Clinical manifestations

Presentation and course

	• A characteristic feature of drug-induced amnesia is temporal association with the drugs.
	• Drug-induced memory disturbances are usually benign and clear up after discontinuation of the offending medication.

There are no characteristic features of drug-induced amnesia except temporal association with the drugs. As examples, some amnesic states associated with the benzodiazepines are:

Triazolam. Most reported amnesic states concern the use of triazolam.

Traveler amnesia. This is a transient global amnesia secondary to triazolam. In addition to anterograde amnesia there is amnesic complex automatism, during which the subjects can perform complicated tasks without errors but have no recollection of having done so afterwards. Some individuals have negotiated and signed complicated agreements after the use of triazolam and had no recollection of the events afterwards.

Triazolam syndrome in the elderly. This syndrome is characterized by reversible delirium, anterograde amnesia, and automatic movements that are causally associated with triazolam used as a hypnotic.

An application of triazolam-induced amnesia is its use as a premedication for surgical patients who wish to have no memory of the operating room (24).

Lorazepam. This is an intermediate-acting benzodiazepine used intravenously to induce preoperative anterograde amnesia. Studies in human volunteers have shown that lorazepam produces dose-related deficits in verbal secondary memory as well as impairment of information acquisition and recall. Memory impairment with lorazepam is independent of increased sedation. In contrast to deficits in episodic memory with sedatives, no lorazepam-induced impairments on tests of semantic memory have been reported.

Midazolam. Midazolam is a benzodiazepine with antianxiety and sedative effects. Because of rapid onset and short duration of action, it is commonly used in diagnostic and therapeutic procedures to create anterograde amnesia, which prevents undesirable memory of the procedure that is painful for the patient. An experimental study has shown that midazolam-induced amnesia reduces memory for details and affects the event-related potentials as correlates of recollection and familiarity (34). An oral dose of midazolam 0.5 to 0.6 mg/kg or intranasal dose of 0.2 mg/kg is acceptable for use in children undergoing voiding cystourethrography for diagnosis and grading of vesicoureteral reflux, which is a very painful and distressing experience (01).

Diazepam. This is an anxiolytic benzodiazepine. Acute administration of diazepam can produce anterograde amnesia of both verbal and visual information. Intravenous diazepam impairs free recall significantly in a dose-dependent manner.

Prognosis and complications

Drug-induced memory disturbances are usually benign and clear up after discontinuation of the offending medication. Patients recover from anterograde amnesia induced by drugs for relieving pain and anxiety of various procedures, and the memory loss is limited to that of the painful procedure. Permanent memory impairment may occur in patients with structural damage to the brain, particularly in the hippocampus region. Prognosis depends on the accompanying cognitive disturbances.

Biological basis

Etiology and pathogenesis

	• Several drugs and pathomechanisms are involved in drug-induced memory impairment.
	• Benzodiazepines and anticholinergic drugs are the most common offending agents.
	• Anticholinergic drugs target the forebrain cholinergic system, which plays an important role in memory.
	• Drugs affecting the hippocampus impair memory.

Table 1 shows categories of drugs that are reported to be associated with memory impairment.

Table 1. Drugs and Other Substances Reported to Impair Memory

• Alcohol
• Analgesics
	- dexmedetomidine infusions (alfa2 agonist) - nonsteroidal anti-inflammatory drugs: ibuprofen, naproxen - opioids
• Anesthesia
	- halothane - ketamine
• Antineoplastic agents
	- cytokines - intrathecal chemotherapy
• Anticholinergic drugs
• Antidepressants
	- selective serotonin reuptake inhibitors - tricyclic antidepressants
• Antiepileptic drugs
	- gabapentin (also used for treatment of neuropathic pain) - lamotrigine - levetiracetam - pregabalin (also used for treatment of neuropathic pain) - topiramate - valproic acid
• Antiparkinsonian drugs
• Antipsychotics
- aripiprazole - chlorpromazine - clozapine - haloperidol
• Benzodiazepines
	- alprazolam - clorazepate - diazepam - lorazepam - triazolam
• Beta-blockers and similar drugs
	- atenolol - propafenone
• Ciclosporin
• Corticosteroids
• Drug abuse
	- amphetamine dependence - marijuana smoking - MDMA (ecstasy)
• Ergot compounds
• Dopaminergic drugs
• Gap junction blockers
• Gonadotrophic-releasing hormone agonist
• Hypnotics:
	- barbiturates - zolpidem
• Immunosuppressive drugs
	- sirolimus - tacrolimus
• Isotretinoin
• Lithium
• Mefloquine
• Oxytocin
• Radiological contrast media
- Iohexol for cerebral angiography - cardiac and peripheral arteriography with nonionic contrast medium
• Statins
• Sildenafil
• Sibutramine
• Sodium oxybate
• Industrial chemicals
	- toluene
Source: (25)

