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Psychotropic Drugs and the Elderly
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Psychotherapeutic Dnlgs And the Elderly
Since the advent of tranquilizers in the mid-1950s, an increasing number of elderly patients have been consuming them-and misusing them. With its increased incidence of diseases, altered metabolic capacities and unique emotional problems, the over-65 population is particularly vulnerable to psychotherapeutic drug misuse and abuse. Out of growing concern for this problem, the HEW National Insti-: tute on Drug Abuse recently published a report, "The Aging Process and Psychoactive Drug Use,"* which underscored the need for more systematic research in this
·"The Aging Process and Psychoactive Drug Use," NIDA Services Research Monograph Series Publication No. 79-813, GPO, 1979, produced under contract by the Stanford Research Institute, Menlo Park, CA 94025.
22
area and for more programs that monitor administration and intervene in drug misuse among the elderly. The recent interest in drug use in the aged is no wonder, considering that people 65 and over represent 10% of the total population but receive 25% of all prescriptions written. Exactly how many of those prescriptions are for psychoactive drugs is not well known, but a past study identified 8 of the 21 most widely used drugs among the elderly as falling into that category. According to the HEW report, the most widely used classes of prescription psychotherapeutic drugs among older men and women were minor tranquilizers/sedatives and hypnotics, both used by greater proportions of older persons than any other age groups. Faced with loss of
occupation, income, status, health, and loved ones, many senior citizens turn to these drugs to help them cope with their changing life situations. Researchers estimated that approximately 20% of the population 65 years and older suffers fr~m some form of psychiatric disorder-including anxiety, depression, insomnia, and physiologically based psychoses. For anxiety, the report pointed to oxazepam as the best benzodiazepine for the elderly. Unlike chlordiazepoxide and diazepam, it is rapidly biotransformed to an inactive product and does not accumulate to build up toxic effects. ()xazepam also is recommended for elderly insomniacs but is contraindicated in cases where patients have previously used barQiturates in high doses. Treatment for depression in elder-
American Pharmacy VoLNS19, No.9, August 1979/486
Iy persons is similar to treatment of younger patients. Both age groups usually receive tricyclic antidepressants, but most elderly patients should begin at lower dosages and increase gradually. Possible adverse effects of these drugs include anticholinergic effects (e.g., disorientation, anxiety, and visual and auditory hallucination), dry mouth, and inhibited bowel motility. Like depression, treatment of psychoses---such as senile dementia and arteriosclerotic psychosis---is the same in older and younger patients. However, starting doses in the elderly are usually reduced by one third to one half the amount given to young patients. Although drug abuse can be largely attributed to the patient's error in usage, physicians also may be responsible for errors in prescribing. For example, the report cited several studies suggesting that physicians in some nursing homes may prescribe psychoactive drugs for patients who do not really need them. Of even more concern is that the aging process produces alterations in the human system which affect the absorption, transport, tissue localization, metabolism, and excretion of drugs. Dosages need to be altered to account for these differences. In addition, prior use of some drugs may cause a predisposition to adverse drug reactions over a long lifetime, another consideration in prescribing and dosing. Factors Affecting Dosages The Food and Drug Administration regulations do not require that studies of drug metabolism include a reasonable sample of elderly subjects. Therefore the physician and the pharmacist should consider the following general factors in deciding on dosage: • Impaired central nervous system-Because of increased central nervous system sensitivity and/or decreased brain sensitivity, the sedative effect of many psychotropic agents is more pronounced-in the elderly.
