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Postoperative Psychosis
Postoperative Psychosis MARK D. ALTSCHULE,
M.D.'~
The sudden appearance of depressions, paranoid reactions, confusional states, or hallucinatory disorders after operations on organs other than the brain usually comes as a surprise to the physicians following such cases. As a rule, patients in whom these complications develop have not previously shown this type of reaction, although in a few cases there may be an antecedent mental or emotional disorder. Indeed, psychotic (schizophrenic) patients show no evidence of exacerbation of their psychoses after operations. The mechanisms responsible for untoward postoperative mental changes are not completely known. However, it is worthy of note that postoperative psychoses are more common in the elderly than in the young. In addition, clinical experience shows that those mental changes are more common in patients with postoperative complications. Perhaps these two factors are connected to some extent, because postoperative complications are more common in the elderly. Little is known about the physiology of aging per se, but a great deal is known about the disordered physiology encountered in postoperative complications: they often are accompanied by malnutrition, electrolyte depletion, excessive adrenal activity, and the use of large numbers and amounts of drugs to treat the complications. We shall not comment on the psychoanalytic writings that relate such mental changes to the belief allegedly held by patients that any operation represents castration, for there is no evidence that postoperative psychoses are prevented by previous castration. Postoperative psychoses may be classified according to etiology as follows: (1) drugs, (2) blood-gas disorders, (3) electrolyte disorders, (4) nutritional disorders, (5) brain damage, (6) adrenal hyperactivity, or (7) undefined.
DRUGS Barbiturates Almost any drug in use today is capable of causing adverse mental reactions; however, the reactions encountered in clinical practice are • Associate Professor of Medicine, Harvard Medical School, Boston; Consultant, McLean Hospital, Belmont, Massachusetts
Surgical Clinics of North America - Vol. 49, No.3, June, 1969
677
678
MARK
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ALTSCHULE
almost always due to one of two classes of drugs, i.e., barbiturates and anticholinergic substances. Although adverse mental reactions caused by barbiturates are infrequent relative to the number of occasions when these drugs are used, the almost routine use of these drugs pre- and postoperatively makes them one of the common causes of such reactions. This is particularly true of elderly or chronically ill patients, but the reactions may occur in patients of any age. The adverse mental reactions fall into three categories: (1) excitement and mania, (2) confusional states, and (3) depression. The occurrence of excitement is unpredictable, and the symptoms are opposite those expected to be produced by the drug. A single dose may have this untoward effect. The short-acting barbiturates, e.g., pentobarbital, are more likely to produce this reaction than the longer-acting barbiturates. I5 Stopping the barbiturate and if necessary administering a tranquilizer terminates the disorder, whereas giving additional amounts of barbiturate is a serious error. As regards confusional states, it must be remembered that a hypnotic dose of a barbiturate always impairs attention, recall, and visual perception for some time. I7 The changes are not striking in most persons but may become so in elderly or debilitated patients, especially after repeated doses. The longer-acting barbiturates are usually the cause of confusional states. I5 Unlike excitement and confusion, which usually occur soon after the start of barbiturate medication, depression takes longer to develop. However, it remits quickly when the drug is stopped. The action of barbiturates on the brain is highly complex and is not completely understood. Hence, the mechanisms of side reactions cannot be stated. Anticholinergic Drugs A vast number of drugs have anticholinergic effects that are either intrinsic to their action or occur as side effects. These two groups will be discussed together here, since all may produce psychoses as side reactions. These combined groups may be classified according to their clinical use; the drugs in these groups that have actually been reported to cause psychotic reactions are as follows: 1. Atropine, Scopolamine, and related compounds. 2. Antitussive agents, e.g., chlophedianol (Ulo, Riker). 3. Antiparkinsonian agents, e.g., benztropine mesylate (Cogentin, Merck Sharp & Dohme); biperiden (Akineton, Knoll); cycrimine (Pagitane, Lilly); orphenadrine (Disipal, Riker); procyclidine (Kemadrin, Burroughs Wellcome); trihexyphenidyl (Artane, Lederle). 4. (A) Tricyclic antidepressant drugs, e.g., imipramine (Tofranil, Geigy); amitriptyline (Elavil, Merck Sharp & Dohme). (B) Benzilate antidepressant drugs, e.g., benactyzine (Deprol, Wallace). 5. Antihistamine drugs used as such, e.g., diphenhydramine (Benadryl, Parke Davis); doxylamine (Decapryn, Merrell); tripelennamine (Pyribenzamine, Ciba); or antihistamines used chiefly as antinausea drugs, e.g., cyclizine (Marezine, Burroughs Wellcome); meclizine (Bonine, Pfizer).
