Comprehensive Psychiatry Official
VOL.
Journal
of the American
16, NO. 1
On the Controversy
Psychopathological
Association
JANI’ARY/FEBRUARY
of Prophylactic
1975
Antidepressants
Fritz A. Freyhan
I
T IS the purpose of this brief presentation to assess our present knowledge on the prophylactic treatment of affective disorders. The history of psychiatry reveals a seemingly unresistable temptation to equate beneficial treatment responses with treatment specificity. Substantial progress in research and treatment tends to be hailed as a breakthrough. Unfortunately, the record is full of disappointments, because psychiatrists failed to distinguish between tentative and valid approaches to etiology and treatment of psychiatric disorders. Not too many years ago, insulin-coma therapy was widely regarded as the scientifically most rational treatment of schizophrenic illness. Whatever the theoretical shortcomings of a rationale that tied insulin coma to a postulated schizophrenic process, insulin became the treatment of choice. After the discovery of the striking effects of neuroleptics on symptoms and syndromes associated with schizophrenic disorders, the literature began to upgrade neuroleptics to the specific status of antischizophrenic drugs. The advent of the antidepressant drugs is a further example of the problems that confuse therapeutic efficacy with illness specificity. After the introduction of the antidepressant drugs, which were believed to be specific by some investigators, an opposing argument was raised by those who considered electroshock to be more specific. This notion was based on the fact that ECT had been shown to be beneficial in the treatment of both manic and depressed states. It should be remembered that the idea of prophylactic treatment for affective disorders goes back to 1951 when Stevenson and Geoghegan introduced “prophylactic electroshock.“’ The authors claimed that electroshock given once monthly for at least 2 years could prevent future manic-depressive episodes. Although no long-term results of this treatment were published, it is a fact that many psychiatrists to this day practice various modifications of maintenance ECT. Based on empirical evidence, these psychiatrists believe that ECT is more specific and therefore more reliable than drugs, including lithium. As is not sufficiently recognized, we have no valid statistics on the popularity of different therapeutic methods of psychiatry. In the area of treatment with psychoactive drugs, recent studies by Pichot and other? have shown that the Presenred ar the Ninrh International Congres.~ qf the Collegium pharn~acologicum. July 7-12. 1974. Paris, France. Fritz A. Freyhan, M.D.: 2015 R Street, N II’. Washington. I).(‘. ,c‘l1975 ht. C;rune & Srratton. Inc.
Comprehensive
Psychiarry, Vol. 16. No. 1 (January/Februaryb
1975
lnrernationale
:Vcurop.rI,cho-
2
FRITZ A. FREYHAN
preference for particular drugs has no detectable scientific explanation. Generally there is a wide gap between the evidence in the scientific literature and the popularity and administration of treatments in everyday practice. In this connection, I find a recent report by Fieve3 relevant. Analyzing the histories of 200 manicdepressive patients attending his lithium clinic, he found that they had been sub jetted to a total of approximately 5,000 shock treatments before coming under lithium control. He postulates an 80% probability of successful prophylaxis with lithium and other drugs and therefore anticipates only a rare need for electroshock. We must not forget, however, that the same confidence in drastic reduction, if not elimination, of electroshock followed the discovery of the antidepressants, and also that the question of the relative merits of depression treatments is still a matter of preference without definitive data based on scientific assessment. Current controversies regarding the therapeutic efficacy of lithium focus no longer on its therapeutic properties but on the issue of prophylaxis. There is no longer any doubt that lithium has emerged as an agent of unique biological importance. It has generated widespread clinical and experimental interest. The most significant claim to therapeutic innovation rests on the expectation that lithium exerts preventive action on cyclic affective disorders. ETIOLOGICAL
CONSIDERATIONS