Alcohol. Neurocognitive deficits, including memory impairment, resulting from chronic alcoholism are well known. This may be due to direct toxic effect of alcohol on the brain as well as other predisposing factors associated with chronic alcoholism. Episodic memory is severely affected in Korsakoff syndrome.

Analgesics. Various forms of cognitive dysfunction, eg, memory deficit and an inability to concentrate, have been associated with nonsteroidal antiinflammatory drug use in retrospective studies involving ibuprofen and naproxen.

Both pain and opioid analgesics affect the central nervous system, and there is contradictory evidence concerning the effects of opioid analgesics on cognitive performance including memory. Studies of long-term opioid use in patients with chronic noncancer pain have found such treatment to improve cognitive function, whereas others have found that it is impaired. A pilot study that has controlled for the use of long-term opioids while measuring cognitive performance in patients with chronic low back pain found that patients receiving long-term opioid analgesics have minor differences from those not taking opioids (38). A systematic review and metaanalysis of studies of neuropsychological effects of long-term use of opioids in patients with chronic noncancer pain concluded that opioids reduce attention when compared with treatments not targeted to the central nervous system and that this effect increases if opioids are used in combination with antidepressants, or anticonvulsants, or both (03).

Antineoplastic agents. Various drugs used for the treatment of cancer can directly affect the central nervous system and cause acute as well as chronic cognitive disturbances. Examples of these treatments are cytokines and chemotherapy. Cancer patients often complain of difficulties with memory and concentration, popularly referred to as "chemobrain" or "chemofog," but some studies suggest that chemotherapy may not be the cause of cognitive impairment as some patients might already have cognitive problems before the treatment is started (43). Experimental studies in rats have provided an explanation for chemotherapy-induced memory disturbances. Prolonged administration of temozolomide, which is used for the treatment of malignant brain tumors, is associated with a decrease in hippocampal adult neurogenesis that may explain the selective deficits in processes of learning whereas memory for previously learned associations is not disrupted (33).

Immunotherapy of cancer with cytokines can produce cognitive impairment including memory disturbances. Duration of therapy is an important determinant of the cognitive effects of interferon-alpha.

Memory impairment is recognized as an adverse effect of chemotherapy and has been reported in several studies of breast cancer patients treated with various chemotherapeutic agents. Memory impairment is more severe in those who receive adjuvant tamoxifen, a hormonal agent, compared with women who received chemotherapy alone. Aromatase inhibitors such as anastrozole have been used instead of tamoxifen for the adjuvant treatment of breast cancer, but a study has shown that women who received anastrozole had poorer verbal and visual learning and memory than women who received tamoxifen (07).

Anticholinergic drugs. Several drugs with anticholinergic properties, listed in Table 2, are used in medical practice. Cognitive adverse effects of anticholinergic drugs include confusion, impaired memory, delirium, hallucinations, and psychosis. Anticholinergics impair memory retrieval, especially free recall. Even over-the-counter H1 antihistaminics, which have anticholinergic effects, can impair cognitive performance.

Drugs with anticholinergic activity are the major pharmacological agents that contribute to the verbal memory deficit observed in patients with schizophrenia. These drugs appear to act by impeding semantic organization at encoding.

Cumulative anticholinergic exposure across multiple medications over 1 year may negatively affect verbal memory and executive function in older men (21).

A longitudinal study of cognitively normal older adults found that use of anticholinergic medications was associated with increased brain atrophy as shown by brain imaging and cognitive decline, including lower mean scores on Weschler Memory Scale-Revised Logical Memory Immediate Recall over a mean follow-up period of 32 months (39).