POSTOPERATIVE PSYCHOSIS
679
Most of the drugs listed are not used specifically in the postoperative period and are mentioned here only because patients who are receiving them may have to undergo operations at some time. On the other hand, the first and fifth groups above are important in relation to surgery, the fifth because antihistamines may be given to patients with urticarial reactions to drugs and blood transfusions and because some antihistamines are used to treat nausea and vomiting. The incidence of untoward mental reactions to these drugs cannot be established. Their tendency to cause these reactions appears to be correlated with their central cholinergic actions and not their peripheral effects. 1s The systematic studies of Pfeiffer6 and of Abood et al. 1 have thrown light on the subject. The mental effects of atropine alkaloids have been reviewed by Eger;6 Bernstein and Leff5 showed that schizophrenic syndromes may be produced by the drugs.
BLOOD-GAS DISORDERS Hypoxia is a well-known cause of mental change. Although cyanosis is usually present when psychosis is caused by this factor, hypoxia may occur in patients who have a normal pink color. The ability of blood to give up its oxygen in the tissues is impaired by certain blood storage procedures. When large amounts of such bank blood are used, as in cardiac surgery, the transfused blood regains its ability to release oxygen slowly,14 and consequently the blood in the patient can carry oxygen but cannot give it up to the tissues normally. It is interesting to conjecture whether this mechanism explains the frequent occurrence of postoperative psychosis after open-heart operations, in which very large amounts of bank blood are used. The prolonged inhalation of 100 per cent oxygen at atmospheric pressure apparently leads to the transformation of catecholamines in the brain into adrenochrome,lO a substance known to be a brain poison. Although this phenomenon has been suggested as the cause of psychotic behavior, there is as yet no evidence of its occurrence in clinical situations. Disorders of blood carbon dioxide tension are also well-known causes of mental change.Hypocapnia may cause confusion; hypercapnia usually causes narcosis but may induce psychotic behavior instead.
ELECTROLYTE DISORDERS Although magnesium deficiency has been suggested as a cause of hallucinatory states, the evidence is not clear, because this deficiency always occurs in combination with others. Nevertheless, it should be sought in psychotic depleted patients and remedied if present. Sodium depletion may cause psychosis, but its occurrence in postoperative patients is rare because they receive large amounts of sodium chloride solution. On the other hand, unless Ringer's solution is used, potassium depletion can occur, especially in patients with vomiting and diarrhea and in patients given large amounts of glucose solution. Psy-
680
MARK
D.
ALTSCHULE
chosis is a common occurrence in patients with postoperative potassium depletion. 7
NUTRITIONAL DISORDERS It is widely recognized that some lesions that ultimately lead to operation may produce malnutrition. What is less well recognized is that certain postoperative practices may induce some types of malnutrition. When patients who are not eating well-or at all-are fed intravenously with glucose solutions, the high carbohydrate intake may cause or aggravate thiamine, riboflavine, and nicotinic acid deficiencies. Severe thiamine deficiency may cause confusion or coma; nicotinic acid deficiency may manifest itself as severe anxiety leading to agitated depression and then to a confusional psychosis. These deficiencies are readily prevented or cured by placing vitamin B complex in the fluids used for intravenous feeding. Although protein deficiency and ascorbic acid deficiency may cause noticeable depression and folate deficiency may cause a variety of psychiatric disorders, their occurrence as complications of postoperative care must be uncommon.
BRAIN DAMAGE When elderly patients are permitted to develop either hypoxia or hypotension during operations they may experience diffuse or localized brain damage. Neurologic findings that reveal the diagnosis appear in such instances, and whatever mental changes develop are understandable, if not treatable.