The term prophylaxis connotes action on the etiological or pathogenetic determinants of an illness. In the case of the affective disorders, the effects on catecholamine metabolism are regarded as basic to cause-directed treatment. Experimental and clinical studies have provided impressive evidence that pathological changes in mood, depression, or mania may be generated by changes in the function of brain biogenic amines. The effects of antidepressant drugs and possibly also of electroshock have been credited to their capability to normalize biogenic amine activity. The biological effects of lithium have been shown to include alterations in catecholamine metabolism. The ultimate significance of this action remains for the present unclear. Schildkraut,4 who has contributed major data in favor of the hypothesis linking affective illness with the role of biogenic amines, cautions that although numerous studies have shown that lithium affects catecholamine metabolism, further investigations will be needed to ascertain whether this accounts for the clinical effects of lithium on mood disorders. Davis,5 evaluating the biology of lithium, concludes that some of the findings are contradictory, some unsubstantiated, and some preliminary findings of unknown significance. The relevance of brain biogenic amines to mood disorders has been questioned by Mendels and Frazer .‘j These investigators reported that administration of drugs to humans in amounts sufficient to produce greater depletion of amines than that reported consistently to occur in depressed patients does not in itself produce depressjon. They are concerned that the biogenic amine hypothesis may be an oversimplistic framework for our understanding of the relationship between psychopathology and underlying biological dysfunctions. Additional doubts regarding lithium specificity for affective illness stems from recent clinical studies that claim lithium to be effective in treating personality, childhood, schizophrenic, and other disorders. If these preliminary reports are
PROPHYLACTIC
ANTIDEPRESSANTS
3
supported by more systematic trials, this would put lithium in the category of broad-spectrum drugs comparable to neuroleptic compounds. These brief citations from the literature confirm that we have as yet no firm grounds for expecting biological specificity on which to base a claim for prophylactic treatment of affective disorders. METHODOLOGICAL
CONSIDERATIONS
After the initial therapeutic successes with neuroleptic and antidepressant drugs, it seemed probable to me that drug-induced improvement, once achieved, could be maintained by continuous medication. The feasibility of a truly compensatory type of antidepressant treatment depends on the drug’s capability to restore and preserve the patient’s functional adequacy.7 In spite of the fact that maintenance treatment became customary all over the world, no efforts were made to standardize therapeutic methods or clinical evaluations on long-term bases. Because of this, the literature on compensatory or maintenance treatment remained scant and scientifically unsatisfactory. The use of lithium put clinical methodology on a long-overdue basis of investigatory sophistication. Because of toxicity, treatment with lithium requires standardized dosage regimes, monitoring of blood levels, and longitudinal and clinical evaluations. If lithium had achieved nothing else, it still would find a prominent place in history for having greatly advanced our approaches to diagnosis and treatment of affective disorders. Perplexing, however, was the premature conclusion that lithium had succeeded where other drugs had failed. Prior to lithium there had been no studies of moodaffective drugs comparable in terms of the stringently controlled conditions of patient selection, monitoring of drug intake, and continuous clinical observation of many years’ duration. Until quite recently, hundreds of studies of lithium concentrated on the clinical evidence of acute and maintenance effectiveness, first uncontrolled and more recently compared to placebo. As Prien* puts it, “When one considers that lithium has been employed as a psychopharmacological agent for 25 years and has been investigated in hundreds of studies, it is surprising to find that there are only about a dozen trials comparing the drug with active medication.” If compared with other drugs, there is currently no evidence of the superiority of lithium. Inasfar as manic states are concerned, lithium is not more effective than chlorpromazine or haloperidol. With depressive disorders, we have only one study comparing lithium with imipramine.g This collaborative study, which was carried out in 18 hospitals during a 2-year period of treatment, is of considerable importance. For unipolar patients, imipramine was found to be as effective as lithium. Thus the oldest antidepressant, if administered under weilcontrolled conditions of the investigation of lithium, proved to be as good a prophylactic compound as lithium. However, the investigators cautioned against using the term prophylaxis, because 42% in the lithium group and 38% in the imipramine group displayed long periods of mild to moderately severe symptomatology during the 2 years of treatment. My own experiences had shown that episode-free intervals are often obscured by persistent morbidity in spite of active therapeutic measures. lo Patients observed in our lithium clinic suffered from fluctuating diurnal mood patterns, periodic sleep disturbances, lability of affect,
