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Non Specific Factors in Psychopharmacotherapy
Non Specific Factors in Psychopharmacotherapy ADAM
J.
KRAKOWSKI,
Accounts of the use of psychopharmaceuticals in the United States show staggering sales, and various surveys, including a report of this writer,! reveal that the non-psychiatric physicians use these drugs routinely and extensively. One may conjecture that an average family practitioner uses more psychotropic agents than an average private psychiatrist. In a strict pharmacological sense drugs influence the patient by a direct action upon the central nervous system via influence of brain chemistry, notably through interacting with its enzymes in appropriate brain centers. This in turn leads to modification of feelings, thought, content and behavior. This is but one mode of action; the other, extremely important, is mostly psychological. The extrapharmacological component consists of various non-specific influences related to both the patient and his doctor. Apart from those engaged in clinical drug research, physicians learn about psychopharmaceuticals from others! and from their own c1inical-empirical experience. The role of non-specific factors is rarely stressed in the literature directed to non-psychiatric physicians. Such omission is truly regrettable. This presentation will address itself to the non-specific factors of psychopharmacotherapy and will stress their importance in treatment of mental illness. THE PATIENT AND HIS ILLNESS
In all forms of therapeutic management the patient must be viewed in a psychosomatic fashion, i.e., as a biological entity influenced by psychological and sociocultural factors who responds to illness and who participates in the therapeutic process. Considering the nature of mental illnesses and the fact that we still know too little about their causes, their natural course and even the specificity of some of the syndromes, the task of management is by no means easy. Mental illness in general, may be viewed as an adaptational disorder2 and the faulty adaptational defenses as an accepted way of existence. This, in a way, complicates the intervention of the doctor, for the treatment may interfere with the abnormal personal adjustment which though disordered is somehow safe • Director, Psychosomatic Unit and Chief, Division of Psychiatric Liaison and Research, Champlain Valley-Physicians Hospital Medical Center, Plattsburgh, N.Y. Presented at the Regional Meeting of the International College of Psychosomatic Medicine, Plattsburgh, N.Y., October 18, 1974. 132
M.D. *
to the patient. This really means that some forms of mental illness, notably neuroses, may be quite useful to the patient in terms of primary or even secondary defensive gains, although such usefulness is only spurious and the symptoms which seem useful at first become finally a neurotic trap to the patient. 3 Therefore, he may not be willing to give up his quasi-successful defenses for fear that the new adaptations by the doctor may not be as useful as the old ones. Another very important factor is the personality of the patient. In general, those capable of establishing a positive therapeutic relationship with the doctor profit more from drugs despite a seeming pessimism they might have expressed initially, a factor so frequently seen among the depressives. Others profit less or not at all. In this sense the chemotherapeutic effect depends upon the personality factors that create acceptance or rejection of the drug or for that matter of any therapeutic procedure because of the acceptance or rejection of the therapist. This whole problem is undoubtedly also related to the psychodynamic meaning of the drug intake and its role in the doctor-patient relationship. Passive and dependent individuals are generally willing to accept drugs and are inclined to report only their be~eficial results. Psychodynamically, drugs facilitate the transference relationship in these patients. One must add to this the symbolism of the drugs used including the aspect of orality. The drug intake may represent an increased dependence on the therapist and may serve the purpose of securing his acceptance especially when he has strongly urged the patient to use the drug. But this may be the patient's attempt to manipulate the physician. The latter's prompt recognition and skillful handling may prevent the patient from becoming dependent upon, or even addicted to the drug. Patients fearful of dependence may reject psychopharmacotherapy because using a drug may symbolize an invasion of privacy. In such patients the active drug or even the inert placebo may produce pronounced side reactions or even a severe phobic feeling causing rejection of drug therapy altogether. Suspicious and aggressive patients may react with mistrust and if strongly encouraged to use drugs they miss doses, claim forgetfulness or become frankly defiant and refuse to take the medication. False, temporary improvements may be observed in such patients when treated in the hospital, but prompt relapses occur after discharge. Finally, paranoid patients may include the Volume XVI
NON SPECIFIC FACfORS-KRAKOWSKI