ADRENOCORTICAL HYPERACTIVITY Adrenocortical activity, either spontaneous or induced with adrenocorticotropic hormone (ACTH), commonly causes at least some degree of mental disorder. Adrenocortical hyperactivity is found in acute or early endogenous psychoses3 and is particularly likely to be associated with severe depression. An increase in adrenocortical secretion is a characteristic finding in the postoperative period. B. 13 Prolonged increases may be accompanied by postoperative complications including psychoses.B. 13 The mechanism is not known, since adrenocortical hyperactivity causes both potassium loss and defective utilization of keto-acid carbohydrate intermediates,2 either of which can produce mental changes.
UNPROVED FACTORS Sensory Deprivation Sensory deprivation may cause illusions, delusions, and hallucinations. This phenomenon has been invoked as a cause of psychosis after bilateral eye operations. However, the demonstration that enormous
681
POSTOPERATIVE PSYCHOSIS
HO
CHOH
HO
CH 2
I
HN
0
----7
/
0
I
CH3 Figure 1.
Oxidative cyclization of epinephrine to adrenochrome.
amounts of atropine may be placed in the eyes of such patients has directed attention to this practice as a cause of mental changes.
Epinephrine Metabolites Under ordinary circumstances, approximately 95 per cent of secreted epinephrine is changed to harmless inert substances via the vanillylmandelic acid (VMA) pathway. This occurs in the tissue, since the blood lacks the enzymes necessary for these transformations. The blood contains an enzyme that transforms epinephrine to adrenochrome,4 which is known to be a brain poison. When epinephrine is added to human blood plasma, it is degraded via the adrenochrome pathway, so that at least for a time it exists as a derivative that is toxic to brain (Fig. 1).12 Cyclopropane apparently inhibits the VMA pathway;9 hence, much of the secreted epinephrine must be metabolized via the adrenochrome pathway. Greatly increased amounts of epinephrine are secreted postoperatively, particularly in complicated cases. S Fortunately, adrenochrome can exist for only a short time in human blood,!l a fact that minimizes the possibility of toxic effects from adrenochrome but by no means eliminates it. Too little is currently known about this field to permit definite statements.
CONCLUSION Postoperative psychosis is almost certainly increasing in incidence as surgery becomes more daring. Even though physiologic data on the subject are scanty, it is nevertheless a fact that most of these psychoses are preventable or curable. All that remains is for physiologic study to increase our understanding of the processes involved so as to make it possible to predict the occurrence of these disorders and to treat them effectively.
REFERENCES J. R.: Structure-activity relationship of 3-piperidyl benzilates with psychotogenic properties. Arch. Internat. Pharmadyn., 120:186,1959. 2. Altschule, M. D.: Carbohydrate metabolism in mental disease; associated changes in phosphate metabolism. In Rimwich, R. E. (ed.): Biochemisty, Schizophrenia and Affective Illnesses. Baltimore, The Williams & Wilkins Co., 1969. 3. Altschule, M. D., and Parkhurst, B. R.: Effect of treatment on excretion of 17-ketosteroids in patients with mental disease. Arch. NeuroL Psychiat., 64:516,1950. 4. Altschule, M. D., unpublished data. 1. Abood, L. G., Ostfeld, A., and Biel,
682
MARK
D.