FRITZ
4
A. FREYHAN
irritability, and uneven work performance. Because of these observations, I proposed to distinguish between compensatory and preventive treatment. Recent clinical reviews now agree that the term prophylaxis is ambiguous. Schou” states: “Often the maintenance treatment serves to attenuate symptoms so that hospitalization and additional treatment are obviated. In these instances, the term ‘stabilization’ might describe the action of lithium more precisely than prophylaxis.” Extensive clinical studies are necessary before we will know how lithium has advanced the prevention of affective disorders. CLINICAL
PROBLEMS
There are clinical problems that should be considered in appraising the efficacy of lithium treatment. As has been the case with all psychoactive compounds, there prevails a considerable gap between treatment administered under the controlled procedures of clinical research and the treatment practiced in hospitals, clinics, and private-practice settings. The following admonition by Schou should be regarded as a motto: “It is only when lithium treatment is carried out with the same vigilance as insulin treatment of diabetes that optimal results can be expected.” Although this seems to be generally agreed upon in principle, it is rarely adhered to in practice. There is a rapidly growing trend to omit laboratory monitoring except to exclude toxicity. Patients are believed to be doing well if they profess to take their medicine regularly. It has long been known that nearly 50% of all ambulatory patients do not take their medication as prescribed. I find it amazing that in spite of this knowledge, lithium-level determinations are performed quite irregularly and often as infrequently as every 3 to 6 months per year. Many physicians, to avoid the trouble of side effects, keep patients on “safe” dosages of 600 mg or less per day. Those investigators12 who have contributed the major share of information on lithium treatment are in agreement that effective lithium treatment requires special outpatient facilities equipped to function as lithium clinics. My own experience in clinics, as well as in private practice, has convinced me that without the expertise of trained staff, lithium will be administered in the same improvised fashion as has been the case with other psychoactive compounds. Imipramine was introduced in 1957; yet the only controlled study of the long-term effects of imipramine was published in 1973. I emphasize this in order to indicate some disturbing loopholes and deficiencies in clinical research. In summary, comparable studies reveal as yet no major advantage of lithium over other treatments of affective disorders. At our stage of clinical experience it is premature to attribute to lithium prophylactic effects on affective illness. There is no magic of maintenance, let alone prophylaxis, that can be relied upon without adequate supervision and monitoring of drug intake. Certainly there is no reason to believe that patients with affective disorders are more reliable in adhering to a regime of lithium than they have been with other psychoactive drugs used in longterm treatment. This brings to the surface the long-smoldering conflict about psychiatry and the medical model. In recent years the medical model has been increasingly rejected. This seems paradoxial, if not irrational, in view of the growing reliance on biological concepts and treatments. Lithium is a perfect example reflecting this conflict. Since it requires medical management, the de-
PROPHYLACTIC
ANTIDEPRESSANTS
5
velopment of specifically designed drug treatment clinics would seem to be the prerequisite for establishing preventive treatment of affective illness or, for that matter, any drug-treatable psychiatric disorder. Yet psychiatrists are very reluctant to go all the way in reforming treatment facilities to meet medical requirements. Lithium and, in fact, the whole issue of prophylactic treatment for any psychiatric illness pose painful questions about the role of the medical model in pharmacopsychiatric treatment. None of these critical considerations should detract from the exciting clinical and theoretical advances that investigations of lithium have introduced into pharmacopsychiatry. REFERENCES I. Stevenson electroshock.
