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Indian J Physiol Phannacol 1994; 38(4) : 241-251

RE\llEW ARTICLE

DRUGS INFLUENCING COGNITIVE FUNCTION

ALICE KURUYILLA* AND YASUNDARA DEYI

Department ofPharmacology. Christian Medical College. Vellore - 632 002

DRUGS INFLUENCING COGNITIVE FUNCTION cerebrovascular disorders with and reversible dementias. Drugs can inOuence cognitive function in several different ways. The cognitrve enhancers or Primary degenerative disorders include the have become a major issue in development during subgroups senile of the Alzheimer's type the last decade. Nootropics arc defined as drugs that (SDAT), Alzheimer's disease, Picks disease and generally increase neuron metabolic activity, improve Huntington's chorea (4). Alzheimer's disease usually cognitive and ,'igilance level and are said to have occurs in individuals past 70 years old and appears to antidemcntia effect (I). These drugs are essential for be in part genetically determin'd (5). the treatment of geriatric disorders like Alzheimer's which have become one of the major problems socially Pathophysiology oj Alzheimer's disease : and medically. Considerable evidence has been gathered Extensive research in the recent years has made major in the last decade to support the observation that advances in understanding the pathogenesis of children with epilepsy have morc learning difficulties Alzheimer's disease (6). The hallmark lesions of than age matched controls (2, 3). Anti-epileptic drugs Alzheimer's disease are neuritic plaques and are useful in controlling the frequency and duration of neurofibrillary tangles. Two amyloid proteins seizures. These drugs can also be the source of side accumulate in Alzheimer's disease, these arc beta effects including cognitive impairment. Since ]975, amyloid protein and paired helical filament protein (7). greater has been given to assess the cognitive Based on the amyloidoses associated with other effects of anti-epileptic drugs. By learning more about diseases, three mechanisms for amyloid formation cognitive effects of anti-epileptic drugs, patients can have emerged. One mechanism involves posllransitional be offered optimal therapy combining excellent seizure event which render a normal protein amyloidogenic. control with the least possible negative impact on Proteolysis, phosphorylation, glycosyiation and intellectual functioning. This review is an update on transglutamination may be the relevant, informatiOn on drugs which can improve cognitive posttranslational events in Alzheimer's disease, another function as well as those which may produce cognitive mechanism for amyloid formation results from dysfuction. expressiol1 of an abnormal gene which in the case of familial Alzheimer's disease may be an rmportant Diseases associated with cognitive impairment: etiological component. A third mechanism involves the Dementia is characterised by decline in memory, accumulatiol1 of a normal protein to a threshold thinking and emotional functions. In the descriptive concentration that spontaneously forms amyloid. diagnosis of dementia disorders, different aspects arc These mechanisms of amyloid formation can becom mentioned; benign senile forgetfulness, primary targets for drug therapy. The number of neuritic plaques degenerative disorders, secondary dementias, and neurofibrillary tangles arc positively correlated to

*CorrcsponJing AUlhor 242 Kuruvilla and Devi Indian J Physiot Pharmacol 1994; 38(4) the severity of clinical symptoms and cognitive studied in rats and mice by various workers. Passive impairment. avoidance with punishment reinforcement termed as step-through method, and two-way active avoidance Neurochemical and neuroendocrine disturbances with punishment reinforcement known as 'shuule-box' of Alzheimer's and SDAT have been described by are reponed as useful methods of testing for learning various workers. Olney reported that there is deficiency and memory. in these animals (15). Various test drugs of the neurotransmitter (8). Autopsy have been used in experimental studies to observe their studies have suggested that neurons are effects on learning and memory. These include selectively lost in these disorders. Cerebrospinal fluid nootropics such as j1iracetam, fipexide, , concentration of acety.lcholine showed good correlation , , citicholine, , with the degree of cognitive impairment (r = 0.7) in a standardised ginseng extract, cholinomimetic sample of carefully diagnosed patients; but metabolites compounds like , , of other neurotransmitters were not related to cognitive inhibitors such as taerine, amiridin, state. This suggest that CSF Ach may be a valid physostigmine and drugs inOuencing monoaminergic measure of cholinergic; degeneration (9). Reduction of neurotransmitter such as MAO inhibitors and 5-HT acetyltransferase activity, a cholinergic marker uptake blockers. has been significantly correlated to the severity of dementia (10). Agnoli et al (11) also observed a Age related changes on learning ana memory correlation among the degree of memory loss, has been observed by Burov et al (16). 