Functional connectivity MRI (fcMRI) has been used as an experimental tool to examine the systems pharmacology of psychoactive drugs and reveals disrupted connectivity within and between default and salience networks in scopolamine-induced amnesia (10). A cross-sectional study has shown that anticholinergic burden, as measured by the Anticholinergic Drug Scale and various other tools, in patients with subjective cognitive decline or neurocognitive disorders is associated with lower functional score (14). Therefore, caution should be exercised in prescribing anticholinergic drugs to patients with memory complaints. A retrospective review of case histories of the patients who presented with the complaint of cognitive impairment, one third were found to be taking anticholinergic drugs (31).

Table 2. Drugs with Anticholinergic Properties

• Antiarrhythmics, eg, propafenone • Antiemetics, eg, meclizine • Antihistaminics, eg, brompheniramine • Antiparkinsonian, eg, benztropine, trihexyphenidyl, amantadine, profenamine • Antispasmodics, eg, atropine • Antiasthmatics, eg, ipratropium bromide • Muscle relaxants, eg, baclofen • Antipsychotics, eg, clozapine, chlorpromazine • Tricyclic antidepressants, eg, amitriptyline

In a 4-year follow-up study, a patient with baclofen-induced accelerated long-term forgetting was retested 18 months after discontinuing baclofen and showed evidence of recovery by improvements in autobiographical memory for recent but not remote events (42).

Dopaminergic drugs. Paradoxical effects have been reported by which the same drug causes cognitive enhancement as well as adverse effects. Individual differences in impulsive personality account for the contrasting effects of dopaminergic drugs on working memory and associated frontostriatal activity.

Antidepressants. Depression is a cause of cognitive impairment and antidepressants generally reduce cognitive deficits. However, the central cholinergic effects of tricyclic antidepressants are the primary cause of the cognitive effects in these agents (25). Amitriptyline can disrupt verbal recall and produce noticeable and significant impairment of cognition and psychomotor function, whereas moclobemide, a selective monoamine oxidase inhibitor, is relatively free from these adverse effects. Selective serotonin reuptake inhibitors usually do not impair memory.

Antiepileptic drugs. Because antiepileptic drugs reduce neuronal irritability, it is suspected that they may reduce neuronal excitability and impair cognitive function. Most of the cognitive effects of antiepileptic drugs are dose related. Assessment of the effects of antiepileptic drugs on cognitive function, however, is a controversial issue because of subject selection, genetic factors, statistical difficulties, choice of cognitive tests, and the impact of seizures on psychological performance. Declarative memory functions show characteristic patterns of impairment in epilepsy when mediotemporal and associated neocortical structures are affected by lesions, ongoing epileptic activity, or the undesired effects of conservative or operative treatment. Evaluation of memory function in most studies is limited, and when effects are recorded, they are possibly secondary to changes in the level of attention or speed of mental processing. Long-term phenobarbital therapy induces a significant impairment in learning ability. Few cognitive side effects have been reported in studies of newer antiepileptic drugs.

Memory deficit is a concomitant disorder in patients suffering from neuropathic pain and is also a side effect of gabapentinoids, gabapentin and pregabalin, which are used for the treatment of neuropathic pain. Experimental studies in rats have shown that 5-HT6 receptor antagonist attenuate the cognitive deficits associated with neuropathic pain treated with gabapentinoids, enabling reduction in the dosage and frequency of administration (26).

Antiparkinsonian drugs. Several new antiparkinsonian drugs have minimal neuropsychiatric side effects. Among the older medications, anticholinergic drugs are still in use. Chronic administration of trihexyphenidyl to patients with Parkinson disease can cause a decrease in performance on recent memory tests, but not on immediate memory tests.

Antipsychotics. Although some atypical antipsychotics may improve cognitive impairment due to schizophrenia, antipsychotic drugs have anticholinergic properties that can impair cognitive function. In a study of institutionalized older adults with dementia, specific impairment of cognitive function such as executive or attentional impairments was associated with antipsychotic medication use (15). A study found significant association between antipsychotic-induced parkinsonism and working memory performance, which are clinically significant because working memory deficits are known to impair patients' social and occupational functions (36).

Benzodiazepines. Clinical features of memory disturbances produced by various benzodiazepines (triazolam, lorazepam, and diazepam) were described in the clinical manifestations section. Benzodiazepines are used for several indications besides their hypnotic action. For example, alprazolam has been used as an anxiolytic in minor surgical procedures, but it produces memory impairment at the dosages necessary to be clinically effective during oral surgery.