American Pharmacy VoI.NS19, No.9, August 1979/487
• Venous congestion-Owing to reduced cardiac reserves and output and frequently diminished vascular elasticity associated with loc~l atherosclerosis, the circulation time of drugs increases, thus impairing their distribution and often delaying their excretion. • Diminished arterial flow-By reducing the size of the absorbing surface a diminished arterial flow can hamper absorption of orally administered agents. • A slowed stomach emptying time decreases the rate at which drugs are absorbed from the intestine. • The lower serum albumin levels decrease the number of available protein binding sites. In the case of drugs that have a high affinity for protein binding, the ratio of free to bound drug increases, and results in enhanced drug toxicity.
its side effects when filling their prescriptions, and only 13.0% went to see their physician to have their medications prescribed; 30% simply called their physician for a prescription, and another 30.5% had the pharmacist call. Drug Use Varies
Although there is no concrete evidence that age has an effect on noncompliance, several researchers have speculated that some elderly patients may be more likely than others to misuse psychotherapeutic drugs. One such study identified probable noncompliers as patients with chronic illnesses requiring long-term therapy, patients who live alone, patients with psychiatric illnesses, and patients who receive several drugs requiring frequent administration. A related study found a tendency among older people to decide for themselves how they will use their medications. Roughly 40% of the respondents reported that they took medications until their physician told them to stop; while 18.8% stopped when their prescriptions ran out, 18.3% stopped when they felt better, and 3.8% stopped when they thought they should. "The increased sensitivity to psy• Replacement of functional tissue by fat-The central nervous choactive drugs among older persystem tissue, as well as other tis- sons, and the potential for altered sues of the body, increases in lipid effects when drugs are used in comcontent with aging. Psychothera- ' bination, are important reasons why peutic agents can become localized drug users and drug regimens in body fats, thus decreasing their should be carefully .scru tinized by intensity or increasing the duration medical personnel," states Stanford of effect before they slowly return to Research Institute gerontologist James Gollub, one of the authors of circula tion. • Diminished hepatic and renal the HEW report. Stressing the need function can prolong the plasma for more monitoring and intervenhalf-life of drugs simply by backing tion programs, Gollub said: "At the the drug up in the bloodstream, re- present'time./. very few pharmacies sulting in an increased risk of drug are capable o(mo-nitoring drug consumption in the community. This toxicity and drug interactions. Improper prescribing is com- problem is complicated by the fact pounded by the lack of vigilance on that drug consumers can move from the part of the elderly. Citing a 1976 pharmacy to pharmacy and can obstudy, the report said that 71.6% of tain multiple prescriptions from difthe elderly participants did not dis- ferent physicians." Computer monitoring and review cuss the prescription of one physician with another, 74.8% neglected appears to be one way of overcomto ask questions about the drug or ing the problems found in the
23
L--ll-yptophan fur 1reatment Of Depression?
study, according to Gollub. Begin- were used, particularly in the case ning with the first computer system of an uncontrolled patient. that combined on-line prescription Intervention Helps processing and review procedures As the ~xtent of psychotherain 1967, several systems are now being tested to monitor the use of peutic drug misuse among the elpsychotherapeutic drugs in both derly becomes clearer, the number hospital and outpatient clinic set- of intervention programs is extings. Such systems are highly tech- pected to increase. According to the nical methods of managing> large report, many of the established proquantities of data and drug-"r elated grams are extensions of pre-existing questions in a short period. Unfor- programs for the treatment of alco- .