G. Geoghegan Am J Psychiatry
J: Prophylactic 107:743. 1951
2. Pichot P, et al: Le Traitement des Depressions. Presented at the International Symposium on Diagnosis and Treatment of Depression in Domiciliary Practice, Jan. 1974, St. Moritz. Vienna, Hans Huber (in press) 3. Fieve
R:
Overview
of
therapeutic
and
prophylactic trials with lithium in psychiatric patients, in Gershon S, Shopsin B (eds): Lithium-Its Role in Psychiatric Research and Treatment. New York, Plenum, 1973. p 317 4. Schildkraut J: Pharmacology-The effects of lithium on biogenic amines: in Gershon S. Shopsin B (eds): Lithium--Its Role in Psychiatric Research and treatment. New York, Plenum,
1973. p 63
5. Davis J, et al: Pharmacology-The biology of lithium in Gershon S, Shopsin B (eds): Lithium-Its Role in Psychiatric Research and Treatment.
New York, Plenum,
6. Mendels
J, Frazer
1973, p 183
A: Brain biogenic
amine
depletion and mood. Arch 30447, 1974 7. Freyhan F: Contributions
Gen.
Psychiatry
to the definition
of therapy-resistance and of the therapy-resistant depressions. Pharmakopsychiat 7:70 75, I974 X. Prien R, Caffey E: Lithium prophylaxis: A critical review. Compr. Psychiatry 15:357, 1974 9. Prien R: The clinical effectiveness of lithium: Comparisons with other drugs. Veterans Administration
Research
Report
97, May 1974,
p 15 IO. Freyhan F, O’Connell R. Mayo J: Treatment of mood disorders with lithium carbonate, in Freyhan F (ed): Lithium: Clinical and Biological Aspects. Il. Schou M: tenance treatment
Basel, S. Karger, 197 I, p I37 Prophylactic lithium mainin recurrent endogenous
affective disorders, in Gershon S, Shopsin B (eds): Lithium-- Its Role in Psychiatric Research and Treatment. New York, Plenum, 1973, p 269 12. Gershon S: Lithium prophylaxis in recurrent alfective 15:365. 1974
disorders.
Compr
Psychiatry
VOL.
Journal
of the American
16, NO. 1
On the Controversy
Psychopathological
Association
JANI’ARY/FEBRUARY
of Prophylactic
1975
Antidepressants
Fritz A. Freyhan
I
T IS the purpose of this brief presentation to assess our present knowledge on the prophylactic treatment of affective disorders. The history of psychiatry reveals a seemingly unresistable temptation to equate beneficial treatment responses with treatment specificity. Substantial progress in research and treatment tends to be hailed as a breakthrough. Unfortunately, the record is full of disappointments, because psychiatrists failed to distinguish between tentative and valid approaches to etiology and treatment of psychiatric disorders. Not too many years ago, insulin-coma therapy was widely regarded as the scientifically most rational treatment of schizophrenic illness. Whatever the theoretical shortcomings of a rationale that tied insulin coma to a postulated schizophrenic process, insulin became the treatment of choice. After the discovery of the striking effects of neuroleptics on symptoms and syndromes associated with schizophrenic disorders, the literature began to upgrade neuroleptics to the specific status of antischizophrenic drugs. The advent of the antidepressant drugs is a further example of the problems that confuse therapeutic efficacy with illness specificity. After the introduction of the antidepressant drugs, which were believed to be specific by some investigators, an opposing argument was raised by those who considered electroshock to be more specific. This notion was based on the fact that ECT had been shown to be beneficial in the treatment of both manic and depressed states. It should be remembered that the idea of prophylactic treatment for affective disorders goes back to 1951 when Stevenson and Geoghegan introduced “prophylactic electroshock.“’ The authors claimed that electroshock given once monthly for at least 2 years could prevent future manic-depressive episodes. Although no long-term results of this treatment were published, it is a fact that many psychiatrists to this day practice various modifications of maintenance ECT. Based on empirical evidence, these psychiatrists believe that ECT is more specific and therefore more reliable than drugs, including lithium. As is not sufficiently recognized, we have no valid statistics on the popularity of different therapeutic methods of psychiatry. In the area of treatment with psychoactive drugs, recent studies by Pichot and other? have shown that the Presenred ar the Ninrh International Congres.~ qf the Collegium pharn~acologicum. July 7-12. 1974. Paris, France. Fritz A. Freyhan, M.D.: 2015 R Street, N II’. Washington. I).(‘. ,c‘l1975 ht. C;rune & Srratton. Inc.