Although as a class, benzodiazepines act rapidly and are well tolerated, their use continues to be associated with issues such as dependence and memory impairment.

A randomized double-blind study with bromazepam showed that it can contribute to a reduced working memory load in areas related to attention processes although it produces higher cortical activation in areas associated with motor learning (13).

Beta-blockers and similar drugs. Lipophilic beta-blockers such as propranolol cause cognitive impairment. Hydrophilic beta-blockers such as atenolol can also cause neuropsychiatric side effects. Drugs with structural similarities to beta-blocker agents can also produce adverse neurologic effects.

Atenolol. There is a case report of a hypertensive man who developed memory impairment after 14-year therapy with atenolol (37). Other causes of memory impairment were ruled out and atenolol was replaced with a combination of amiloride and hydrochlorothiazide. One month later the patient showed 75% recovery, thus, confirming atenolol as the cause of memory impairment.

Propafenone. This antiarrhythmic drug has structural similarities to beta-blocker agents. Reported central nervous system effects include seizures, psychoses, confusion, dizziness, ataxia, headaches, tremor, and depression. Several cases of memory disturbances have been reported.

Corticosteroids. Chronic treatment with corticosteroids can produce neuropsychiatric and memory disturbances in patients with systemic diseases without brain lesions. Whereas natural glucocorticoids modulate body homeostasis and coordinate adaptive responses to stress, synthetic glucocorticoids can produce neuropsychiatric disturbances, including memory impairment, with structural changes in brain target areas with long-term use (17). Pulsed methylprednisolone has been shown to induce reversible impairment of memory in patients with relapsing-remitting multiple sclerosis.

Drug abuse. Abuse of recreational drugs is associated with memory impairment. Some examples are:

Amphetamines. Drugs in this category are associated with cerebral vasculitis and intracerebral as well as subarachnoid hemorrhage. Cognitive function impairment in illicit amphetamine users has been tested by a neuropsychological test battery (Wechsler Memory Scale--revised), and the severity of amphetamine dependence was found to be associated with poor performance on memory, attention, and concentration indices. Continuous use of methamphetamine, one of the most widely used psychostimulants, leads to drug addiction and memory loss due drug-induced neurotoxicity. Neuronal impairment by methamphetamine is closely related to oxidative stress, transcription factor activation, DNA damage, excitotoxicity, and involvement of various apoptosis pathways (28).

3,4 Methylenedioxymethamphetamine (MDMA or ecstasy). This amphetamine derivative has become increasingly popular as a recreational drug. There are several reports of neuropsychiatric disturbances as well as cerebral infarctions following MDMA use. Memory disturbances have also been reported. MDMA is also neurotoxic with significant deleterious effects on serotonergic neurons, memory, and mood (16).

MDMA is known to damage brain presynaptic 5-HT neurons. Because loss of 5-HT neurons has been implicated in memory loss, it is possible that MDMA use may produce changes in postsynaptic 5-HT receptors and memory function in humans. Altered 5-HT neuronal function has been correlated with memory impairment in abstinent MDMA users.

Marijuana. Several studies have examined the residual effects of cannabis on neuropsychological performance. Subjects with a more prolonged history of cannabis use have a greater deficit in short-term memory and better conserved long-term memory (12). Heavy users display significantly greater impairment than light users on attentional and executive function as evidenced by reduced learning and recall of visual and visuospatial information. The question as to whether this impairment is due to a residue of the drug in the brain, withdrawal effect from the drug, or a direct neurotoxic effect of the drug remains unanswered. Functional brain imaging can show altered brain function after marijuana, but the regions showing these abnormalities have not been localized. Data from the “Coronary Artery Risk Development in Young Adults” study were followed up for 25 years from 1986 to 2011 to estimate cumulative years of exposure to marijuana and showed that past exposure to marijuana is associated with deterioration of verbal memory, but other domains of cognitive function appear to be unaffected (05).