----B-y-C-A-R-O-L-C-O-L-V-I-N-----f tunately, most pharmacists and holism and the elderly alcoholic. community clinics do not have ac- The new drug intervention proL-tryptophan, an essential a mino cess to or cannot afford to purchase grams include outpatient facilities acid, recently has been advocated the service of these monitoring emphasizing outreach, referral, folby several clinicians as an altersystems. low-up, and education; inpatient native to more traditional an tideA more economical alternative drug abuse treatment in hospital pressive therapy involving the may be a manual monitoring sys- and nursing home settings; educatricyclics and "electroconvulsive tem. For example, one program tion and counseling programs; and therapy (ECT). proved successful in monitoring peer counseling. One example is Since L-tryptophan is available mentally ill patients in the commun- THEE DOOR, a service organization over the counter in the U nited ity and has a high degree of rele- in Florida, which initiated an outpaStates from pharmacies and h ealth vance to psychoactive drug use tient counseling center specifically food stores, it has been under inamong formerly institutionaliz~d el- oriented toward misuse of prescripcreasing investigation in several derly patients returning to the com- tion medication by the elderly (overlaboratories and centers. munity. The Tennessee Medication dosage, duplication of prescripCurrently, the biogenic amine Main tenance Program set up a , tions, swapping of medications, and permissive hypothesis as described model service in a community phar- use of outdated drugs). Another by Prange l is the most widely macy that dealt with problems such _program, organized by the Institute accepted explanation for the bioas medication noncompliance, drug for the Study of Aging at the Unichemical basis of affective disorders. side effects, drug interactions, and versity of Miami, trained elderly There are two types of biogenic minor alterations in the patient's persons as peer counselors. In addiamines: catecholamines (dopamine, mental status. Telephone consulta- tion, three programs have been set norepinephrine, and epinephrine) tion s with the . trists also up in Minnesota that center on deand indoleamines (tryptamine a nd toxifying chemically dependent paserotonin). The hypothesis suggests tients . that a decrease in central indoleuThe most disconcerting aspect of aminergic transmission predisposes the trend in development of drug (Upermits") a patient to an affective interventions for elderly psychoacdisorder but does not in itself cause tive drug misusers," Gollub said, Uis the disorder. A change in central the lack of central information clearcatecholaminergic transmission, acinghouses where health care procompanied by the indoleamine defifessionals can make contact and cit, is thought to be responsible for share their design concepts and serthe change in mood. vice problems." Gollub cited a lack An extension of the hypothesis of contact between service providers indicates that depression is due to a in the field of direct intervention decrease in both indoleaminergic and pharmacists interested in proand catecholaminergic transmismoting drug monitoring activities. sion, while mania is due to elevated He feels that the interaction be- I=============================:::::::j tween those prescribing and disCarol Colvin is a pharmacy student at pensing drugs also should facilitate the University of California School of more effective program intervenPharmacy, and lives at 1499 Fifth A vetions and alternatives for elderly nue, San Francisco, CA 94122 . This psychoactive drug misusers. paper was written for credit in clinical -LT pharmacy.
24
American Pharmacy Vol.NS19, No.9, August 1979/488
catecholaminergic transmission in the presence of indoleamine deficit. 1, If the hypothesis is correct, a ra-. tional therapeutic goal would be to restore normal indoleamine levels to remove "permission" for affective disorders to occur. Recent studies indicate that the lowered cerebral content of indoleamines in depressed patients is probably due more to a low rate of synthesis than to increased degradation.3•5 Research is now concentrating on increasing synthesis of indoleamines . Thus far, serotonin has not been found effective in increasing central concentration because it does not cross the blood-brain barrier. 3•4 Preliminary studies with 5-0H tryptophan have had little success.3 Now, interest is centered on L-tryptophan. Clinical Studies Early studies by Herrington 6 and others4 on L-tryptophan had indicated that the drug was not as effective as conventional therapy. However, in more recent studies, Ltryptophan was found to be as effective as electroconvulsive therapy in one study and as effective as tricyclics in others: • The studies by Kline and Shah 7 demonstrated equal efficacy with 3-6 g of L-tryptophan and with 150225 mg of imipramine. Eight of the 14 subjects in each treatment group showed either some or marked improvement. • Herrington 3 found that ECT was more effective than 6-8 g/day of L-tryptophan in severe depression; however, less severely depressed patients taking L-tryptophan improved at the same rate and to the same extent as patients taking 150 mg/day of amitriptyline . On the basis of current work, Herrington suggests that L-tryptophan may have a place in therapy of mild depressive disorders. On the basis of prior studies he also suggests that male patients with bipolar (manicdepressive) illness and "those with less anxious personalities" respond