18 months old intellectual impairment, the quantity of senile plaques, rats showed much less learning abiliLy in comparison and a decrease in choline acetyltransferase and wiLh that of 3 months old rats. 20 days treatment of acetylcholinesterase activity in patients affected by old rats with amiridin. lacrine and piraceLam improved senile dementia of the Alzheimer's type. latency in passive avoidance test to the level of 3 months old rats. Mondadori et al (17) also studied the The monoaminergic neurotransmission deficit effects of new compound on age-related cognitive seen in dementia of the Alzheimer's type (DAT) is dysfunctions in rats using one way active avoidance linked to a known increased activity of type B cerebral situation. Petkov et al (18) used rats of age varying monoamine oxidase (12). Drugs that can b'lock this from 2 to 22 months in experiments using active abnormal activity have been found to be useful in the avoidance with punishment reinforcement (maze and treatment of some cognitive delicits. Postmortem human shuttle-box and passive avoidance (step-down) to brain studies have shown a disturbed of observe age related differences in memory. On their serotonin and overactivity of neuroendocrine controlling factors in the hypothalamus (13). Somatostatin is study the nootropics adafenoxate, meclofenoxate, consistently diminished in brains of patients with citicholine, aniracetam and the standardised ginseng Alzheimer's disease (14). Cortisol dysregulation may extract administered orally for 7-lO days usuaUy be a marker for abnormalities in other neurotransmitter facilitated learning and improved memory in the nUs systems, particularly the noradrenergic system. of all ages. Old rats showed pronounced favourable Aetiological factors associated with Alzheimer's disease effects by some of the indices. The biochemical changes arc genetic factors, aluminium or other toxic factors, observed with aging are d.ecrease in the activity of immunological disturbances, disturbed glucose acetylcholinesterase, reduction of unsaturated fatty metabolism, deficiency of essential nutrients and stress. acids, the increase of content and the increase of microviscosily of membranes of brain A1\L\IALS l\IODELS FOR LABORATORY EVALUATION synaptosomes. Mult,iple treatment with amiridin, OF COG1\ITIVE FCNCTION and tacrine normalised these indices. A. Learning and memory Scopolamine impaire i TTJcmory has been used The changes in learning and memory has been, by Petkov et al (19) to detemlme drug effects. In these Indian J Physiol Phannacol 1994; 38(4) Drugs Influencing Cognitive Function 243

experiments scopolamine (2 mg/kg, ip) was used and has been used by Lazarova, Bakarova and step-through passive avoidance method was used to co-workers (23) to observe the inOucnce of nootropics determine the memory changes. Test drugs were given Uke piracetam, aniracetam, mcclofenoxate and fipcxide. for 7 days before training or immediately after training. The changes ·in learning and memory were studied by The test drugs adafenoxate, meclofenoxate, piracetam two way active avoidance with punishment and citicholine prevented the scopolamine induced reinforcement (shuttle-box). Clonicline injected retrograde amnesia partially or completely. Lenegre et intraperitoneally at a dose of 0.1 mg/kg immediately al (20) used scopolamine, diazepam and after a one-day shuttle box training significantly electroconvulsive shock to produce amnesia in mice impaired retention. A 5-day treatment before the with passive avoidance procedure. Amnesia was training session with test drugs completely abolished induced by injecting scopolamine or diazepam (l mg/ the memory-impairing effect of clonidine. Sharma and kg, ip), 30 min before the passive avoidance task. Kulkarni (24) have used elevated plus-maze as the Electroconvulsive