsy (delay of onset of first REM period). Since the mechanism of action responsible for antidepressant effects is not known, various methods for the potentiation of the therapeutic effectiveness of tri18
cyclic antidepressants have been developed. Among these are the supplementation of tricyclic antidepressants with methylphenidate, i.e. by increasing free catecholamine levels in the brain (Perel et al 1969); with l'dopa or 5-hydroxytryptophan, i.e. by increasing free catecholamine or indoleamine levels in the brain (Goodwin and Gordon 1973); with a monoamine oxidase inhibitor or reserpine, i.e. by increasing free monoamine levels in the brain (Ban 1974); and with thyroid stimulating hormone or I'triiodothyronine, i.e. by sensitizing receptors to monoamines in the brain (Prange et al 1971). Nevertheless. the clinical usefulness of these methods remains to be seen. THERAPY BASED ON BIOCHEMICAL HYPOTHESES
Systematic pharmacological studies brought to attention the possible role of neurotransmitter monoamines, i.e. the indoleamine serotonin, and the catecholamine dopamine and norepinephrine in the pathogenesis of depression. Indoleamine Hypothesis The indoleamine hypothesis of affective disorder is based on the generalization of the findings, that certain drugs which cause depletion and inactivation of serotonin (5HT) centrally, produce sedation in animal and/ or depression in man, while certain drugs which cause an increase or potentiate 5HT centrally produce stimulation in animal and/ or elation in man and may have antidepressant effects (Bain 1953; Pletscher, Shore and Brodie 1956). On the basis of these observations it was suggested that depression might be associated with a relative deficiency of 5HT, whereas elevation of mood might be associated with an excess of 5HT. at functionally important receptor sites in the brain (Richter 1967). In favor of the indoleamine hypothesis of affective disorder are the findings of low 5HT (and 5-hydroxyindo1eacetic acid) concentrations in suicide brain tissues; the antidepressant effects of clomipramine, a selective blocker of serotonin reuptake into the neuron; and the clinical observations on the antimanic effects of antiserotonin agents, such as methysergide and cinanserin (Ban 1974). Nevertheless, the finding that administration of parachlorophenylalanine, a specific blocker of tryptophan-5-hydroxylase activity which produces an 80 to 90 percent reduction of serotonin concentration in the brain, does not induce depressionand may even produce hypersexuality with increased responsiveness to the environment in animals - is the most important argument against the indoleamine hypothesis of affective disorder to date (Mendels and Frazer 1974). While the indoleamine hypothesis of affective disorder could not be fully substantiated by experimental findings, the possibility was raised that there might be a subgroup within the depressed patient population Volum~
XVl
PHARMACOTHERAPY OF DEPRESSION-BAN
which is characterized by low 5-hydroxyindoleacetic acid (5HIAA) concentration, the major metabolite of 5HT, in the cerebrospinal fluid. While in the course of systematic studies, Ashcroft et aI (1974) were able to demonstrate that unipolar, but not bipolar, depressed patients were characterized by low 5HIAA concentration in the cerebrospinal fluid, they found no change (increase) in the concentration of this acid metabolite in the course of successive treatment with psychoactive drugs. Even more, in Post and Goodwin's (I974) study. treatment with tricyclic antidepressant drugs, produced a decrease, instead of an increase, of 5HIAA. Nevertheless, Van Praag and his associates ( 1972) reported on favourable therapeutic effects with 5-hydroxytryptophan - the precursor of 5HT - in a group of patients with low concentration of serotonin metabolites in their cerebrospinal fluid. These findings, however, need to be further substantiated in appropriately controlled clinical studies.
findings, the possibility was raised, that there might be a subgroup within the depressed patient population which is characterized by low homovanillic acid (HVA) concentration, the major metabolite of OM in the cerebrospinal fluid. While in the course of systematic studies Ashcroft et al (1974) were able to demonstrate that unipolar, but not bipolar, depressed patients were characterized by low HVA concentrations in the cerebrospinal fluid, they found no change (increase) in the concentration of this acid metabolite in the course of successive treatment with psychoactive drugs. Similarly, Post and Goodwin (1974) found no significant change of HVA in the course of treatment with tricyclic antidepressant drugs, i.e. imipramine and amitriptyline. Nevertheless, Van Praag and Korf (1971) reported on favorable therapeutic effects with I'dopa the precursor of OM and NE - in a group of patients with low concentration of HVA in their cerebrospinal fluid. These findings, however, need to be further substantiated in appropriately controlIed clinical studies.