American Pharmacy VoI.NS19. No.9. August 1979/489
better than other patients to Ltryptophan. • In a well-designed doubleblind study, Cop pen et al./l found 9 g of L-tryptophan to be as eHective as 150 mg of imipramine. Addition of liothyronine (T3) to the study did not affect improvement with Ltryptophan but significantly increased the response to imipramine. • Another study by Coppen's group9 concluded that L-tryptophan was equivalent in efficacy to ECT, but differences in the sample populations cast doubt on the credibility of the results. • Prange et al. 10 obtained a generally better response with 6 g of Ltryptophan than with 400 mg of chlorpromazine in treating patients with mania. All studies found in the literature were conducted on patients sufficiently depressed to require hospitalization. Often these patients had been refractory to treatment with tricyclic antidepressants. This selection factor presents a substantial bias and would prevent an accurate comparison between tricyclic antidepressants and L-tryptophan in most cases. For ethical reasons, no patients received placebo only. L-tryptophan was compared to traditional modes of therapy, which are presumed to be more effective than a placebo alone. If there was no significant difference between the response to Ltryptophan and to usual therapy, then L-tryptophan was concluded to be more effective than placebo in treating depression. Ascorbic acid and pyridoxine were often given with L-tryptophan on the assumption that they are necessary cofactors in indoleamine synthesis.8 Whether a difference is seen in therapeutic results when these vitamins are included has not been established. In some studies, response to Ltryptophan was increased when it was coadministered with a monoamine oxidase inhibitor. 4 •9 Rationale for this treatment involves decreased degradation of indoleamines.
Other Factors The normal biological half-life of tryptophan is reported to be 15.8 hours. 11 Tryptophan is broken down by tryptophan pyrrolase. Activity of this hepatic enzyme is increased by cortisol and oral contraceptives and is decreased in tryptophan itself.4 Estrogens displace Ltryptophan from plasma protein binding sites, increasing the percentage unbound. The significance of this interaction has not been determined . 12 Tryptophan has been shown to increase duration of sleep in both normal and depressed patients4 and is used clinically for this purpose. A significant advantage of Ltryptophan is that side effects are rare and relatively mild. Nausea, anorexia, vomiting, and drowsiness have been reported,4.13 but no serious adverse reactions are known at this time. Dosage forms include capsules of 125, 200, and 250 mg and tablets of 125, 200, 250, 500, and 667 mg. 14 Difficulty in swallowing due to the large size of the tablets and capsules is a disadvantage of its use. Tryptophan is relatively expensive, costing approximately 75 cents per gram. Studies Needed Although the results of the studies cited here seem to indicate that L-tryptophan may be useful in the treatment of depression, clinical studies have been scarce . Since Ltryptophan is readily available, it would appear that a larger number of well-designed and controlled studies would be advisable to determine the usefulness of this drug in depression therapy and prophylaxis. 0 References L 2. 3. 4. 5. 6. 7. 8. 9. 10. 1L 12. 13. 14.
AI . Prange. P•.¥chia tr. Am, .. 3; 56 (1 973). D.M . Sha w . Po.t!(rad . Med . /.. 52. Suppl. 3. 47 (1976). R.N . He rringto n. Scott . Med . , .• 23. 75 (1978). Dru!( alld Therapeutics Bulletill . 10. 75 (1972). D.L. Murph y. Am . , . Psychia try . 129. 141 (1 972). R.N . Herringto n. e t a l.• Lillleet. 11. 731 (1974 ). N .S . Kline a nd B.K. Shah . Cllrr. Ther. Res .. 15.484 (1973) A Coppe n et al .. Arch . Cell . P.y chiatry . 26. 234 (1972). A . Coppen e t a l.• Lillleet. 11. 1178 (1967). A I. Pra nge et al. . Arch. Cen . P'ycl,iatry . 30. 56 (1974). W .A. Ritschel. Drug . 111te11. c/ill. Pharm .. 4. 332 (1 970). A. Coppen a nd K. Wood. Scott . M ed . , .. 23. 75 (1978). Medical Letter of Dru!(s alld Therap" "tic• . 19. 108 (1 977). " Facts a nd Compa risons," Facts and Comparisons, Inc., St. Lo uis. MO . Dec. 1978. p . 55.