seemingly harmful effects of drugs as a part of their paranoid system. It can not be overemphasized that prescribing drugs should be preceded by at least a cursory evaluation of the patient's personality and his attitude towards drugs including his previous experiences. If the attitude is negative and can not be overcome by reassurance, the persistent anti-drug attitude will cause the drug to exert no satisfactory results, or even create untoward side reactions because of negative placebo response. THE THERAPY
The ideal goal of therapy would be a total cure consisting of a complete and permanent remission of symptoms. Except for a very few spontaneous cures, such a utopian goal is unrealistic especially with psychiatric patients. A realistic goal is to create a satisfactory improvement permitting personal, social and vocational adjustment compatible with an independent, productive existence. In such management drugs serve as catalysts to the strengthening of adaptational defenses which is achieved through psychological methods of milieu therapy and psychotherapy. The pharmacological role in psychotics is probably more than catalytic and the same is true when very severe anxiety disrupts the adaptational ability of a neurotic. What are then the psychological properties of drugs? Why do psychotropic agents show such a great degree of non-specificity in the treatment of certain given target symptoms? Why is each patient affected in a different way by similar doses of drugs, even when an appropriate measure is used to consider the severity of symptoms, and even the law of initial values 4 ? Why do some patients develop more side reactions than others? The answers and explanations are at least partly produced by the ever-growing experience concerning placebo reactions which have attracted more attention in drug research than in drug practice. Shapiroll supplies the following definition: "A placebo is defined as any therapeutic procedure (or the component of a procedure) which is given deliberately to have an effect or which unknowingly has an effect upon a patient, symptom, disease or syndrome, but which is objectively without specific activity for the condition being treated. The placebo is also used to describe an adequate control in experimental studies. A placebo effect is defined as the changes produced by placebos." It is widely accepted that for thousands of years the placebo effect was responsible for the beneficial influence of almost all drugs, 6 and even as recently as 1952 an analysis performed in England of over 17,000 prescriptions revealed that roughly one-third were ~onsidered to be placebos. i Interestingly enough, the latter figure approximates the positive placebo responses found by many investigators in controlled July / August/September, 1975
studies and a recently published paper by Shapiro et al confirms this. 8 The same author found that physicians are prone to believe that other physicians' drugs work as placebo three times more often.9 Placebo reactions, positive or negative (favorable or unfavorable), are generally ascribed to the suggestibility of the patient who believes he is taking the active drug. lO Such factors as the personality make-up, already mentioned, previous experience and the quality of hopeful anticipation determine the degree of reaction. It likely depends also upon psychological factors related to: a. the doctor, b. the doctor-patient relationship, c. cultural circumstances and d. the conditions of treatment. On the other hand, race, sex, ethnic elements, intelligence, social class and type and length of illness are of little influence.!! The doctor himself undoubtedly influences the placebo effect by a positive concern about the patient or a less than concerned attitude, the quality of his therapeutic handling of the patient and the demonstration of his own positive self-esteem, his persuasive ability or his forceful dominance. The placebo effect is increased by such physician-related factors as his importance in the medical community, the fame of his scientific status, his role in research and probably also his high fees. The positive doctor-patient relationship seems more important than the suggestibility of the patient. This has been amply shown in a study in which a large percentage of a group of neurotic patients obtained relief of symptoms although they had been told they were being treated with an inert placebo.!2 An active drug may in some instances exert only a seemingly pharmacological effect due to placebo reaction. This is portrayed by the fact that a drug previously ineffective may become useful for the same patient when given by another physician. Cultural factors require special consideration and are beyond the scope of this presentation. The conditions and circumstances surrounding the treatment are very important. The active drug's effect is usually augmented by the effect of coexisting formal or informal psychotherapy while the same drug used alone have been proved less effective. The effect of drugs is augmented by hospitalization; thus drugs which are effective while the patient is hospitalized may become ineffective after discharge. In the last two instances the psychotherapy and the hospitalization might have acted themselves as placebos. Those in the environment of the patient play either a synergistic or antagonistic role, enhancing the positive or negative placebo response respectively, when they demonstrate either a positive or an anti-drug attitude.!:! 133