shock is applied immediately after method to evaluate learning and memory mechanisms the first session of the passive avoidance task for in rats and mice. Transfer-latency (TL) was used as a producing amnesia. Pintcetam when administered in parameter for acquisition and retention of memory varying doses 60 min before first session attenuated process on elevated plus-maze in rats and mice. the memory deficits induced by the three amnesic Shorwned TL on 2nd day trial in old rats and mice as treatments but did not affect either sco[X)lamine induced a parameter for retention or consolidation of memory hyperactivity, diazepam-induced release of punished was reduced by nootropics. The drugs producing behaviour or ECS induced convulsions. These results acquisition deficits like scopolamine does not show point to the specificity of piracetam's anti-amnesic any effect on the reten lion parameter like the shortened activity and suggest that piracetam can suppress the transfer latency. memory disturbances without inOuencing actions of diazepam. Exposure to pre and postnatally is known to influence learning and memory (25). Using Potassium ethylxanthogenate, the inhibitor of conditioned-reOex meti;ods for active and passive dopamine-beta hydroxylase, has been used by some avoidance with punishment reinforcement, memory workers (21) to induce changes in learning and memory. deficit was noted in 12 week old rats exposed This compound when injected intraperitoneal'ly in a perinataHy to alcohol. The nootropics piracetam and dose of 100 mg/kg, markedly impaired learning and meclofenoxate administered orally for 5 days before memory by the active conditional avoidance method the training session were effective in decreasing with negative reinforcement (shuttle-box) and the memory deficits. passive avoidance method (step-down). Piracetam, aniracetam, meclofenoxate and fipexide adlninistered Hypoxia is another stimulus which induces orally five days before step-down training, completely deficits in learning. Behavioural studies with linopirdine prevented the impairing effect of potassium have shown that it enhances acquisition of active ethylxanthogente on the cognitive processes. avoidance and protects against hypoxia induced deficits of passive avoidance in rals. Acquisition of lever Voronina et al (22) reported on the anti-amnestic pressing for food in native rats is another behavioural action of using experimental methods based model. Linopirdine is reponed to enhance performance on passive avoidance responses. Amnesia was induced motivated by foot shock or food as well as behaviour by maximal electroshock and scopolamine in mice and involving active or passive responding (26). The by paradoxical in rats. In this study behaviouraI activities of piracetam and oxiracet2m were nicergoline demonstrated well-expressed anti-amnestic studied during the learning tests active avoidance, effect as compared to reference drugs like piracetam passive avoidances, and T-maize. The levels of the and meclofenoxate. Memory-impairing effect of orientation reaction and emolionality of the animals 244 Kuruvilla and Devi Indian J Physiol Pharmacot1994; 38(4)

were determined by the "openfield method. Both (amyloid precursor protein) promoter to express the nootropics facilitated the learning of the animals, but B/A4 domain of human APP in transgenic mice (6). failed to change their behaviour in the open field. Transgenic models of cerebral B/A4 amyloidosis should provide powerful tools for assessing the role of B/A4 Animal models for testing antidementia effect in Alzheimer's disease. specifically: Basal forebrain lesioned rat is one of the widely used animal models for the study of learning Biochemical studies: In vitro on the effects of impairment (27). Stereotoxic injection of iboteinic acid drugs like amiridin, tacrine, physostigmine and into the basal forebrain produces marked decrease of piracetarn were tested on monoamine oxidase A and B acetyl'choline as well as cholineacetyl transferase and activity in the rat brain. Piracetam increased MAO-A acetylcholinesterase activities. Choljneacetyl transferase and MAO-B activity dose dependently (29). Piracetam levels are reported to be decreased after 7 days and also had a potential action in scavenging free radicals. may return to control values (87%) after 12 weeks. This antioxidation effect may be related to its clinical Significant neuronal loss and diminution of size of effects on amnesia and