25
Psychotherapeutic Dnlgs And the Elderly
Since the advent of tranquilizers in the mid-1950s, an increasing number of elderly patients have been consuming them-and misusing them. With its increased incidence of diseases, altered metabolic capacities and unique emotional problems, the over-65 population is particularly vulnerable to psychotherapeutic drug misuse and abuse. Out of growing concern for this problem, the HEW National Insti-: tute on Drug Abuse recently published a report, "The Aging Process and Psychoactive Drug Use,"* which underscored the need for more systematic research in this
·"The Aging Process and Psychoactive Drug Use," NIDA Services Research Monograph Series Publication No. 79-813, GPO, 1979, produced under contract by the Stanford Research Institute, Menlo Park, CA 94025.
22
area and for more programs that monitor administration and intervene in drug misuse among the elderly. The recent interest in drug use in the aged is no wonder, considering that people 65 and over represent 10% of the total population but receive 25% of all prescriptions written. Exactly how many of those prescriptions are for psychoactive drugs is not well known, but a past study identified 8 of the 21 most widely used drugs among the elderly as falling into that category. According to the HEW report, the most widely used classes of prescription psychotherapeutic drugs among older men and women were minor tranquilizers/sedatives and hypnotics, both used by greater proportions of older persons than any other age groups. Faced with loss of
occupation, income, status, health, and loved ones, many senior citizens turn to these drugs to help them cope with their changing life situations. Researchers estimated that approximately 20% of the population 65 years and older suffers fr~m some form of psychiatric disorder-including anxiety, depression, insomnia, and physiologically based psychoses. For anxiety, the report pointed to oxazepam as the best benzodiazepine for the elderly. Unlike chlordiazepoxide and diazepam, it is rapidly biotransformed to an inactive product and does not accumulate to build up toxic effects. ()xazepam also is recommended for elderly insomniacs but is contraindicated in cases where patients have previously used barQiturates in high doses. Treatment for depression in elder-
American Pharmacy VoLNS19, No.9, August 1979/486
Iy persons is similar to treatment of younger patients. Both age groups usually receive tricyclic antidepressants, but most elderly patients should begin at lower dosages and increase gradually. Possible adverse effects of these drugs include anticholinergic effects (e.g., disorientation, anxiety, and visual and auditory hallucination), dry mouth, and inhibited bowel motility. Like depression, treatment of psychoses---such as senile dementia and arteriosclerotic psychosis---is the same in older and younger patients. However, starting doses in the elderly are usually reduced by one third to one half the amount given to young patients. Although drug abuse can be largely attributed to the patient's error in usage, physicians also may be responsible for errors in prescribing. For example, the report cited several studies suggesting that physicians in some nursing homes may prescribe psychoactive drugs for patients who do not really need them. Of even more concern is that the aging process produces alterations in the human system which affect the absorption, transport, tissue localization, metabolism, and excretion of drugs. Dosages need to be altered to account for these differences. In addition, prior use of some drugs may cause a predisposition to adverse drug reactions over a long lifetime, another consideration in prescribing and dosing. Factors Affecting Dosages The Food and Drug Administration regulations do not require that studies of drug metabolism include a reasonable sample of elderly subjects. Therefore the physician and the pharmacist should consider the following general factors in deciding on dosage: • Impaired central nervous system-Because of increased central nervous system sensitivity and/or decreased brain sensitivity, the sedative effect of many psychotropic agents is more pronounced-in the elderly.