ALTSCHULE
5. Bernstein, S., and Leff, R: Toxic psychosis from sleeping medicines containing scopolamine. New Eng. J. Med., 277:638,1967. 6. Eger, E. I.: Atropine, scopolamine, and related compounds. AnesthesioL, 23:365,1962. 7. Eliel, L. P., Pearson, O. H., and Rawson, R W.: Postoperative potassium deficit and metabolic acidosis. New Eng. J. Med., 243:471,1950. 8. Franksson, C., Gemzell, C. A., and Enler, U. S.: Cortical and medullary adrenal activity in surgical and allied c;:onditions. J. Clin. Endoc. Metab., 14:608,1954. 9. Gardier, R W., Endahl, G. L., and Hamelberg, W.: Cyclopropane: Effect on catecholamine bio transformation. AnesthesioL, 28:677,1967. 10. Gershenovich, Z. S., Krichevskaya, A. A., and Alekseenko, L. P.: Adrenaline substance of the brain and suprarenals under increased oxygen pressure. Ukrain. Biokhim. Zhur., 27:3,1955 (Chern. Abstr., 49:10470,1955). 11. Hegedus, Z. L., and Altschule, M. D.: Studies on aminochromes. I. Behavior of adrenochrome added to human plasma. Arch. Internat. PhysioL Biochim., 85 :690, 1967. 12. Hegedus, Z. L., and Altschule, M. D.: Studies on aminochromes. III. Transformation of epinephrine, adrenochrome and adrenolutin into plasma-soluble melanins during incubation in human blood plasma. Arch. Biochem., 126:388, 1968. 13. La Femine, A. A., Marks, L. J., Teter, J. G., Leftin, J. H., Leonard, M. P., and Baker, D. V.: The adrenocortical response in surgical patients. Ann. Surg., 146:26, 1957. 14. O'Brien, T. G., and Watkins, E., Jr.: Gas exchange dynamics of glycerolized frozen blood. J. Thorac. Cardiov. Surg., 40:611, 1960. 15. Osol, A., Pratt, R, and Altschule, M. D.: The United States Dispensatory and Physicians' Pharmacology. 26th edition. Philadelphia, J. B. Lippincott Co., 1967, p. 183. 16. Pfeiffer, C. C.: Parasympathetic neurohumors: Possible precursors and effect on behavior. Internat. Rev. NeurobioL,l :195,1959. 17. von Felsinger, J. M., Lasagna, L., and Beecher, H. K.: The persistence of mental impairment following a hypnotic dose of a barbiturate. J. PharmacoL Exper. Therap., 109:274,1953.
18. White, R P., and Carlton, R A.: Evidence indicating central atropine-like actions of psychotogenic piperidyl benzilates. Psychopharmacologia, 4:459,1963. McLean Hospital Belmont, Massachusetts 02178
M.D.'~
The sudden appearance of depressions, paranoid reactions, confusional states, or hallucinatory disorders after operations on organs other than the brain usually comes as a surprise to the physicians following such cases. As a rule, patients in whom these complications develop have not previously shown this type of reaction, although in a few cases there may be an antecedent mental or emotional disorder. Indeed, psychotic (schizophrenic) patients show no evidence of exacerbation of their psychoses after operations. The mechanisms responsible for untoward postoperative mental changes are not completely known. However, it is worthy of note that postoperative psychoses are more common in the elderly than in the young. In addition, clinical experience shows that those mental changes are more common in patients with postoperative complications. Perhaps these two factors are connected to some extent, because postoperative complications are more common in the elderly. Little is known about the physiology of aging per se, but a great deal is known about the disordered physiology encountered in postoperative complications: they often are accompanied by malnutrition, electrolyte depletion, excessive adrenal activity, and the use of large numbers and amounts of drugs to treat the complications. We shall not comment on the psychoanalytic writings that relate such mental changes to the belief allegedly held by patients that any operation represents castration, for there is no evidence that postoperative psychoses are prevented by previous castration. Postoperative psychoses may be classified according to etiology as follows: (1) drugs, (2) blood-gas disorders, (3) electrolyte disorders, (4) nutritional disorders, (5) brain damage, (6) adrenal hyperactivity, or (7) undefined.
DRUGS Barbiturates Almost any drug in use today is capable of causing adverse mental reactions; however, the reactions encountered in clinical practice are • Associate Professor of Medicine, Harvard Medical School, Boston; Consultant, McLean Hospital, Belmont, Massachusetts
Surgical Clinics of North America - Vol. 49, No.3, June, 1969
677
678
MARK
D.