PSYCHOSOMATICS
The elfect of therapy depends also upon the type and course of the patient's illness; thus improvement ascribed to a drug might have consisted of a remission of s:/mptoms in a self-limited illness. This is true in patients with serious character disorders in whom the crisis symptoms recede spontaneously as a result of the placebo effect of the hospital. Hysterics, when their anxiety becomes bound and neutralized, and hysterics with depression, show remissions of freefloating anxiety and depression respectively independently of drugs. Temporary pseudo-improvement in depressive neurotics may be wrongly interpreted as a permanent remission of symptoms; similarly a patient with a serious depressive illness may recover in no time when chemotherapy is applied at the very end of the depressive cycle. All of these examples show natural remissions and pharmacotherapy should not be used in most of them. THE THERAPIST
As stated, the ideal use of chemotherapy of neuroses is adjunctive when the patient requires measures to enhance psychotherapy during a serious crisis. In psychoses the role of drugs is more essential but psychotherapy always potentiates the pharmacological effect. Physicians with an "organic" orientation may be prone to overuse drugs while the analytically oriented psychiatrists may shun chemotherapy altogether. With psychopharmacology it is easier to obtain improvement than to maintain it. For this reason the patient who is to be maintained for a long period must be reassured about side reactions and warned about toxic effects or the drug may acquire the quality of negative placebo. The therapist should follow the patient closely for the duration of therapy or unadjusted doses will create the same negative results. At no time should psychopharmacology be used for the mere sake of convenience of the doctor either because he knows no other method or because he seeks relief from pressure of his own anxiety about the patient. The anxious physician is more likely to use other than optimum doses and misinterpret the symptoms described by the patient as side reactions. Impatient for a prompt cure he may too quickly substitute one brand of drug for another. The placebo effect of the active drug, both positive and negative must be recognized. The recognition is easy because the placebo effect is almost immediate 13 and, therefore, in most instances much faster than the expected pharmacological response. Such recognition is especially important in depression. If a depressed
134
patient shows an immediate alleviation of symptoms after an antidepressant drug is given, his remission is undoubtedly the placebo effect. Such patients should be followed up to determine whether or not the improvement persists, for recurrence of symptoms may be responsible for a suicide. Because psychopharmachotherapy shows better effects with concurrent psychotherapy, at least of a supportive type, merely prescribing drugs and refilling them upon telephone requests leads to wasting a good therapeutic method. SUMMARY
The psychosomatic model of treatment of mental illness follows the understanding that causes of mental illness are multiple. It requires biological and psychosocial approaches to treatment. The non-specific factors in psychopharmacology relate to the psychosocial components of illness. These factors, but especially the placebo effects, are as important as the pharmacological influences. All should be well understood before any meaningful chemotherapy of mental illness is undertaken. 210 Cornelia St., Suite 103, Plattsburgh, NY 12901 REFERENCES 1. Krakowski, AJ., Role of Consultation Psychiatry in Teaching Psychopharmacology in the General Hospital, N.Y.S.J. Med. 73: 1987, 1973. 2. Wolff, A, Concept of Disease, Psychosom. Med. 24: I, 1962. 3. Krakowski, AJ., Comprehensive Approach to Psychopharmacology, N.Y.S.J. Med. 69:2886, 1969. 4. Wilder, J., Basimetric Approach to Psychiatry, in Ari.:ti, S. ed. American Handbook of Psychiatry. Vol. III, New York Basic Books, 1966. p. 333. 5. Shapiro, AK., A Historic and Heuristic Definition of the Placebo, Psychiat. 27: 52, 1964. 6. Houston, W., Doctor Himself as Therapeutic Agent. Ann. Intern. Med. 11:1416, 1938. 7. Dunlop, D., Henderson, T., and Inch, R., Survey of 17,301 Prescriptions on Form EC 10, Brit. Med. J. 1: 292, 1952. 8. Shapiro, AK., Mike, D., Barten, H. and Shapiro, E., Study of the Placebo Effect with a Self-Administered Placeho Test. Compo Psychiat. 14:535, 1973. 9. Shapiro, A.K., Placebo Effects in Psychotherapy and PsychoanalY5is, J. Clin. Psychopharmacol. 10:73, 1970. 10. Kurland, A.A, The Drug Placebo: Its Psychodynamic and Conditional Reflex Action. Behav. Sc 2: 101, 1967. 11. Tibbets, R.W., and Hawkins, J.R., The Placebo Response, J. Ment. Sc. 102:60, 1956. 12. Park, L.C., and Covi, Non-Blind Placebo Trial: An Exploration of Neurotic Patients' Responses to Placebo When its Inert Content Was Disclosed. Arch. Gen. Psychiat. 12:36, 1965. 13. Krakowski, AJ., Psychophysiologic Gastro-Intestinal Disorders in Children, Psychosomatics, 8:326, 1967.