American Pharmacy VoI.NS19, No.9, August 1979/487
• Venous congestion-Owing to reduced cardiac reserves and output and frequently diminished vascular elasticity associated with loc~l atherosclerosis, the circulation time of drugs increases, thus impairing their distribution and often delaying their excretion. • Diminished arterial flow-By reducing the size of the absorbing surface a diminished arterial flow can hamper absorption of orally administered agents. • A slowed stomach emptying time decreases the rate at which drugs are absorbed from the intestine. • The lower serum albumin levels decrease the number of available protein binding sites. In the case of drugs that have a high affinity for protein binding, the ratio of free to bound drug increases, and results in enhanced drug toxicity.
its side effects when filling their prescriptions, and only 13.0% went to see their physician to have their medications prescribed; 30% simply called their physician for a prescription, and another 30.5% had the pharmacist call. Drug Use Varies
Although there is no concrete evidence that age has an effect on noncompliance, several researchers have speculated that some elderly patients may be more likely than others to misuse psychotherapeutic drugs. One such study identified probable noncompliers as patients with chronic illnesses requiring long-term therapy, patients who live alone, patients with psychiatric illnesses, and patients who receive several drugs requiring frequent administration. A related study found a tendency among older people to decide for themselves how they will use their medications. Roughly 40% of the respondents reported that they took medications until their physician told them to stop; while 18.8% stopped when their prescriptions ran out, 18.3% stopped when they felt better, and 3.8% stopped when they thought they should. "The increased sensitivity to psy• Replacement of functional tissue by fat-The central nervous choactive drugs among older persystem tissue, as well as other tis- sons, and the potential for altered sues of the body, increases in lipid effects when drugs are used in comcontent with aging. Psychothera- ' bination, are important reasons why peutic agents can become localized drug users and drug regimens in body fats, thus decreasing their should be carefully .scru tinized by intensity or increasing the duration medical personnel," states Stanford of effect before they slowly return to Research Institute gerontologist James Gollub, one of the authors of circula tion. • Diminished hepatic and renal the HEW report. Stressing the need function can prolong the plasma for more monitoring and intervenhalf-life of drugs simply by backing tion programs, Gollub said: "At the the drug up in the bloodstream, re- present'time./. very few pharmacies sulting in an increased risk of drug are capable o(mo-nitoring drug consumption in the community. This toxicity and drug interactions. Improper prescribing is com- problem is complicated by the fact pounded by the lack of vigilance on that drug consumers can move from the part of the elderly. Citing a 1976 pharmacy to pharmacy and can obstudy, the report said that 71.6% of tain multiple prescriptions from difthe elderly participants did not dis- ferent physicians." Computer monitoring and review cuss the prescription of one physician with another, 74.8% neglected appears to be one way of overcomto ask questions about the drug or ing the problems found in the
23
L--ll-yptophan fur 1reatment Of Depression?
study, according to Gollub. Begin- were used, particularly in the case ning with the first computer system of an uncontrolled patient. that combined on-line prescription Intervention Helps processing and review procedures As the ~xtent of psychotherain 1967, several systems are now being tested to monitor the use of peutic drug misuse among the elpsychotherapeutic drugs in both derly becomes clearer, the number hospital and outpatient clinic set- of intervention programs is extings. Such systems are highly tech- pected to increase. According to the nical methods of managing> large report, many of the established proquantities of data and drug-"r elated grams are extensions of pre-existing questions in a short period. Unfor- programs for the treatment of alco- .