ALTSCHULE
almost always due to one of two classes of drugs, i.e., barbiturates and anticholinergic substances. Although adverse mental reactions caused by barbiturates are infrequent relative to the number of occasions when these drugs are used, the almost routine use of these drugs pre- and postoperatively makes them one of the common causes of such reactions. This is particularly true of elderly or chronically ill patients, but the reactions may occur in patients of any age. The adverse mental reactions fall into three categories: (1) excitement and mania, (2) confusional states, and (3) depression. The occurrence of excitement is unpredictable, and the symptoms are opposite those expected to be produced by the drug. A single dose may have this untoward effect. The short-acting barbiturates, e.g., pentobarbital, are more likely to produce this reaction than the longer-acting barbiturates. I5 Stopping the barbiturate and if necessary administering a tranquilizer terminates the disorder, whereas giving additional amounts of barbiturate is a serious error. As regards confusional states, it must be remembered that a hypnotic dose of a barbiturate always impairs attention, recall, and visual perception for some time. I7 The changes are not striking in most persons but may become so in elderly or debilitated patients, especially after repeated doses. The longer-acting barbiturates are usually the cause of confusional states. I5 Unlike excitement and confusion, which usually occur soon after the start of barbiturate medication, depression takes longer to develop. However, it remits quickly when the drug is stopped. The action of barbiturates on the brain is highly complex and is not completely understood. Hence, the mechanisms of side reactions cannot be stated. Anticholinergic Drugs A vast number of drugs have anticholinergic effects that are either intrinsic to their action or occur as side effects. These two groups will be discussed together here, since all may produce psychoses as side reactions. These combined groups may be classified according to their clinical use; the drugs in these groups that have actually been reported to cause psychotic reactions are as follows: 1. Atropine, Scopolamine, and related compounds. 2. Antitussive agents, e.g., chlophedianol (Ulo, Riker). 3. Antiparkinsonian agents, e.g., benztropine mesylate (Cogentin, Merck Sharp & Dohme); biperiden (Akineton, Knoll); cycrimine (Pagitane, Lilly); orphenadrine (Disipal, Riker); procyclidine (Kemadrin, Burroughs Wellcome); trihexyphenidyl (Artane, Lederle). 4. (A) Tricyclic antidepressant drugs, e.g., imipramine (Tofranil, Geigy); amitriptyline (Elavil, Merck Sharp & Dohme). (B) Benzilate antidepressant drugs, e.g., benactyzine (Deprol, Wallace). 5. Antihistamine drugs used as such, e.g., diphenhydramine (Benadryl, Parke Davis); doxylamine (Decapryn, Merrell); tripelennamine (Pyribenzamine, Ciba); or antihistamines used chiefly as antinausea drugs, e.g., cyclizine (Marezine, Burroughs Wellcome); meclizine (Bonine, Pfizer).
POSTOPERATIVE PSYCHOSIS
679
Most of the drugs listed are not used specifically in the postoperative period and are mentioned here only because patients who are receiving them may have to undergo operations at some time. On the other hand, the first and fifth groups above are important in relation to surgery, the fifth because antihistamines may be given to patients with urticarial reactions to drugs and blood transfusions and because some antihistamines are used to treat nausea and vomiting. The incidence of untoward mental reactions to these drugs cannot be established. Their tendency to cause these reactions appears to be correlated with their central cholinergic actions and not their peripheral effects. 1s The systematic studies of Pfeiffer6 and of Abood et al. 1 have thrown light on the subject. The mental effects of atropine alkaloids have been reviewed by Eger;6 Bernstein and Leff5 showed that schizophrenic syndromes may be produced by the drugs.
BLOOD-GAS DISORDERS Hypoxia is a well-known cause of mental change. Although cyanosis is usually present when psychosis is caused by this factor, hypoxia may occur in patients who have a normal pink color. The ability of blood to give up its oxygen in the tissues is impaired by certain blood storage procedures. When large amounts of such bank blood are used, as in cardiac surgery, the transfused blood regains its ability to release oxygen slowly,14 and consequently the blood in the patient can carry oxygen but cannot give it up to the tissues normally. It is interesting to conjecture whether this mechanism explains the frequent occurrence of postoperative psychosis after open-heart operations, in which very large amounts of bank blood are used. The prolonged inhalation of 100 per cent oxygen at atmospheric pressure apparently leads to the transformation of catecholamines in the brain into adrenochrome,lO a substance known to be a brain poison. Although this phenomenon has been suggested as the cause of psychotic behavior, there is as yet no evidence of its occurrence in clinical situations. Disorders of blood carbon dioxide tension are also well-known causes of mental change.Hypocapnia may cause confusion; hypercapnia usually causes narcosis but may induce psychotic behavior instead.
