Psychopathology, Psychopharmacology and the Organic Brain Syndromes THOMAS
A.
BAN,
M.D.
Part 11* Psychopharmacology There are three major therapeutic approaches in the pharmacological treatment of organic brain syndrome: symptomatic (by psychotropic drugs), palliative (by drugs with an effect on cerebral circulation) and causal (by substitution or replacement). Because of its increasing importance, pharmacotherapy in psychogeriatrics has become a special field in the clinical psychopharmacology of organic brain syndromes. SYMPTOMATIC
Psychotropic Drugs Treatment by psychotropic drugs in the organic hrain syndrome is essentially symptomatic. In other terms, it is directed toward the relief of psychopathological and behavioral manifestations that may accompany the organic disorder, without an apparent effect on the underlying disease (Table II). Hypnotics Insomnia or inverse sleep rhythm, with restlessness at night and sleepiness or drowsiness in the daytime, are commonly encountered in patients with an organic brain syndrome. For the symptomatic treatment of these sleep disturbances hypnotic drugs are usually employed. While there is no doubt that barbiturates decrease cerebral metabolism and thereby tend to increase agitation and confusion, especially in elderly organic brain syndrome patients, Stotsky and his collaborators report, ~I on the basis of a controlled study, that one of the slower acting barbiturates, sodium butabarbitat is both safe and effective in moderate doses for elderly patients with sleep disorders that are refractory to other hypnotics. Among the nonbarbiturate hypnotics, for some time chloral hydrate (a chloral derivative) and paraldehyde (a cyclic ether) were the most frequently used in organic brain syndrome patients. More recently, however, they have been increasingly replaced by glutethimide. methyprylon (both piperidinediones), ethchlorvynol, methylparafynol (both tertiary acetylenic alcohols), ethinamate (a carbon acid ester of alcohol) and methaqualone (a quinazolone)." Dr. Ban is Director, Division of Psychopharmacology, Department of Psychiatry, McGill University, Montreal, Quebec, Canada. "'Pa:·t I of this two part article appeared in the Second Quarter. 1976 issue. July August September. 1976
A nxiolytics For the symptomatic relief of anxiety, tension and restlessness in organic brain syndrome patients, anxiolytic drugs are used. Among the various anxiolytic preparations, benzodiazepines (i.e. chlordiazepoxide, diazepam and oxazepam), substituted diols (i.e. meprobamate and tybamate) and diphenylmethanes (i.e. hydroxyzine, diphenylhydramine and benactyzine) are the ones most frequently employed. While there is definite evidence that anxiolytic drugs are therapeutically more effective than inactive placebo preparations, comparative studies could not reveal any major difference among the anxiolytic drugs in their therapeutic effect on organic brain syndromeY"~' In view of the fact that administration of anxiolytic drugs may induce paradoxical behavioral reactions (i.e. an increa~e instead of a decrease of agitation, aggressiveness and irritability) as well as impairment of cognitive functions and ataxia, treatment with anxiolytics should always be initiated by using the lowest dosage form of the drug and it must be carried out with the utmost caution and care, especially when higher dosages are employed. A ntipsychotics In addition to their tranquilizing properties, antipsychotic drugs-or major tranquilizers-arc specifically indicated for the treatment of psychotic symptoms such as hallucinations, delusions and manneristic TABLE II Psychotropic drugs used in the treatment of organic brain syndromes. Pharmacological Group
Chemical Catcgory
Prototype Drug
Hypnotics
Barhiturates Nonbarbituratcs
Butaharbital Ethchlorvynol
A lI.rio/ytics
Benzodiazepines Substituted diols Diphenylmcthanes
Chlol'lliazepoxide Meprobamate Hypdroxyzinc
A ntipsYc!lOtic.\·
Phenothiazines Thioxanthencs Butyrophenones
Thioridazine Thiothixcne Halopcridol
Stim1I1a/lIs
Amphetamines
Dextroamphetamine
A IItidepressallls
Tricyclics MAOI's
Imipramine Phenelzine 131
PSYCHOSOMATICS
behavior in organic brain syndrome patients. Of the four commercially available antipsychotic categories, the usc of Rauwolfia alkaloids (e.g. reserpine) has virtually been abandoned, because of their hypotensive and mood depressant effects. While the two relatively newer classes of anti psychotics, i.e. butyrophenones (e.g. haloperidol) and thiothixanthenes (e.g. chlorprothixene and thiothixene) are increasingly used, the phenothiazines are still the most frequently prescribed antipsychotic drugs in organic brain syndromes. While there is no definitive evidence that cne phenothiazine is superior to another in the treatment of organic brain syndrome patients, there are indications that acetophenazine (a piperazine) and thioridazine (a piperidyl) are the ones most frequently employed.3i.6~ The major advantage of thioridazine is the relatively low incidence of extrapyramidal reactions, while the major disadvantage of this drug is the disproportionately high incidence of electrocardiographic abnormalities. 56 Since the administration of antipsychotic agents may yield to toxic confusional states in organic brain syndrome patients more often than in other diagnostic categories, treatment with antipsychotic drugs should always be initiated by using one of the lower dose forms.