Alzheimer's disease (30), neurons and decrease of Ache activity are noted in Cholinomimetic and anticholinesterase activity of these chronic basal forebrain lesioned rats. However, various compounds have been tested in vivo and in neurofibrillary tangles or neuritic plaqlles are not vitro to determine their effects. Long lasting inhibition observed. of the metabolism of acetylcholine has been attributed to the pharmacological effects of tacrine (31). Learning impairment of the basal forebrain Cholinergic muscarnic binding capacity of peripheral lesioned rats are evaluated by passive avoidance lymphocytes of patients with senile dementia of response. Post-training of basal forebrain lesioned rats the Alzheimer's type exhibited a marked reduction in ~cquired caus s rapid extinction at pasyivc avoidance binding capacity. Treatment of these patients with respon e (27). Acquisition and retention of learning antimuscarinic drugs was associated with increased can be measured using passive avoidance test. muscarinic binding by peripheral blood lymphocytes. Aniracetam given in as dose of 50 mg/kg one hour These results indicate that cholinergic muscarinic hefore the trial has been reported to show an increase binding by peripheral blood lymphocytes may be useful in the percentage of conditioned active avoidance in the study of sensilc dementia of the Alzheimer's responses and a reduction of the latency times (28). type as well as in evaluating changes induced by certain This improvement in behavioural performance has been cholinergic drug treatments. Rat brain slices have been correlated with biochemical studies involving activation used to study drug effects. Stimulus induced release of transducing systems in brain such as acetylcholine have been used to study drug effects. Stimulus induced release and inositol phosphate production in cortical release (K+ st,imulated release) of Ach is useful for the synaptosomcs. study of drug effects. Receptor binding studies with linopirdine have shown a unique receptor to which it Another recent development is related to the advance in technology associated with genetic has a specific and exclusive affinity. These receptors engineering. Transgenic mice mimicing Alzheimer's are regionally distributed in the same areas as in pathology have been considered as u suitable model. Alzheimer's. Correlation has been shown between The germ-line DNA of mice can be manipulated in binding and functional effect of stimulus induced such a way that the abnormal gene is incorporated in release of Ach. the DNA sequence. The injected DNA becomes Relationship of steroids to the memory enhancing integrated into the mou e chromosomal DNA on a effects of noolropics and cholinomimetics has been fraction of the injected cells. These animals can be studied in mice by Mondnclori et al (32). Elevated used to breed and to obtain transgenic or mutant mous steroid levels suppress the memory enhancing effects strains. Unterbeck and colleagues used the APP of these agenLs. Hausler et al (33) also observed that Indian J Physiol Phannacol 1994; 38(4) Drugs Influencing Cognitive Function 245 adrenalectomy blocks the memory-improving effect of DRUG THERAPY IN ALZHEfMER'S DISEASE piraceUlm like compounds in mice. These effects were overcome by replacement with corticosterone or Drugs may be part of the treatment for aldosterone given in the drinking fluid. Amnestic Alzheimer's disease. Drug treatment can be divided syndrome associated w,ith multiple injections of into two categories, treatment to improve (i) cognitive scopolamine resulted in significant deterioration of rats function (ii) abnormal behaviours. There are atlcast 16 performance in pa,ssive avoidance test. Behavioural new drugs undergoing evaluation that may improve disorders were accompanied by changes in lipid cognitive function. Some of these drugs are intended composition of brain synaptosomes which indicated a to augment function of the neurotransmitter decreased membrane fluidity. Amiridin and tacrine as acetylcholine. Others are nootropics that improve weB as piracetam showed antiamnestic action which neuronal function. Drugs which may influence the correlated with their normalising effect on Ilipid content behaviour in Alzheimer's disease include neuroleptics, of synaptosomes. Electroencephalographic studies have and antinlge drugs. Another category of been done in rats to observe the effect of nootropics. drugs useful in this disease state are those drugs that Linopirdine is reported to increase relative power in modify other defects such as blood supply to brain 0). beta waves and decrease relative power in slow waves, thus demonstrating a vigilance pallern. DRUGS IMPROVING CHOLINERGIC FUNCTION