Volume XVI
J.
KRAKOWSKI,
Accounts of the use of psychopharmaceuticals in the United States show staggering sales, and various surveys, including a report of this writer,! reveal that the non-psychiatric physicians use these drugs routinely and extensively. One may conjecture that an average family practitioner uses more psychotropic agents than an average private psychiatrist. In a strict pharmacological sense drugs influence the patient by a direct action upon the central nervous system via influence of brain chemistry, notably through interacting with its enzymes in appropriate brain centers. This in turn leads to modification of feelings, thought, content and behavior. This is but one mode of action; the other, extremely important, is mostly psychological. The extrapharmacological component consists of various non-specific influences related to both the patient and his doctor. Apart from those engaged in clinical drug research, physicians learn about psychopharmaceuticals from others! and from their own c1inical-empirical experience. The role of non-specific factors is rarely stressed in the literature directed to non-psychiatric physicians. Such omission is truly regrettable. This presentation will address itself to the non-specific factors of psychopharmacotherapy and will stress their importance in treatment of mental illness. THE PATIENT AND HIS ILLNESS
In all forms of therapeutic management the patient must be viewed in a psychosomatic fashion, i.e., as a biological entity influenced by psychological and sociocultural factors who responds to illness and who participates in the therapeutic process. Considering the nature of mental illnesses and the fact that we still know too little about their causes, their natural course and even the specificity of some of the syndromes, the task of management is by no means easy. Mental illness in general, may be viewed as an adaptational disorder2 and the faulty adaptational defenses as an accepted way of existence. This, in a way, complicates the intervention of the doctor, for the treatment may interfere with the abnormal personal adjustment which though disordered is somehow safe • Director, Psychosomatic Unit and Chief, Division of Psychiatric Liaison and Research, Champlain Valley-Physicians Hospital Medical Center, Plattsburgh, N.Y. Presented at the Regional Meeting of the International College of Psychosomatic Medicine, Plattsburgh, N.Y., October 18, 1974. 132
M.D. *
to the patient. This really means that some forms of mental illness, notably neuroses, may be quite useful to the patient in terms of primary or even secondary defensive gains, although such usefulness is only spurious and the symptoms which seem useful at first become finally a neurotic trap to the patient. 3 Therefore, he may not be willing to give up his quasi-successful defenses for fear that the new adaptations by the doctor may not be as useful as the old ones. Another very important factor is the personality of the patient. In general, those capable of establishing a positive therapeutic relationship with the doctor profit more from drugs despite a seeming pessimism they might have expressed initially, a factor so frequently seen among the depressives. Others profit less or not at all. In this sense the chemotherapeutic effect depends upon the personality factors that create acceptance or rejection of the drug or for that matter of any therapeutic procedure because of the acceptance or rejection of the therapist. This whole problem is undoubtedly also related to the psychodynamic meaning of the drug intake and its role in the doctor-patient relationship. Passive and dependent individuals are generally willing to accept drugs and are inclined to report only their be~eficial results. Psychodynamically, drugs facilitate the transference relationship in these patients. One must add to this the symbolism of the drugs used including the aspect of orality. The drug intake may represent an increased dependence on the therapist and may serve the purpose of securing his acceptance especially when he has strongly urged the patient to use the drug. But this may be the patient's attempt to manipulate the physician. The latter's prompt recognition and skillful handling may prevent the patient from becoming dependent upon, or even addicted to the drug. Patients fearful of dependence may reject psychopharmacotherapy because using a drug may symbolize an invasion of privacy. In such patients the active drug or even the inert placebo may produce pronounced side reactions or even a severe phobic feeling causing rejection of drug therapy altogether. Suspicious and aggressive patients may react with mistrust and if strongly encouraged to use drugs they miss doses, claim forgetfulness or become frankly defiant and refuse to take the medication. False, temporary improvements may be observed in such patients when treated in the hospital, but prompt relapses occur after discharge. Finally, paranoid patients may include the Volume XVI
NON SPECIFIC FACfORS-KRAKOWSKI