Comprehensive
Psychiarry, Vol. 16. No. 1 (January/Februaryb
1975
lnrernationale
:Vcurop.rI,cho-
2
FRITZ A. FREYHAN
preference for particular drugs has no detectable scientific explanation. Generally there is a wide gap between the evidence in the scientific literature and the popularity and administration of treatments in everyday practice. In this connection, I find a recent report by Fieve3 relevant. Analyzing the histories of 200 manicdepressive patients attending his lithium clinic, he found that they had been sub jetted to a total of approximately 5,000 shock treatments before coming under lithium control. He postulates an 80% probability of successful prophylaxis with lithium and other drugs and therefore anticipates only a rare need for electroshock. We must not forget, however, that the same confidence in drastic reduction, if not elimination, of electroshock followed the discovery of the antidepressants, and also that the question of the relative merits of depression treatments is still a matter of preference without definitive data based on scientific assessment. Current controversies regarding the therapeutic efficacy of lithium focus no longer on its therapeutic properties but on the issue of prophylaxis. There is no longer any doubt that lithium has emerged as an agent of unique biological importance. It has generated widespread clinical and experimental interest. The most significant claim to therapeutic innovation rests on the expectation that lithium exerts preventive action on cyclic affective disorders. ETIOLOGICAL
CONSIDERATIONS
The term prophylaxis connotes action on the etiological or pathogenetic determinants of an illness. In the case of the affective disorders, the effects on catecholamine metabolism are regarded as basic to cause-directed treatment. Experimental and clinical studies have provided impressive evidence that pathological changes in mood, depression, or mania may be generated by changes in the function of brain biogenic amines. The effects of antidepressant drugs and possibly also of electroshock have been credited to their capability to normalize biogenic amine activity. The biological effects of lithium have been shown to include alterations in catecholamine metabolism. The ultimate significance of this action remains for the present unclear. Schildkraut,4 who has contributed major data in favor of the hypothesis linking affective illness with the role of biogenic amines, cautions that although numerous studies have shown that lithium affects catecholamine metabolism, further investigations will be needed to ascertain whether this accounts for the clinical effects of lithium on mood disorders. Davis,5 evaluating the biology of lithium, concludes that some of the findings are contradictory, some unsubstantiated, and some preliminary findings of unknown significance. The relevance of brain biogenic amines to mood disorders has been questioned by Mendels and Frazer .‘j These investigators reported that administration of drugs to humans in amounts sufficient to produce greater depletion of amines than that reported consistently to occur in depressed patients does not in itself produce depressjon. They are concerned that the biogenic amine hypothesis may be an oversimplistic framework for our understanding of the relationship between psychopathology and underlying biological dysfunctions. Additional doubts regarding lithium specificity for affective illness stems from recent clinical studies that claim lithium to be effective in treating personality, childhood, schizophrenic, and other disorders. If these preliminary reports are
PROPHYLACTIC
ANTIDEPRESSANTS
3
supported by more systematic trials, this would put lithium in the category of broad-spectrum drugs comparable to neuroleptic compounds. These brief citations from the literature confirm that we have as yet no firm grounds for expecting biological specificity on which to base a claim for prophylactic treatment of affective disorders. METHODOLOGICAL
CONSIDERATIONS