STUDIES IN HUMAN SUBJECTS ON LEARNING AND Attempts at pharmacotherapy have been directed MEMORY towards the enhancement of cholinergic function wiulin the central . Cholinesterase inhibitors Psychometric tests and EEG have been done in such as physostigmine salicylate, tacrine, amiridin have elderly patients to test the effect of oxiracetam and been used. They are effective in the treatment of piracetanl. In one study (34) on 2 subgroups of patient,> cognitive deficits and memory loss associated with with Alzheimer's dis ase, piracetam produced a senile dementia of the Alzheimer's type (39, 40). decrease in EEG power and improvement in some Patients with Alzheimt:r's disease are known to have psychomelIic tests. EEG spectral analysis showed good decreased cell membrane protein-protein interactions. correlation with improvement in some psychometric Tacrine reverses this cell membrane defect at least in tests. Studies can be done in human volunteers to test erythrocytes. Tacrine may have a wicler inOuence on the effects of drugs on memory. Two major classes of brain function than just as a cholinesterase inhibitor. studies have been conducted in human subjects; the Velnacrine, a cholinesterase inhibitor and a metabolite first is analogous to that dealing with animals and of tacrine increased the word and object recognition utilises nonverbal material, while the second is memory and regional cerebral blood flow in patients concerned with verbal learning. Nonverbal learning may with Alzheimer's disease (41). Another drug treatment be exemplified by eye-lid and galvanic skin response strategy is to increase acetylcholine precursors in an and salivary conditioning. Another nonverbal form of effort to increase acetylcholine production (42). It may human learning is found in the development of motor be useful as an adjunct with other drugs. Acetylcholine skills such as tracking on a pursuit rotor or aULOIl1obile­ releasers exemplified by linopirdine (Dup 996) and driving (35). Weiss and Laties (36) have reviewed agents which act as at the various muscarinic studies reporting enhancement of human performance subtypes as exemplified by FKS-508 appear to enhance by and . Danian and co-workers cognitive function in animal models. (37) have used verbal tests such as free- task, word-completion task and a puzzle test to study the 1\OOTROPICS effect of and on explicit The mechanism by which the nootropics affect memory. Effects of has been tested using memory is not known and most of them stimulate recaB and information processing in verbal and spatial phospholipid turnover and protein synthesis and learning by Mungas and co-workers (38). 246 Kuruvilla and Devi Indian J Physiol Phannacol1994; 38(4) enhance cholinergic nel'Jrotransmission. Piracetam a Oxazepam is safer than the long acting benzodiazepines in .combination with acetylcholine precursors in the treatment of behavioural disturbances in geriatric, (Eg ) may have some benefit in a subgroup of psychogeriatric and demented patients (55). pa.tients with Alzheimer's disease, particularly the group wIth some quantity of remaining functional Antirage drugs- hydrochloride has usefu~ acetylcholine neurons (43). On long term administration been in treating rage and violent behaviour in in high doses piracetam may slow the progression of demented patients (56, 57). has been cognitive deterioration in patients with Alzheimer's used successfully to treat agitation in dementia (58). disease (44). Oxiracetam has been used with success Patients with manic episodes may especially benef}t in patients with primary degenerative, multi-infarct or from the addition of carbamazepine to haloperidol mixed dementia (45,46). Aniracetam, a new nootropic treatment (59). There are also case reports of successful drug has also been effective in the treatment of dementia treatment of aggressive agitations in dementia using of Alzheimer's type. the serotonin reuptake blocker hydrochloride (60). VASCULAR SYSTEM CLINICAL S'l'UDIES The most widely used specific drug treatment for dementia is a compound of ergoloid mesylates (Eg. Clinical studies involving phase III programme Hydergine). They decrease vascular resistance and has been undertaken for