ELECTROLYTE DISORDERS Although magnesium deficiency has been suggested as a cause of hallucinatory states, the evidence is not clear, because this deficiency always occurs in combination with others. Nevertheless, it should be sought in psychotic depleted patients and remedied if present. Sodium depletion may cause psychosis, but its occurrence in postoperative patients is rare because they receive large amounts of sodium chloride solution. On the other hand, unless Ringer's solution is used, potassium depletion can occur, especially in patients with vomiting and diarrhea and in patients given large amounts of glucose solution. Psy-
680
MARK
D.
ALTSCHULE
chosis is a common occurrence in patients with postoperative potassium depletion. 7
NUTRITIONAL DISORDERS It is widely recognized that some lesions that ultimately lead to operation may produce malnutrition. What is less well recognized is that certain postoperative practices may induce some types of malnutrition. When patients who are not eating well-or at all-are fed intravenously with glucose solutions, the high carbohydrate intake may cause or aggravate thiamine, riboflavine, and nicotinic acid deficiencies. Severe thiamine deficiency may cause confusion or coma; nicotinic acid deficiency may manifest itself as severe anxiety leading to agitated depression and then to a confusional psychosis. These deficiencies are readily prevented or cured by placing vitamin B complex in the fluids used for intravenous feeding. Although protein deficiency and ascorbic acid deficiency may cause noticeable depression and folate deficiency may cause a variety of psychiatric disorders, their occurrence as complications of postoperative care must be uncommon.
BRAIN DAMAGE When elderly patients are permitted to develop either hypoxia or hypotension during operations they may experience diffuse or localized brain damage. Neurologic findings that reveal the diagnosis appear in such instances, and whatever mental changes develop are understandable, if not treatable.
ADRENOCORTICAL HYPERACTIVITY Adrenocortical activity, either spontaneous or induced with adrenocorticotropic hormone (ACTH), commonly causes at least some degree of mental disorder. Adrenocortical hyperactivity is found in acute or early endogenous psychoses3 and is particularly likely to be associated with severe depression. An increase in adrenocortical secretion is a characteristic finding in the postoperative period. B. 13 Prolonged increases may be accompanied by postoperative complications including psychoses.B. 13 The mechanism is not known, since adrenocortical hyperactivity causes both potassium loss and defective utilization of keto-acid carbohydrate intermediates,2 either of which can produce mental changes.
UNPROVED FACTORS Sensory Deprivation Sensory deprivation may cause illusions, delusions, and hallucinations. This phenomenon has been invoked as a cause of psychosis after bilateral eye operations. However, the demonstration that enormous
681
POSTOPERATIVE PSYCHOSIS
HO
CHOH
HO
CH 2
I
HN
0
----7
/
0
I
CH3 Figure 1.
Oxidative cyclization of epinephrine to adrenochrome.
amounts of atropine may be placed in the eyes of such patients has directed attention to this practice as a cause of mental changes.
Epinephrine Metabolites Under ordinary circumstances, approximately 95 per cent of secreted epinephrine is changed to harmless inert substances via the vanillylmandelic acid (VMA) pathway. This occurs in the tissue, since the blood lacks the enzymes necessary for these transformations. The blood contains an enzyme that transforms epinephrine to adrenochrome,4 which is known to be a brain poison. When epinephrine is added to human blood plasma, it is degraded via the adrenochrome pathway, so that at least for a time it exists as a derivative that is toxic to brain (Fig. 1).12 Cyclopropane apparently inhibits the VMA pathway;9 hence, much of the secreted epinephrine must be metabolized via the adrenochrome pathway. Greatly increased amounts of epinephrine are secreted postoperatively, particularly in complicated cases. S Fortunately, adrenochrome can exist for only a short time in human blood,!l a fact that minimizes the possibility of toxic effects from adrenochrome but by no means eliminates it. Too little is currently known about this field to permit definite statements.