seemingly harmful effects of drugs as a part of their paranoid system. It can not be overemphasized that prescribing drugs should be preceded by at least a cursory evaluation of the patient's personality and his attitude towards drugs including his previous experiences. If the attitude is negative and can not be overcome by reassurance, the persistent anti-drug attitude will cause the drug to exert no satisfactory results, or even create untoward side reactions because of negative placebo response. THE THERAPY
The ideal goal of therapy would be a total cure consisting of a complete and permanent remission of symptoms. Except for a very few spontaneous cures, such a utopian goal is unrealistic especially with psychiatric patients. A realistic goal is to create a satisfactory improvement permitting personal, social and vocational adjustment compatible with an independent, productive existence. In such management drugs serve as catalysts to the strengthening of adaptational defenses which is achieved through psychological methods of milieu therapy and psychotherapy. The pharmacological role in psychotics is probably more than catalytic and the same is true when very severe anxiety disrupts the adaptational ability of a neurotic. What are then the psychological properties of drugs? Why do psychotropic agents show such a great degree of non-specificity in the treatment of certain given target symptoms? Why is each patient affected in a different way by similar doses of drugs, even when an appropriate measure is used to consider the severity of symptoms, and even the law of initial values 4 ? Why do some patients develop more side reactions than others? The answers and explanations are at least partly produced by the ever-growing experience concerning placebo reactions which have attracted more attention in drug research than in drug practice. Shapiroll supplies the following definition: "A placebo is defined as any therapeutic procedure (or the component of a procedure) which is given deliberately to have an effect or which unknowingly has an effect upon a patient, symptom, disease or syndrome, but which is objectively without specific activity for the condition being treated. The placebo is also used to describe an adequate control in experimental studies. A placebo effect is defined as the changes produced by placebos." It is widely accepted that for thousands of years the placebo effect was responsible for the beneficial influence of almost all drugs, 6 and even as recently as 1952 an analysis performed in England of over 17,000 prescriptions revealed that roughly one-third were ~onsidered to be placebos. i Interestingly enough, the latter figure approximates the positive placebo responses found by many investigators in controlled July / August/September, 1975
studies and a recently published paper by Shapiro et al confirms this. 8 The same author found that physicians are prone to believe that other physicians' drugs work as placebo three times more often.9 Placebo reactions, positive or negative (favorable or unfavorable), are generally ascribed to the suggestibility of the patient who believes he is taking the active drug. lO Such factors as the personality make-up, already mentioned, previous experience and the quality of hopeful anticipation determine the degree of reaction. It likely depends also upon psychological factors related to: a. the doctor, b. the doctor-patient relationship, c. cultural circumstances and d. the conditions of treatment. On the other hand, race, sex, ethnic elements, intelligence, social class and type and length of illness are of little influence.!! The doctor himself undoubtedly influences the placebo effect by a positive concern about the patient or a less than concerned attitude, the quality of his therapeutic handling of the patient and the demonstration of his own positive self-esteem, his persuasive ability or his forceful dominance. The placebo effect is increased by such physician-related factors as his importance in the medical community, the fame of his scientific status, his role in research and probably also his high fees. The positive doctor-patient relationship seems more important than the suggestibility of the patient. This has been amply shown in a study in which a large percentage of a group of neurotic patients obtained relief of symptoms although they had been told they were being treated with an inert placebo.!2 An active drug may in some instances exert only a seemingly pharmacological effect due to placebo reaction. This is portrayed by the fact that a drug previously ineffective may become useful for the same patient when given by another physician. Cultural factors require special consideration and are beyond the scope of this presentation. The conditions and circumstances surrounding the treatment are very important. The active drug's effect is usually augmented by the effect of coexisting formal or informal psychotherapy while the same drug used alone have been proved less effective. The effect of drugs is augmented by hospitalization; thus drugs which are effective while the patient is hospitalized may become ineffective after discharge. In the last two instances the psychotherapy and the hospitalization might have acted themselves as placebos. Those in the environment of the patient play either a synergistic or antagonistic role, enhancing the positive or negative placebo response respectively, when they demonstrate either a positive or an anti-drug attitude.!:! 133