A double-blind, randomized, placebo-controlled trial showed the acute and delayed effects of delta-9-tetrahydrocannabinol intoxication on susceptibility to false memory in healthy volunteers (29). Cannabis seems to increase false-memory proneness, with decreasing strength of association between an event and a test item, as assessed by different false-memory paradigms. These findings have implications for how and when the police should interview suspects and witnesses who have been smoking marijuana. A cannabinoid has been approved as an antiepileptic drug. Other cannabinoids are now under clinical investigation for therapeutic use in conditions such as chronic pain. Behavioral studies suggest that a disruption of normal hippocampal function contributes to impairment of memory and learning in marijuana smokers.

There is a case report of acute toxic reversible amnesia involving a 34-year-old man admitted to the emergency room for sudden anterograde amnesia with history of consumption of marijuana and cocaine and without loss of consciousness or any localizing neurologic signs (41). Toxicological screening revealed positive results for cocaine and marijuana in urine, and MRI showed bilateral cortical hippocampal diffusion restriction with hyperintensity without abnormal contrast-enhancement or other brain lesions. He recovered without further memory problems.

Ergot compounds. Transient global amnesia has been reported two patients with a history of migraines after taking ergotamine and dihydroergotamine to treat an attack of migraine (20).

Gap junction blockers. Gap junctions can be involved in the regulation of arousal and memory among other functions. Gap junction blockers can disrupt neuronal activity, block seizure activity, and impair cognitive functions including memory (27). Examples of gap junction blockers are quinine, quinidine, mefloquine, carbenoxolone, retinoic acid, and several anesthetics. Some of these drugs have been considered under other categories as well.

Hypnotics. Zolpidem is a nonbenzodiazepine hypnotic of the imidazopyridine class. It acts by modulation of a subunit of GABA receptor chloride channel macromolecular complex. Reported central nervous system adverse effects include cognitive impairment, confusion, psychoses, and vertigo. Amnesic events have also been reported following ingestion of normal doses of the drug as a hypnotic. Benzodiazepines are called "acquisition-impairing" molecules because they are generally considered to affect anterograde memory processes. However, they have an impact on retrograde memory as well and more particularly on retrieval processes.

A randomized, double-blind, crossover study compared the effect of single nighttime therapeutic doses of zaleplon, zolpidem, and triazolam and found no impairment of memory with zaleplon (a nonbenzodiazepine hypnotic), whereas the other two drugs produced psychomotor and memory impairment.

Oxytocin. The neuropeptide oxytocin is essential for parturition and lactation. A single dose of intranasal oxytocin in healthy volunteers significantly impaired recall performance as compared with placebo treatment irrespective of the meaning of words in the cued recall test (22).

Statins. Statins are used widely for the treatment of hypercholesterolemia. Experimental studies support links between cholesterol intake and amyloid synthesis. Statins are of prophylactic value in preventing the progression of Alzheimer disease. However, several reports have attributed memory loss to statins. It is possible that, in rare cases, statins may be associated with memory impairment, although no causal relation has been established. A case of rosuvastatin-related short-term memory loss was reported in a man with hypercholesterolemia but resolved gradually following discontinuation of the drug (19).

Sibutramine. Sibutramine, a serotonin and noradrenaline reuptake inhibitor, is widely used in the management of obesity. World Health Organization's international database contains several reports of amnesia associated with sibutramine, but they are rarely published. A case of transient global amnesia has been reported in a patient on sibutramine treatment (18). The possible mechanism is the increase synaptic serotonin concentrations by sibutramine. Discontinuation of sibutramine led to improvement of memory in most of the cases.

Sodium oxybate. This medical formulation of gamma-hydroxybutyrate is used for the treatment of cataplexy in patients with narcolepsy, and illicit use is alleged to cause amnesia. A comparative double-blind study in healthy volunteers showed that sodium oxybate significantly impaired working memory and the encoding of episodic memory during the period of drug effect, but episodic memory tasks were impaired to a lesser extent after sodium oxybate than after triazolam at doses that produce equivalent subjective effects (08).

Industrial chemicals. High levels of toluene, over 50 ppm, are known to produce neurotoxicity. Lower concentrations, 2 to 27 ppm in a printing plant, were associated with decreased performance on tests of memory function (11).