----B-y-C-A-R-O-L-C-O-L-V-I-N-----f tunately, most pharmacists and holism and the elderly alcoholic. community clinics do not have ac- The new drug intervention proL-tryptophan, an essential a mino cess to or cannot afford to purchase grams include outpatient facilities acid, recently has been advocated the service of these monitoring emphasizing outreach, referral, folby several clinicians as an altersystems. low-up, and education; inpatient native to more traditional an tideA more economical alternative drug abuse treatment in hospital pressive therapy involving the may be a manual monitoring sys- and nursing home settings; educatricyclics and "electroconvulsive tem. For example, one program tion and counseling programs; and therapy (ECT). proved successful in monitoring peer counseling. One example is Since L-tryptophan is available mentally ill patients in the commun- THEE DOOR, a service organization over the counter in the U nited ity and has a high degree of rele- in Florida, which initiated an outpaStates from pharmacies and h ealth vance to psychoactive drug use tient counseling center specifically food stores, it has been under inamong formerly institutionaliz~d el- oriented toward misuse of prescripcreasing investigation in several derly patients returning to the com- tion medication by the elderly (overlaboratories and centers. munity. The Tennessee Medication dosage, duplication of prescripCurrently, the biogenic amine Main tenance Program set up a , tions, swapping of medications, and permissive hypothesis as described model service in a community phar- use of outdated drugs). Another by Prange l is the most widely macy that dealt with problems such _program, organized by the Institute accepted explanation for the bioas medication noncompliance, drug for the Study of Aging at the Unichemical basis of affective disorders. side effects, drug interactions, and versity of Miami, trained elderly There are two types of biogenic minor alterations in the patient's persons as peer counselors. In addiamines: catecholamines (dopamine, mental status. Telephone consulta- tion, three programs have been set norepinephrine, and epinephrine) tion s with the . trists also up in Minnesota that center on deand indoleamines (tryptamine a nd toxifying chemically dependent paserotonin). The hypothesis suggests tients . that a decrease in central indoleuThe most disconcerting aspect of aminergic transmission predisposes the trend in development of drug (Upermits") a patient to an affective interventions for elderly psychoacdisorder but does not in itself cause tive drug misusers," Gollub said, Uis the disorder. A change in central the lack of central information clearcatecholaminergic transmission, acinghouses where health care procompanied by the indoleamine defifessionals can make contact and cit, is thought to be responsible for share their design concepts and serthe change in mood. vice problems." Gollub cited a lack An extension of the hypothesis of contact between service providers indicates that depression is due to a in the field of direct intervention decrease in both indoleaminergic and pharmacists interested in proand catecholaminergic transmismoting drug monitoring activities. sion, while mania is due to elevated He feels that the interaction be- I=============================:::::::j tween those prescribing and disCarol Colvin is a pharmacy student at pensing drugs also should facilitate the University of California School of more effective program intervenPharmacy, and lives at 1499 Fifth A vetions and alternatives for elderly nue, San Francisco, CA 94122 . This psychoactive drug misusers. paper was written for credit in clinical -LT pharmacy.
24
American Pharmacy Vol.NS19, No.9, August 1979/488
catecholaminergic transmission in the presence of indoleamine deficit. 1, If the hypothesis is correct, a ra-. tional therapeutic goal would be to restore normal indoleamine levels to remove "permission" for affective disorders to occur. Recent studies indicate that the lowered cerebral content of indoleamines in depressed patients is probably due more to a low rate of synthesis than to increased degradation.3•5 Research is now concentrating on increasing synthesis of indoleamines . Thus far, serotonin has not been found effective in increasing central concentration because it does not cross the blood-brain barrier. 3•4 Preliminary studies with 5-0H tryptophan have had little success.3 Now, interest is centered on L-tryptophan. Clinical Studies Early studies by Herrington 6 and others4 on L-tryptophan had indicated that the drug was not as effective as conventional therapy. However, in more recent studies, Ltryptophan was found to be as effective as electroconvulsive therapy in one study and as effective as tricyclics in others: • The studies by Kline and Shah 7 demonstrated equal efficacy with 3-6 g of L-tryptophan and with 150225 mg of imipramine. Eight of the 14 subjects in each treatment group showed either some or marked improvement. • Herrington 3 found that ECT was more effective than 6-8 g/day of L-tryptophan in severe depression; however, less severely depressed patients taking L-tryptophan improved at the same rate and to the same extent as patients taking 150 mg/day of amitriptyline . On the basis of current work, Herrington suggests that L-tryptophan may have a place in therapy of mild depressive disorders. On the basis of prior studies he also suggests that male patients with bipolar (manicdepressive) illness and "those with less anxious personalities" respond