After the initial therapeutic successes with neuroleptic and antidepressant drugs, it seemed probable to me that drug-induced improvement, once achieved, could be maintained by continuous medication. The feasibility of a truly compensatory type of antidepressant treatment depends on the drug’s capability to restore and preserve the patient’s functional adequacy.7 In spite of the fact that maintenance treatment became customary all over the world, no efforts were made to standardize therapeutic methods or clinical evaluations on long-term bases. Because of this, the literature on compensatory or maintenance treatment remained scant and scientifically unsatisfactory. The use of lithium put clinical methodology on a long-overdue basis of investigatory sophistication. Because of toxicity, treatment with lithium requires standardized dosage regimes, monitoring of blood levels, and longitudinal and clinical evaluations. If lithium had achieved nothing else, it still would find a prominent place in history for having greatly advanced our approaches to diagnosis and treatment of affective disorders. Perplexing, however, was the premature conclusion that lithium had succeeded where other drugs had failed. Prior to lithium there had been no studies of moodaffective drugs comparable in terms of the stringently controlled conditions of patient selection, monitoring of drug intake, and continuous clinical observation of many years’ duration. Until quite recently, hundreds of studies of lithium concentrated on the clinical evidence of acute and maintenance effectiveness, first uncontrolled and more recently compared to placebo. As Prien* puts it, “When one considers that lithium has been employed as a psychopharmacological agent for 25 years and has been investigated in hundreds of studies, it is surprising to find that there are only about a dozen trials comparing the drug with active medication.” If compared with other drugs, there is currently no evidence of the superiority of lithium. Inasfar as manic states are concerned, lithium is not more effective than chlorpromazine or haloperidol. With depressive disorders, we have only one study comparing lithium with imipramine.g This collaborative study, which was carried out in 18 hospitals during a 2-year period of treatment, is of considerable importance. For unipolar patients, imipramine was found to be as effective as lithium. Thus the oldest antidepressant, if administered under weilcontrolled conditions of the investigation of lithium, proved to be as good a prophylactic compound as lithium. However, the investigators cautioned against using the term prophylaxis, because 42% in the lithium group and 38% in the imipramine group displayed long periods of mild to moderately severe symptomatology during the 2 years of treatment. My own experiences had shown that episode-free intervals are often obscured by persistent morbidity in spite of active therapeutic measures. lo Patients observed in our lithium clinic suffered from fluctuating diurnal mood patterns, periodic sleep disturbances, lability of affect,
FRITZ
4
A. FREYHAN
irritability, and uneven work performance. Because of these observations, I proposed to distinguish between compensatory and preventive treatment. Recent clinical reviews now agree that the term prophylaxis is ambiguous. Schou” states: “Often the maintenance treatment serves to attenuate symptoms so that hospitalization and additional treatment are obviated. In these instances, the term ‘stabilization’ might describe the action of lithium more precisely than prophylaxis.” Extensive clinical studies are necessary before we will know how lithium has advanced the prevention of affective disorders. CLINICAL
PROBLEMS
There are clinical problems that should be considered in appraising the efficacy of lithium treatment. As has been the case with all psychoactive compounds, there prevails a considerable gap between treatment administered under the controlled procedures of clinical research and the treatment practiced in hospitals, clinics, and private-practice settings. The following admonition by Schou should be regarded as a motto: “It is only when lithium treatment is carried out with the same vigilance as insulin treatment of diabetes that optimal results can be expected.” Although this seems to be generally agreed upon in principle, it is rarely adhered to in practice. There is a rapidly growing trend to omit laboratory monitoring except to exclude toxicity. Patients are believed to be doing well if they profess to take their medicine regularly. It has long been known that nearly 50% of all ambulatory patients do not take their medication as prescribed. I find it amazing that in spite of this knowledge, lithium-level determinations are performed quite irregularly