llinopirdine (Dup 996). E 2020, ~hereby increase cerebral blood flow (47, 48). They a new cholinesterase. inhibitor with a novel chemical increase alertness. Another ergot drug, nicergoline structure has undergone pharmacokinehic study in produced an improvement in disorientation in 30% of healthy human subjects. It is generally well tolerated treated patients (49). Capwpril, which is an angiotensin and the pharmacokinetic data suggests dosage regimen of 2 mg once a day. Galanthamine, which is a converting enzyme inhibitor :113y be of use in the treatment of Alzheimer's disease in improving the cholinesterase inhibitor was found to bring a positive cognitive function (1). change in competence of everyday routine and in the emotional situation in patients with Alzheimer's disease MISCELLANEOUS NEUROACTIVE DRUGS (61). Glebs et al (62) demonstrated the use of huperzine­ A, a potent acetylcholinesterase inhibitor in the Attempts have been made to increase other treatment of Alzheimer's disease. Oral physostigmine, central neurotransmitters. The most successful has been a chohnesterase inhibitor and lecithin, a choline the use of selegiline (L-deprenyl), a MAO-B inhibitor containing phospholipid has been tried in patients with which increased brain serotonin and nor-epinephrine Alzheimer's disease (63). Peak improvement was (50,51). Sunderland et al (52) focussed on the concept observed with doses of 2 to 2.5 mg. An inverted U­ of combination of as a therapeutic shaped dQse response curve has been found during strategy. Combination of physostigmine and L-deprenyl treatment with intravenous physostigmine for memory have been reported to be more beneficial than either impairment, suggesting a narrow therapeutic window agent alone because of the additive effect of these two response to this drug. Long term continuous infusion drugs (53). of the muscarinic cholinergic arecholine DRUGS AFFECTING BEHAVIOUR improves the verbal memory in dementia of the Alzheimer's type (64). N- (n-propyl) - N- (4-Pyridinyl) These are. grouped into three categories I H-indol-l- hydrochloride (HP-749, 1) a non­ neuroleptics, anxiolytics and antirage drugs. receptor dependent cholinergic agent has been tested Neuroleptics that are useful in the treatmeht of patients for the treatment of Alzhemier's disease (65). Nor­ with dementia are haloperidol, thlOthixene intervention alone is unlikely to be effective hydrochloride (54). Anxiotytics chiefly, in Alzheimer's disease (66). A novel compound HP benzodiazepines may be useful in treating agitation. 128 which manifests adrenergic and cholinergic Indian J Physio! Phannaco!1994; 38(4) Drugs Influencing Cognitive Function 247 properties has undergone clinical trials and found to mecobalamin, fo~ic acid, thiamine, acetyl-L-carnitine the safe and well tolerated in patients with Alzheimer's are still in progress (70, 73, 74, 75). disease. It needs further evaluation for its use (67). Clinical trials with chofinergic agents suggests that , a calcium has been cholinergic hypertrophy may be beneficial in the tested (76) and is known to affect primarily brain treatment of Alzheimer's disease. Recent findings vasculature. It increases cerebral blood flow and reduces substantiate the view that nerve growth factor (NGF) focal ischaemia (77). Memory related intraneuronal selectively acts on cholinergic neurons. In animal mechanisms are affected by calcium activated enzymes. studies it has been proved that nerve growth factor Aging or dementia may result in dangerously high produces trophic actions on cholinergic neurons and inlraneuronal calcium levels. Calcium ions are prevents age-related neuronal atrophy suggesting the especially toxic to hypoxic neurons. Hence, calcium possibility of the eventual development of channel blockers may be helpful by blocking calcium pharmacological application of nerve growtn factor fOI" entry into injured or hypoxic neurons (78). the treatment of Alzheimer's disease (68). hydrochloride which has more activity at the cellular levyl and less vascular effect may also be useful in Phase I studies have been undertaken by Allain patients with early dementia of Alzheimer's type (79). et al (69) using (ZY 15119) in the elderly Immune mediated autodestructive processes may occur patients. This compound is reported to act preferentially in Alzheimer's disease and hence exploration of the on memory process. The tolerability of this drug has effectiveness of anti-inflammatory agents may