Stimulants Chronic organic brain syndrome patients are frequently withdrawn, sluggish and inert. To overcome these behavioral manifestations, a variety of stimulant drugs have been proposed, e.g. caffeine. Amphetamines and methylphenidate are powerful stimulants but they may produce anxiety, with or without agitation, and/or effects on the autonomic nervous system. Psychotic, perceptual and conceptual disorganization, if present, may be increased, or if not present, may be induced. The claims for the therapeutic effects of deanol, ethamivan and glumatic acid (a stimulant of cerebral metabolism) have not been substantiated. On the other hand, pentetrazol produced significant improvement in unusual thought content, irritability and disturbance of consciousness, with a trend towards improvement in psychometric and memory test performance, at least in one clinical report. 48 The same applies to pipradrol, another central nervous system stimulant which in high (5 mg daily)-but not in low (2 mg daily)-doses, produced significant improvement of "ward behavior".ii Antidepressants A great number of tricyclic antidepressants have been tried and found effective in the treatment of depression in organic brain syndrome patients.43.51.55 Because of their hypotensive effect, all commercially available tricyclic antidepressants should be used with caution in patients with a clinical hi:;tory of circulatory, e.g. coronary insufficiency, or with electrocardiographic abnormalities. Furthermore, because of their distinct 132
anticholingeric properties, extreme caution should be exercised when they are prescribed for patients with prostatic enlargement and/or glaucoma. Since the administration of tricyclic antidepressants may elicit a toxic confusional state in organic brain syndrome patients more often than in other diagnostic categories, treatment with tricyclic antidepressants should always be initiated by using one of the lower dose forms. Side effects and complications are more common with monoamine oxidase inhibitors (MAOI) than with tricyclic antidepressants. Because of this, MAOI's should only be employed when treatment with tricyclic antidepressants has failed. 49 PALLIATIVE
Drugs Influencing Cerebral Circulation Since decrease of cerebral blood flow results in a decrease in brain metabolism which in turn may lead to psychopathological manifestations. various methods have been tried to improve circulation in the central nervous system. 42 .59 Anticoagulants The use of anticoagulants is based on the assumption that at least some organic brain syndromes are caused by sclerosis combined with thrombosis or sludging in the arteries, veins and capillaries63 .69 Nevertheless, Walsh'si9.80 favorable therapeutic findings with bishydroxycoumarin were associated with severe adverse reactions, i.e. bleeding, in the course of treatment, and thromboembolic complications, following discontinuation of therapy. After Walsh's81 positive therapeutic findings, conflicting reports appeared and, at present there is considerable scepticism regarding the therapeutic application of anticoagulants in the treatment of the organic brain syndromes. 31.51.56.64 Vasodilators The use of vasodilators is based on the assumption that at least some of the organic brain syndromes are the result of insufficient blood supply of neurons which is caused by vasoconstriction and/or the sclerotic narrowing of cerebral vessels. However, vasodilating drugs such as papaverine, isoxsuprine, nicotinyl alcohol, by their lowering effect on blood pressure may produce a decrease instead of an increase in the blood supply of the cerebrum. 25 .511 In keeping with these findings are the results of clinical psychopharmacological studies in which papaverine-a non-narcotic alkaloid derivative of opium-was found to be practically ineffective in treating intellectual impairment in patients with chronic organic brain syndrome.ai.66.i2 The same applies to hydergine, a combination of three hydrogenated ergot alkaloids.i .22.28.30.i6 Nevertheless, while papaverine and hydergine have virtually no effect on intellectual impairment, there is increasing evidence that they improve behavior. Cyclandelate is the only Volume XVII
ORGANIC BRAIN SYNDROMES-BAN