and often as infrequently as every 3 to 6 months per year. Many physicians, to avoid the trouble of side effects, keep patients on “safe” dosages of 600 mg or less per day. Those investigators12 who have contributed the major share of information on lithium treatment are in agreement that effective lithium treatment requires special outpatient facilities equipped to function as lithium clinics. My own experience in clinics, as well as in private practice, has convinced me that without the expertise of trained staff, lithium will be administered in the same improvised fashion as has been the case with other psychoactive compounds. Imipramine was introduced in 1957; yet the only controlled study of the long-term effects of imipramine was published in 1973. I emphasize this in order to indicate some disturbing loopholes and deficiencies in clinical research. In summary, comparable studies reveal as yet no major advantage of lithium over other treatments of affective disorders. At our stage of clinical experience it is premature to attribute to lithium prophylactic effects on affective illness. There is no magic of maintenance, let alone prophylaxis, that can be relied upon without adequate supervision and monitoring of drug intake. Certainly there is no reason to believe that patients with affective disorders are more reliable in adhering to a regime of lithium than they have been with other psychoactive drugs used in longterm treatment. This brings to the surface the long-smoldering conflict about psychiatry and the medical model. In recent years the medical model has been increasingly rejected. This seems paradoxial, if not irrational, in view of the growing reliance on biological concepts and treatments. Lithium is a perfect example reflecting this conflict. Since it requires medical management, the de-
PROPHYLACTIC
ANTIDEPRESSANTS
5
velopment of specifically designed drug treatment clinics would seem to be the prerequisite for establishing preventive treatment of affective illness or, for that matter, any drug-treatable psychiatric disorder. Yet psychiatrists are very reluctant to go all the way in reforming treatment facilities to meet medical requirements. Lithium and, in fact, the whole issue of prophylactic treatment for any psychiatric illness pose painful questions about the role of the medical model in pharmacopsychiatric treatment. None of these critical considerations should detract from the exciting clinical and theoretical advances that investigations of lithium have introduced into pharmacopsychiatry. REFERENCES I. Stevenson electroshock.
G. Geoghegan Am J Psychiatry
J: Prophylactic 107:743. 1951
2. Pichot P, et al: Le Traitement des Depressions. Presented at the International Symposium on Diagnosis and Treatment of Depression in Domiciliary Practice, Jan. 1974, St. Moritz. Vienna, Hans Huber (in press) 3. Fieve
R:
Overview
of
therapeutic
and
prophylactic trials with lithium in psychiatric patients, in Gershon S, Shopsin B (eds): Lithium-Its Role in Psychiatric Research and Treatment. New York, Plenum, 1973. p 317 4. Schildkraut J: Pharmacology-The effects of lithium on biogenic amines: in Gershon S. Shopsin B (eds): Lithium--Its Role in Psychiatric Research and treatment. New York, Plenum,
1973. p 63
5. Davis J, et al: Pharmacology-The biology of lithium in Gershon S, Shopsin B (eds): Lithium-Its Role in Psychiatric Research and Treatment.
New York, Plenum,
6. Mendels
J, Frazer
1973, p 183
A: Brain biogenic
amine
depletion and mood. Arch 30447, 1974 7. Freyhan F: Contributions
Gen.
Psychiatry
to the definition
of therapy-resistance and of the therapy-resistant depressions. Pharmakopsychiat 7:70 75, I974 X. Prien R, Caffey E: Lithium prophylaxis: A critical review. Compr. Psychiatry 15:357, 1974 9. Prien R: The clinical effectiveness of lithium: Comparisons with other drugs. Veterans Administration
Research
Report
97, May 1974,
p 15 IO. Freyhan F, O’Connell R. Mayo J: Treatment of mood disorders with lithium carbonate, in Freyhan F (ed): Lithium: Clinical and Biological Aspects. Il. Schou M: tenance treatment
Basel, S. Karger, 197 I, p I37 Prophylactic lithium mainin recurrent endogenous
affective disorders, in Gershon S, Shopsin B (eds): Lithium-- Its Role in Psychiatric Research and Treatment. New York, Plenum, 1973, p 269 12. Gershon S: Lithium prophylaxis in recurrent alfective 15:365. 1974
disorders.
Compr
Psychiatry