be been tested in young healthy volunteers in phase I warranted (80). Potassium-channel blockers such as 4­ studies using increasing doses of 400, 800 and 1600 aminopyridine, DGAVP Citrate (Drg 5667) a mg. In a randomizedl, double blind trial in elderly related peptide and D-cycloserin-c have been patients with mild to moderate cognitive impairment considered for treatment of Alzheimer's disease but for a period of 9 weeks, improvement has been reported the results are inconclusive (81, 82, 83). in subgroups of patients classified as primary degenerative dementia. Pharmacokinelic sludlies have Of the various categories of drugs used to been done on ccbaracclam in heallhy, female volunteers improve cognitive functions, anticholinesterses, (69). It was well tolerated in both acule and chronic nootropics and blockers seem to hold administration and half life after a single dose in about the most promise. Alzheimer's disease is a progressive 16 hours. The cognitive enhancing effects of degenerative dementia and no so far is , a nootropic drug in animal models of predicted to reverse its course. Because Alzheimer's learning and memory are characterised by an inverted diseaseinvolves multiple defects, multi-drug treatment U-shaped dose response curve. The anti-dementia effect regimens may offer the best chance for effective therapy of this drug has been evaluated in patients with (84). In conclusion, we can hope to achieve beneficial Alzheimer's disease but the results are inconclusive. therapy for Alzheimer's disease and senile dementia within this decade by using drugs which have specific The selective 5-hydroxytryptamine re-uptake effects on cognitive functions. blocker, citalopram has proven effective in reducing DRUGS PRODUCING COGNITIVE DYSFUNClION overactivity on the hypothalam(c-pituitary-adrenal axis and in improving emotional disturbances in patients In the past 15 years, a number of clinical studies with dementia (70). It produces a significant have evaluated the effect of antiepileptic drugs on improvement in emotional bluntness, confusion, cognitive performance (85). Because of its irritability, anx,iety, fear, panic, depressed mood and properties, has long been cited for its no improvement in psychomotor and cognitive potential cognitive effects. In an epidemiological survey bctlaviour. This drug is considered as an emotional of drug reactions with antiepileptic therpay, we have , stabilizer (71, 72). Treatment trials with B12 observed spontaneous reporting by patients about 248 KuruviLla and Devi Indian J Physiol Pharmacol1994; 38(4) cognitive difficulties such as forgetfulness, loss of Carbamazepine may have some adverse effects on task memory, loss of concentration (86). The highest performance although impairment is less with incidence (4-6%) of such reactions is reponed by carbamazcpine than with or phenobarbital. patients receiving phenobarbitone. Phenytoin sodium has shown no effect on learning tasks when also produce similar effects, but incidence is lower. added to preexisting therapy and produced minimal Camfield and Camfield (87) studied the nature of adverse effects on psychological tests. Selection of the phenobarbital induced effects on in otherwise, drug, monotherapy, optimal dosage and withdrawal at healLhy children presenting with febrile seizures. the right time are factors which can have an impact on Memory and concentration scores decreased as drug cognitive dysfunction. levels increased in phenobarbital treated patients. From their study, these authors concluded that phenobarbital Psychopharmacological agents such as has potential for long term cognitive and behavioural benzodiazepines, lithium, tricyclic are effects. Phenytoin, carbamazepii1e, sodium valproate known to inOuence learning and memory. Recently a and clobazam have been studied for cognitive effects. growing number of anecdotal reports have indicated Phenytoin affects performance on neuropsychological that triazolam, a short acting benzodiazepine tend to tests of problem solving and visuomotor tasks. Ability cause anterograde amnesia (88). Some detrimental to pay attention is also impaired. Impairment especially effects on selective attentional functioning have been in motor or timed ac;tivities is greater when blood levels observed after triazolam. Another category of drugs are in the upper levels of the therapeutic range. which may impair memory are steroids (89).

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