vasodilator substance, which so far has been shown to improve mental functions in organic brain syndromes. I.~l; Until Heyck's"" demonstration that nicotiniC acid significantly increased cerebral blood flow in patients suffering from cerebral arteriosclerosis, there had been a controversy regarding the effect of nicotinic acid on cerebral circulation.'; Similarly, there had been a considerable difference of opinion as to whether nicotinic acid ctfects improvement in organic brain syndrome patients.;!:; In one clinical trial carried out at thc Douglas Hospital in Verdun, high dosages of nicotinic acid (3()()() I11g per day) significantly decreased anxiety and perceptual disorder of a psychotic nature in geriatric patients with an organic brain syndrome.:'~ Nevertheless. in a follow-up study the administration of nicotinic acid in the samc dosage remained entirely inelfective in a group of chronically hospitalized geriatric patients.:" Since patients were randomly chosen for this latter study, it was speculated that the results in a more homogenous geriatric population in respect to organicity might have provided different and possibly more favorable results. But even then, the question of whether the therapeutic effects of nicotinic acid are due to cerebral vasodilation or to the metabolic action of the substance has remained undecided to date.o; CAUSAL
Drugs for Substitution or Replacement Therapy Hormones It has been shown that androgens increase initiative, muscular strength and produce a feeling of well-being in the aging male. There is also at least one report in which androgen administration improved one particular category of memory function (i.e. recall of meaningful material), without an effect on the total memory score. 1Ii In another study, however, a number of patients on androgen (i.e. fluoxymesterone) treatment had to be terminated because of impending impairment of liver function. I:!.•" Needless to say, in women the administration of male sex hormones is limited by its masculinizing effect.:·"
Vitamins Vitamins (e.g. B I , B;;, Bo;, B)~, C) are extensively used in the treatment of patients with organic brain syndrome. Besides its vasodilating properties, nicotinic acid
A.
BAN,
M.D.
Part 11* Psychopharmacology There are three major therapeutic approaches in the pharmacological treatment of organic brain syndrome: symptomatic (by psychotropic drugs), palliative (by drugs with an effect on cerebral circulation) and causal (by substitution or replacement). Because of its increasing importance, pharmacotherapy in psychogeriatrics has become a special field in the clinical psychopharmacology of organic brain syndromes. SYMPTOMATIC
Psychotropic Drugs Treatment by psychotropic drugs in the organic hrain syndrome is essentially symptomatic. In other terms, it is directed toward the relief of psychopathological and behavioral manifestations that may accompany the organic disorder, without an apparent effect on the underlying disease (Table II). Hypnotics Insomnia or inverse sleep rhythm, with restlessness at night and sleepiness or drowsiness in the daytime, are commonly encountered in patients with an organic brain syndrome. For the symptomatic treatment of these sleep disturbances hypnotic drugs are usually employed. While there is no doubt that barbiturates decrease cerebral metabolism and thereby tend to increase agitation and confusion, especially in elderly organic brain syndrome patients, Stotsky and his collaborators report, ~I on the basis of a controlled study, that one of the slower acting barbiturates, sodium butabarbitat is both safe and effective in moderate doses for elderly patients with sleep disorders that are refractory to other hypnotics. Among the nonbarbiturate hypnotics, for some time chloral hydrate (a chloral derivative) and paraldehyde (a cyclic ether) were the most frequently used in organic brain syndrome patients. More recently, however, they have been increasingly replaced by glutethimide. methyprylon (both piperidinediones), ethchlorvynol, methylparafynol (both tertiary acetylenic alcohols), ethinamate (a carbon acid ester of alcohol) and methaqualone (a quinazolone)." Dr. Ban is Director, Division of Psychopharmacology, Department of Psychiatry, McGill University, Montreal, Quebec, Canada. "'Pa:·t I of this two part article appeared in the Second Quarter. 1976 issue. July August September. 1976