Catecholamine Hypothesis The catecholamine hypothesis of affective disorder is based on the generalization of the findings, that certain drugs which cause depletion or inactivation of dopamine (OM) and norepinephrine (NE) centrally produce sedation in animal and/ or depression in man, while certain drugs which cause an increase or potentiate OM and NE centrally produce stimulation in animal and/ or elation in man and may have antidepressant effects. On the basis of these observations, it was suggested, that depression might be associated with a relative deficiency of catecholamines whereas mania might be associated with an excess of OM and NE, at functionally important receptor sites (Schildkraut 1965; Van Praag and Korf 1971). In favour of the catecholamine hypothesis of affective disorder are the findings of low urinary concentrations of 3-methoxy-4-hydroxy-phenyl-glycol (MHPG), the major urinary metabolite of NE from the brain pool, in depressed patients (Maas, FawcelI and Oekirmenjian 1968; Schildkraut 1973); the antidepressant effects of desipramine, a selective blocker of norepinephrine reuptake into the neuron; and the antimanic effects of lithium salts which facilitate the intracelIular deamination of NE and thereby decrease the urinary excretion of normetanephrine and increase the urinary excretion of vanylmandelic acid. Nevertheless, the finding, that administration of alpha-methylparatyrosine, a specific blocker of tyrosine hydroxylase activity which selectively depletes the brain of OM and NE, does not produce depression, is the most important argument against the catecholamine hypothesis of affective disorder to date (Mendels and Frazer 1974). While the catecholamine hypothesis of affective disorder could not be fuIIy substantiated by experimental January /February /March, 1975
CONCLUSIONS
In a recent report, based on the findings in two multihospital studies, Raskin (1974) confirms the notion, that depression is a self-limiting illness with a high spontaneous recovery and high placebo response rate. He noted, that neurotic depressed patients did as well or better with placebo as with active treatment within the seven week experimental period. Anergia and motor retardation responded best to tricyclic antidepressants, while hostility became not infrequently aggravated by the same drugs. In the control of anxiety and sleep disturbance the effectiveness of anxiolytic sedatives, tricyclic antidepressants and neuroleptics was approximately the same. As far as psychotic depressions are concerned, there is now sufficient evidence to believe that there is a genetic and biochemical difference between bipolar and unipolar depressions; and that the primary choice of maintenance therapy in bipolar depression is with lithium salts and in unipolar depression with tricyclic antidepressants (Prien 1974). While none of the hypotheses of affective disorder, based on one or another pharmacological actions of tricyclic antidepressants, could be fully substantiated to date, systematic psychopharmacological studies with tricyclic antidepressants have provided sufficient data to hypothesize, that in psychomotor retardation catecholamines, and in sleep disturbance indoleamines, may play an important role. Nevertheless, the fact remains, that there is no evidence that clomipramine, a drug with a great specificity to interfere with serotonin reuptake, is therapeutically superior to desipramine, a drug with a great specificity to interfere with catecholamine reuptake, in unipolar depressed patients with prevailing sleep disturbance; nor is there evidence, 19
PSYCHOSOMATICS
that desipramine is therapeutically superior to clomipramine in unipolar depressed patients with prevailing motor disturbance. This corresponds with the finding that there is decreased concentration of both 5HIAA and HVA in the spinal fluid of unipolar depressed patients. REFERENCES Angst, J.: Clinical aspects of imipramine. In: Tofrani/, Verlag Stampfli & Cie, AG Berne 1970. Ashcroft, G.W., Blackburn, Ivy. Eccleston, D., Glen, A, Hartley. W., Kinloch, Nancy, Lonergan, Mary, Murray, L.G. and Pullar, I.A: Changes on recovery in the concentrations of tryptophan and the biogenic amine metabolites in the cerebrospinal fluid of patients with affective illness. Psychol. Med. 3: 319-325. 1973. Ban, T.A.: Depression and the Tricyclic Antidepressants. Ronaids Federated Graphics, Ltd .. Montreal 1974. Bein, H.J.: Zur Pharmakologie des Reserpin, eines neuen Alkaloids aus Rauwolfia serpentia benth. Experiell/ia 9: 107110, 1953. Blashki, T.G.: A controlled trial of an antidepressant (amitriptyline) in general practice. In: Davies, B., Carroll, B.J. an.j Mowbray, R.M. (eds.): Depressil'e Illness. Charles C. Thomas. Springfield 1972. Coppen. A.: Indoleamines and affective disorders. J. Psychiat. Res. 9: 167-171,1972. Covi. L., Lipman, R., Derogatis, L., Smith, J .E. and Pattison, J.: Drugs and group psychotherapy in neurotic depression. Amer. J. Psychiat. 