CONCLUSION Postoperative psychosis is almost certainly increasing in incidence as surgery becomes more daring. Even though physiologic data on the subject are scanty, it is nevertheless a fact that most of these psychoses are preventable or curable. All that remains is for physiologic study to increase our understanding of the processes involved so as to make it possible to predict the occurrence of these disorders and to treat them effectively.
REFERENCES J. R.: Structure-activity relationship of 3-piperidyl benzilates with psychotogenic properties. Arch. Internat. Pharmadyn., 120:186,1959. 2. Altschule, M. D.: Carbohydrate metabolism in mental disease; associated changes in phosphate metabolism. In Rimwich, R. E. (ed.): Biochemisty, Schizophrenia and Affective Illnesses. Baltimore, The Williams & Wilkins Co., 1969. 3. Altschule, M. D., and Parkhurst, B. R.: Effect of treatment on excretion of 17-ketosteroids in patients with mental disease. Arch. NeuroL Psychiat., 64:516,1950. 4. Altschule, M. D., unpublished data. 1. Abood, L. G., Ostfeld, A., and Biel,
682
MARK
D.
ALTSCHULE
5. Bernstein, S., and Leff, R: Toxic psychosis from sleeping medicines containing scopolamine. New Eng. J. Med., 277:638,1967. 6. Eger, E. I.: Atropine, scopolamine, and related compounds. AnesthesioL, 23:365,1962. 7. Eliel, L. P., Pearson, O. H., and Rawson, R W.: Postoperative potassium deficit and metabolic acidosis. New Eng. J. Med., 243:471,1950. 8. Franksson, C., Gemzell, C. A., and Enler, U. S.: Cortical and medullary adrenal activity in surgical and allied c;:onditions. J. Clin. Endoc. Metab., 14:608,1954. 9. Gardier, R W., Endahl, G. L., and Hamelberg, W.: Cyclopropane: Effect on catecholamine bio transformation. AnesthesioL, 28:677,1967. 10. Gershenovich, Z. S., Krichevskaya, A. A., and Alekseenko, L. P.: Adrenaline substance of the brain and suprarenals under increased oxygen pressure. Ukrain. Biokhim. Zhur., 27:3,1955 (Chern. Abstr., 49:10470,1955). 11. Hegedus, Z. L., and Altschule, M. D.: Studies on aminochromes. I. Behavior of adrenochrome added to human plasma. Arch. Internat. PhysioL Biochim., 85 :690, 1967. 12. Hegedus, Z. L., and Altschule, M. D.: Studies on aminochromes. III. Transformation of epinephrine, adrenochrome and adrenolutin into plasma-soluble melanins during incubation in human blood plasma. Arch. Biochem., 126:388, 1968. 13. La Femine, A. A., Marks, L. J., Teter, J. G., Leftin, J. H., Leonard, M. P., and Baker, D. V.: The adrenocortical response in surgical patients. Ann. Surg., 146:26, 1957. 14. O'Brien, T. G., and Watkins, E., Jr.: Gas exchange dynamics of glycerolized frozen blood. J. Thorac. Cardiov. Surg., 40:611, 1960. 15. Osol, A., Pratt, R, and Altschule, M. D.: The United States Dispensatory and Physicians' Pharmacology. 26th edition. Philadelphia, J. B. Lippincott Co., 1967, p. 183. 16. Pfeiffer, C. C.: Parasympathetic neurohumors: Possible precursors and effect on behavior. Internat. Rev. NeurobioL,l :195,1959. 17. von Felsinger, J. M., Lasagna, L., and Beecher, H. K.: The persistence of mental impairment following a hypnotic dose of a barbiturate. J. PharmacoL Exper. Therap., 109:274,1953.
18. White, R P., and Carlton, R A.: Evidence indicating central atropine-like actions of psychotogenic piperidyl benzilates. Psychopharmacologia, 4:459,1963. McLean Hospital Belmont, Massachusetts 02178