A nxiolytics For the symptomatic relief of anxiety, tension and restlessness in organic brain syndrome patients, anxiolytic drugs are used. Among the various anxiolytic preparations, benzodiazepines (i.e. chlordiazepoxide, diazepam and oxazepam), substituted diols (i.e. meprobamate and tybamate) and diphenylmethanes (i.e. hydroxyzine, diphenylhydramine and benactyzine) are the ones most frequently employed. While there is definite evidence that anxiolytic drugs are therapeutically more effective than inactive placebo preparations, comparative studies could not reveal any major difference among the anxiolytic drugs in their therapeutic effect on organic brain syndromeY"~' In view of the fact that administration of anxiolytic drugs may induce paradoxical behavioral reactions (i.e. an increa~e instead of a decrease of agitation, aggressiveness and irritability) as well as impairment of cognitive functions and ataxia, treatment with anxiolytics should always be initiated by using the lowest dosage form of the drug and it must be carried out with the utmost caution and care, especially when higher dosages are employed. A ntipsychotics In addition to their tranquilizing properties, antipsychotic drugs-or major tranquilizers-arc specifically indicated for the treatment of psychotic symptoms such as hallucinations, delusions and manneristic TABLE II Psychotropic drugs used in the treatment of organic brain syndromes. Pharmacological Group
Chemical Catcgory
Prototype Drug
Hypnotics
Barhiturates Nonbarbituratcs
Butaharbital Ethchlorvynol
A lI.rio/ytics
Benzodiazepines Substituted diols Diphenylmcthanes
Chlol'lliazepoxide Meprobamate Hypdroxyzinc
A ntipsYc!lOtic.\·
Phenothiazines Thioxanthencs Butyrophenones
Thioridazine Thiothixcne Halopcridol
Stim1I1a/lIs
Amphetamines
Dextroamphetamine
A IItidepressallls
Tricyclics MAOI's
Imipramine Phenelzine 131
PSYCHOSOMATICS
behavior in organic brain syndrome patients. Of the four commercially available antipsychotic categories, the usc of Rauwolfia alkaloids (e.g. reserpine) has virtually been abandoned, because of their hypotensive and mood depressant effects. While the two relatively newer classes of anti psychotics, i.e. butyrophenones (e.g. haloperidol) and thiothixanthenes (e.g. chlorprothixene and thiothixene) are increasingly used, the phenothiazines are still the most frequently prescribed antipsychotic drugs in organic brain syndromes. While there is no definitive evidence that cne phenothiazine is superior to another in the treatment of organic brain syndrome patients, there are indications that acetophenazine (a piperazine) and thioridazine (a piperidyl) are the ones most frequently employed.3i.6~ The major advantage of thioridazine is the relatively low incidence of extrapyramidal reactions, while the major disadvantage of this drug is the disproportionately high incidence of electrocardiographic abnormalities. 56 Since the administration of antipsychotic agents may yield to toxic confusional states in organic brain syndrome patients more often than in other diagnostic categories, treatment with antipsychotic drugs should always be initiated by using one of the lower dose forms.
Stimulants Chronic organic brain syndrome patients are frequently withdrawn, sluggish and inert. To overcome these behavioral manifestations, a variety of stimulant drugs have been proposed, e.g. caffeine. Amphetamines and methylphenidate are powerful stimulants but they may produce anxiety, with or without agitation, and/or effects on the autonomic nervous system. Psychotic, perceptual and conceptual disorganization, if present, may be increased, or if not present, may be induced. The claims for the therapeutic effects of deanol, ethamivan and glumatic acid (a stimulant of cerebral metabolism) have not been substantiated. On the other hand, pentetrazol produced significant improvement in unusual thought content, irritability and disturbance of consciousness, with a trend towards improvement in psychometric and memory test performance, at least in one clinical report. 48 The same applies to pipradrol, another central nervous system stimulant which in high (5 mg daily)-but not in low (2 mg daily)-doses, produced significant improvement of "ward behavior".ii Antidepressants A great number of tricyclic antidepressants have been tried and found effective in the treatment of depression in organic brain syndrome patients.43.51.55 Because of their hypotensive effect, all commercially available tricyclic antidepressants should be used with caution in patients with a clinical hi:;tory of circulatory, e.g. coronary insufficiency, or with electrocardiographic abnormalities. Furthermore, because of their distinct 132
anticholingeric properties, extreme caution should be exercised when they are prescribed for patients with prostatic enlargement and/or glaucoma. Since the administration of tricyclic antidepressants may elicit a toxic confusional state in organic brain syndrome patients more often than in other diagnostic categories, treatment with tricyclic antidepressants should always be initiated by using one of the lower dose forms. Side effects and complications are more common with monoamine oxidase inhibitors (MAOI) than with tricyclic antidepressants. Because of this, MAOI's should only be employed when treatment with tricyclic antidepressants has failed. 49 PALLIATIVE