131: 191-198,1974. Degkwitz, R.: The effect of imipramine (Tofranil) in different kinds of depressions in comparison with electro-shock treatment. A report on 600 cases. In: Proceedings of the 3rd World Congress of Psychiatry, Montreal 1961. University of Toronto Press. Toronto 1961. Goodwin, F.K. and Gordon, E.K.: Cerebrospinal fluid amine metabolites in affective illness: the probenecid therapy. Amer. I. Psychiat. 130: 73-79, 1973. Hordern, A., Burt. e.G., Gordon, W.F. and Holt, N.F.: Amitriptyline in depressive states: six month treatment results. Brit. J. Psychiat. 110: 641-647, 1964. lanowsky, D.S., EI-Yousef, M.K., Davis, J.M. and Sekerke, H.J.: A cholinergic-adrenergic hypothesis of mania and depression. Lancet 2: 632-635, 1972. Kessell, A. and Holt, N. F.: Depression - an analysis of follOW-lip study. Brit. J. Psychiat. 3: 1143-1153, 1965. Klein, D.F. and Davis, J.M.: Diagnosis and Dmg Treatment of Psychiatric Disorders. Williams and Wilkins, Baltimore 1969. Klerman, G.L. and Cole, J.D.: Clinical pharmacology of imipramine and related antidepressant compounds. Pharmacol. Rei'. 17: 101-141,1965. Kraepelin, E.: Manic-Depressive Insanity and Paranoia. Livingstone, Edinburgh 1921. Kupfer, D.J. and Foster, F.G.: Interval between onset of sleep and rapid eye movement sleep as an indicator of depression. Lancet 2: 684-686, 1972. Lehmann, H.E.: Psychiatric concepts of depression: nomencla-
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ture and classification. Canad. Psychiat. Ass. J. 4: SI-SIO, 1959. Leonhard, K.: Auftei/ung der Endogenen Psychosen. Akademie Verlag, Berlin 1959. Maas, J.E., Fawcett, J.A. and Dekirmenjian, H.: Catecholamine metabolism in depressive illness and drug response. Arch. Gen. Psychiat. 26: 252-262, 1968. Mendels, J. and Frazer, A: Brain biogenic amine depletion and mood. Arch. Gen. Psychiat. 30: 447-451, 1974. Mowbray, R.M.: The classification of depression. In: Davies, B., Carroll, B.J. and Mowbray, RM. (eds.): Depressi\'e J/lness. Charles C. Thomas, Springfield 1972. Perel, J.M., Black, N., Wharton, R N. and Marlitz, S.: Inhibition of imipramine metabolism by methylphenidate. Fed. Proc. 28: 418, 1969. Pletscher, A., Shore, P.A. and Brodie, B.B.: Serotonin as a mediator of reserpine action in brain. J. Pharmacal. Exp. Therap. 116: 84-89, 1956. Post, R.M. and Goodwin, F.K.: Effects of amitriptyline and imipramine on amine metabolites in the cerebrospinal fluid of depressed patients. Arch. Gen. Psychiat. 30: 234-239, 1974. Prange, AJ., Wilson, I.e., Knox, A., McClane, R.K. and Lipton, M.A.: Enhancement of imipramine by thyroid stimulating hormone: clinical and theoretical implications. Amer. J. Psychiat. 127: 191-195,1971. Prien, R.F.: Prophylactic treatment of recurrent depression: observations from a multihospital collaborative study. Veteran's Administration Central Neuropsychiatry Laboratory Research Report No. 98 March 1974. Raskin, A.: A guide for drug use in depressive disorders. Amer. J. Psychiat. 131: 181-185,1974. Richter, D.: Tryptophan metabolism in mental illness. In: Himwich, H.E., Kety, S.S. and Smythies, J.R. (eds): Ambles and Schizophrenia. Pergamon Press, London 1967. Ross, RA: Discussion on manic-depressive psychosis. Brit. Med. J. 2: 877, 1926. Schildkraut, J.J.: The catecholamine hypothesis of affective disorders: a review of supporting evidence. Amer. J. Psychiat. 122: 509-522, 1965. Schildkraut, J.J.: Norepinephrine metabolites as biochemical criteria for classifying depressive disorders and predicting response to treatment. Preliminary findings. Amer. J. Psychiat. 130: 695-699, 1973. Schildkraut, J J. and Keeler, Barbara A: MHPG excretion in depressive disorders: relation to clinical subtypes and desynchronized sleep. Science 181: 762-764, 1973. Theobald, W.: Experimental studies. In: Tofrani/. Verlag Stampfli et Cie. AG Berne 1970. Usdin, E. and Efron, D.: Psychotropic Dmgs and Related Compol/nds (Second Edition). DHEW Publication No. (HSM) 72-9074, Washington 1972. Van Praag, H.M. and Korf, J.: Retarded depressions and the dopamine metabolism. Psychopharmacologia 19: 199203, 1971. Van Praag. H.M., Korf, J., Dols, L.e.W. and Schut, T.: A pilot study of the predictive value of the probenecid test in application of 5-hydroxytryptophan as antidepressant. Psychopharmacologia 25: 14-21, 1972.
Volume XVI