American Pharmacy VoI.NS19. No.9. August 1979/489
better than other patients to Ltryptophan. • In a well-designed doubleblind study, Cop pen et al./l found 9 g of L-tryptophan to be as eHective as 150 mg of imipramine. Addition of liothyronine (T3) to the study did not affect improvement with Ltryptophan but significantly increased the response to imipramine. • Another study by Coppen's group9 concluded that L-tryptophan was equivalent in efficacy to ECT, but differences in the sample populations cast doubt on the credibility of the results. • Prange et al. 10 obtained a generally better response with 6 g of Ltryptophan than with 400 mg of chlorpromazine in treating patients with mania. All studies found in the literature were conducted on patients sufficiently depressed to require hospitalization. Often these patients had been refractory to treatment with tricyclic antidepressants. This selection factor presents a substantial bias and would prevent an accurate comparison between tricyclic antidepressants and L-tryptophan in most cases. For ethical reasons, no patients received placebo only. L-tryptophan was compared to traditional modes of therapy, which are presumed to be more effective than a placebo alone. If there was no significant difference between the response to Ltryptophan and to usual therapy, then L-tryptophan was concluded to be more effective than placebo in treating depression. Ascorbic acid and pyridoxine were often given with L-tryptophan on the assumption that they are necessary cofactors in indoleamine synthesis.8 Whether a difference is seen in therapeutic results when these vitamins are included has not been established. In some studies, response to Ltryptophan was increased when it was coadministered with a monoamine oxidase inhibitor. 4 •9 Rationale for this treatment involves decreased degradation of indoleamines.
Other Factors The normal biological half-life of tryptophan is reported to be 15.8 hours. 11 Tryptophan is broken down by tryptophan pyrrolase. Activity of this hepatic enzyme is increased by cortisol and oral contraceptives and is decreased in tryptophan itself.4 Estrogens displace Ltryptophan from plasma protein binding sites, increasing the percentage unbound. The significance of this interaction has not been determined . 12 Tryptophan has been shown to increase duration of sleep in both normal and depressed patients4 and is used clinically for this purpose. A significant advantage of Ltryptophan is that side effects are rare and relatively mild. Nausea, anorexia, vomiting, and drowsiness have been reported,4.13 but no serious adverse reactions are known at this time. Dosage forms include capsules of 125, 200, and 250 mg and tablets of 125, 200, 250, 500, and 667 mg. 14 Difficulty in swallowing due to the large size of the tablets and capsules is a disadvantage of its use. Tryptophan is relatively expensive, costing approximately 75 cents per gram. Studies Needed Although the results of the studies cited here seem to indicate that L-tryptophan may be useful in the treatment of depression, clinical studies have been scarce . Since Ltryptophan is readily available, it would appear that a larger number of well-designed and controlled studies would be advisable to determine the usefulness of this drug in depression therapy and prophylaxis. 0 References L 2. 3. 4. 5. 6. 7. 8. 9. 10. 1L 12. 13. 14.
AI . Prange. P•.¥chia tr. Am, .. 3; 56 (1 973). D.M . Sha w . Po.t!(rad . Med . /.. 52. Suppl. 3. 47 (1976). R.N . He rringto n. Scott . Med . , .• 23. 75 (1978). Dru!( alld Therapeutics Bulletill . 10. 75 (1972). D.L. Murph y. Am . , . Psychia try . 129. 141 (1 972). R.N . Herringto n. e t a l.• Lillleet. 11. 731 (1974 ). N .S . Kline a nd B.K. Shah . Cllrr. Ther. Res .. 15.484 (1973) A Coppe n et al .. Arch . Cell . P.y chiatry . 26. 234 (1972). A . Coppen e t a l.• Lillleet. 11. 1178 (1967). A I. Pra nge et al. . Arch. Cen . P'ycl,iatry . 30. 56 (1974). W .A. Ritschel. Drug . 111te11. c/ill. Pharm .. 4. 332 (1 970). A. Coppen a nd K. Wood. Scott . M ed . , .. 23. 75 (1978). Medical Letter of Dru!(s alld Therap" "tic• . 19. 108 (1 977). " Facts a nd Compa risons," Facts and Comparisons, Inc., St. Lo uis. MO . Dec. 1978. p . 55.
25