Drugs Influencing Cerebral Circulation Since decrease of cerebral blood flow results in a decrease in brain metabolism which in turn may lead to psychopathological manifestations. various methods have been tried to improve circulation in the central nervous system. 42 .59 Anticoagulants The use of anticoagulants is based on the assumption that at least some organic brain syndromes are caused by sclerosis combined with thrombosis or sludging in the arteries, veins and capillaries63 .69 Nevertheless, Walsh'si9.80 favorable therapeutic findings with bishydroxycoumarin were associated with severe adverse reactions, i.e. bleeding, in the course of treatment, and thromboembolic complications, following discontinuation of therapy. After Walsh's81 positive therapeutic findings, conflicting reports appeared and, at present there is considerable scepticism regarding the therapeutic application of anticoagulants in the treatment of the organic brain syndromes. 31.51.56.64 Vasodilators The use of vasodilators is based on the assumption that at least some of the organic brain syndromes are the result of insufficient blood supply of neurons which is caused by vasoconstriction and/or the sclerotic narrowing of cerebral vessels. However, vasodilating drugs such as papaverine, isoxsuprine, nicotinyl alcohol, by their lowering effect on blood pressure may produce a decrease instead of an increase in the blood supply of the cerebrum. 25 .511 In keeping with these findings are the results of clinical psychopharmacological studies in which papaverine-a non-narcotic alkaloid derivative of opium-was found to be practically ineffective in treating intellectual impairment in patients with chronic organic brain syndrome.ai.66.i2 The same applies to hydergine, a combination of three hydrogenated ergot alkaloids.i .22.28.30.i6 Nevertheless, while papaverine and hydergine have virtually no effect on intellectual impairment, there is increasing evidence that they improve behavior. Cyclandelate is the only Volume XVII
ORGANIC BRAIN SYNDROMES-BAN
vasodilator substance, which so far has been shown to improve mental functions in organic brain syndromes. I.~l; Until Heyck's"" demonstration that nicotiniC acid significantly increased cerebral blood flow in patients suffering from cerebral arteriosclerosis, there had been a controversy regarding the effect of nicotinic acid on cerebral circulation.'; Similarly, there had been a considerable difference of opinion as to whether nicotinic acid ctfects improvement in organic brain syndrome patients.;!:; In one clinical trial carried out at thc Douglas Hospital in Verdun, high dosages of nicotinic acid (3()()() I11g per day) significantly decreased anxiety and perceptual disorder of a psychotic nature in geriatric patients with an organic brain syndrome.:'~ Nevertheless. in a follow-up study the administration of nicotinic acid in the samc dosage remained entirely inelfective in a group of chronically hospitalized geriatric patients.:" Since patients were randomly chosen for this latter study, it was speculated that the results in a more homogenous geriatric population in respect to organicity might have provided different and possibly more favorable results. But even then, the question of whether the therapeutic effects of nicotinic acid are due to cerebral vasodilation or to the metabolic action of the substance has remained undecided to date.o; CAUSAL
Drugs for Substitution or Replacement Therapy Hormones It has been shown that androgens increase initiative, muscular strength and produce a feeling of well-being in the aging male. There is also at least one report in which androgen administration improved one particular category of memory function (i.e. recall of meaningful material), without an effect on the total memory score. 1Ii In another study, however, a number of patients on androgen (i.e. fluoxymesterone) treatment had to be terminated because of impending impairment of liver function. I:!.•" Needless to say, in women the administration of male sex hormones is limited by its masculinizing effect.:·"
Vitamins Vitamins (e.g. B I , B;;, Bo;, B)~, C) are extensively used in the treatment of patients with organic brain syndrome. Besides its vasodilating properties, nicotinic acid