PSYCHOSOMATICS
The elfect of therapy depends also upon the type and course of the patient's illness; thus improvement ascribed to a drug might have consisted of a remission of s:/mptoms in a self-limited illness. This is true in patients with serious character disorders in whom the crisis symptoms recede spontaneously as a result of the placebo effect of the hospital. Hysterics, when their anxiety becomes bound and neutralized, and hysterics with depression, show remissions of freefloating anxiety and depression respectively independently of drugs. Temporary pseudo-improvement in depressive neurotics may be wrongly interpreted as a permanent remission of symptoms; similarly a patient with a serious depressive illness may recover in no time when chemotherapy is applied at the very end of the depressive cycle. All of these examples show natural remissions and pharmacotherapy should not be used in most of them. THE THERAPIST
As stated, the ideal use of chemotherapy of neuroses is adjunctive when the patient requires measures to enhance psychotherapy during a serious crisis. In psychoses the role of drugs is more essential but psychotherapy always potentiates the pharmacological effect. Physicians with an "organic" orientation may be prone to overuse drugs while the analytically oriented psychiatrists may shun chemotherapy altogether. With psychopharmacology it is easier to obtain improvement than to maintain it. For this reason the patient who is to be maintained for a long period must be reassured about side reactions and warned about toxic effects or the drug may acquire the quality of negative placebo. The therapist should follow the patient closely for the duration of therapy or unadjusted doses will create the same negative results. At no time should psychopharmacology be used for the mere sake of convenience of the doctor either because he knows no other method or because he seeks relief from pressure of his own anxiety about the patient. The anxious physician is more likely to use other than optimum doses and misinterpret the symptoms described by the patient as side reactions. Impatient for a prompt cure he may too quickly substitute one brand of drug for another. The placebo effect of the active drug, both positive and negative must be recognized. The recognition is easy because the placebo effect is almost immediate 13 and, therefore, in most instances much faster than the expected pharmacological response. Such recognition is especially important in depression. If a depressed
134
patient shows an immediate alleviation of symptoms after an antidepressant drug is given, his remission is undoubtedly the placebo effect. Such patients should be followed up to determine whether or not the improvement persists, for recurrence of symptoms may be responsible for a suicide. Because psychopharmachotherapy shows better effects with concurrent psychotherapy, at least of a supportive type, merely prescribing drugs and refilling them upon telephone requests leads to wasting a good therapeutic method. SUMMARY
The psychosomatic model of treatment of mental illness follows the understanding that causes of mental illness are multiple. It requires biological and psychosocial approaches to treatment. The non-specific factors in psychopharmacology relate to the psychosocial components of illness. These factors, but especially the placebo effects, are as important as the pharmacological influences. All should be well understood before any meaningful chemotherapy of mental illness is undertaken. 210 Cornelia St., Suite 103, Plattsburgh, NY 12901 REFERENCES 1. Krakowski, AJ., Role of Consultation Psychiatry in Teaching Psychopharmacology in the General Hospital, N.Y.S.J. Med. 73: 1987, 1973. 2. Wolff, A, Concept of Disease, Psychosom. Med. 24: I, 1962. 3. Krakowski, AJ., Comprehensive Approach to Psychopharmacology, N.Y.S.J. Med. 69:2886, 1969. 4. Wilder, J., Basimetric Approach to Psychiatry, in Ari.:ti, S. ed. American Handbook of Psychiatry. Vol. III, New York Basic Books, 1966. p. 333. 5. Shapiro, AK., A Historic and Heuristic Definition of the Placebo, Psychiat. 27: 52, 1964. 6. Houston, W., Doctor Himself as Therapeutic Agent. Ann. Intern. Med. 11:1416, 1938. 7. Dunlop, D., Henderson, T., and Inch, R., Survey of 17,301 Prescriptions on Form EC 10, Brit. Med. J. 1: 292, 1952. 8. Shapiro, AK., Mike, D., Barten, H. and Shapiro, E., Study of the Placebo Effect with a Self-Administered Placeho Test. Compo Psychiat. 14:535, 1973. 9. Shapiro, A.K., Placebo Effects in Psychotherapy and PsychoanalY5is, J. Clin. Psychopharmacol. 10:73, 1970. 10. Kurland, A.A, The Drug Placebo: Its Psychodynamic and Conditional Reflex Action. Behav. Sc 2: 101, 1967. 11. Tibbets, R.W., and Hawkins, J.R., The Placebo Response, J. Ment. Sc. 102:60, 1956. 12. Park, L.C., and Covi, Non-Blind Placebo Trial: An Exploration of Neurotic Patients' Responses to Placebo When its Inert Content Was Disclosed. Arch. Gen. Psychiat. 12:36, 1965. 13. Krakowski, AJ., Psychophysiologic Gastro-Intestinal Disorders in Children, Psychosomatics, 8:326, 1967.
Volume XVI