Pathomechanisms of drug-induced memory disturbances are as follows:

	• The basal forebrain cholinergic system plays an important role in memory. Patients with Alzheimer disease often show degeneration of the central cholinergic system. Anticholinergic drugs are known to impair memory.
	• Drug-induced seizures may be followed by an amnesic syndrome. Status epilepticus is followed by amnesia in patients with theophylline-induced seizures.
	• The hippocampi, essential for episodic memory function, are targets of MDMA neurotoxicity in experimental animals.
	• Two drugs that produce amnesia, midazolam and atropine, alter theta oscillations in the hippocampal CA1 region. Computational modeling has shown that these effects can be produced by simultaneous changes in the active somatic and distal dendritic inputs, which indicates a common basis for impaired memory encoding although they target different receptors (06).
	• Glucocorticoids, whether administered or generated in response to stress, have been shown to have an adverse effect on the rodent brain, particularly in the hippocampus, a structure vital to learning and memory and a location of a high concentration of receptors for glucocorticoids. Several days of exposure to cortisol at doses and plasma concentrations associated with physical and psychological stress in humans can reversibly decrease specific elements of memory in otherwise healthy individuals. Hippocampal atrophy has been attributed to glucocorticoid overproduction in patients with Cushing syndrome and posttraumatic stress disorder. These observations imply that high-dose corticosteroid therapy can produce hippocampal atrophy in humans and explain the memory impairment.
	• Dopaminergic mechanisms are possibly involved in morphine-induced memory impairment.
	• Memory storage is believed to be initiated by neuronal transmission increasing Ca2+ influx via NMDA receptors.
	• GABA is a major inhibitory neurotransmitter in the brain. The classical benzodiazepines potentiate GABA-stimulated chloride flux.

Amnesia and sedation. Drug-induced amnesia is often assumed to be related to the sedating effects of drugs. Electrophysiological evidence indicates that sedation and amnesia may not correlate. Midazolam and propofol affect memory differentially from their sedative effects, as revealed by a study of specific components of the auditory event-related potential.

Benzodiazepine-induced amnesia. Drugs of this category affect the encoding stage of memory by disturbing attention and impair the transference of material from short-term storage to long-term memory. Another possible mechanism is that long-term memory deficit could be the result of failure of memory consolidation during rapid sleep onset. Neuroanatomically, the subcortical structures appear to play an important role in the consolidation of newly learned information. Results of various PET studies are consistent with behavioral evidence that benzodiazepines impair prefrontal control processes as well as contextual memory and episodic binding processes.

Pharmacologically, benzodiazepines potentiate the effect of GABA, a major inhibitory neurotransmitter. GABA facilitation is likely to impair the function of these structures in the consolidation process. At a neurophysiological level, the disruption of consolidation that occurs in these structures may be mediated through the effect of GABA on long-term potentiation, a phenomenon in which relatively short periods of electrical stimulation result in enduring changes in the synaptic efficiency. Thus, benzodiazepines, as GABA agonists, may impair long-term potentiation and cause deficits both in the acquisition and retention of information through their immediate and long-term effects on consolidation.

In long-term administration of benzodiazepines, the acquisition phase of memory may be affected and delayed recall may be impaired for the material learned during the intoxication period. Benzodiazepine dependence in the elderly can cause memory impairment that can persist into the early drug-free period. Amnestic effects of benzodiazepines are mediated by the benzodiazepine receptor and can be blocked by specific benzodiazepine receptor antagonists in animal models.

Frequency and severity of cognitive impairment resulting from the use of benzodiazepines has been correlated with pharmacokinetic and pharmacodynamic factors. Elimination half-life, receptor-binding affinity, effects on the locus coeruleus-norepinephrine and hypothalamic-pituitary-adrenal axis, and the interaction of these factors appear to be the major determinants of the frequency and severity of these adverse reactions.

Drug-induced amnesia as a tool for memory research. Drug-induced amnesia has implications for cognitive neuropsychological investigations of memory. Cholinergic drugs have been used as tools to manipulate the functional state of the cerebral cortex based on the theory that the cholinergic system controls the functional state of the cortex. Cholinergic blockage by scopolamine impairs performance on tasks involving sustained and selective attention. It also reduces the working memory capacity and argues for a cholinergic modulation of a common, resource-limited, information processing system.

Epidemiology

• Drugs contribute to cognitive impairment in approximately 10% of patients evaluated for dementia.

Attempts to design studies for determining the incidence of memory disturbance are problematic because memory disturbance is not a unitary phenomenon and tests of neuropsychologic function may vary as a function of sensitivity and selectivity among tests. Various clinical variables affecting results are drug dosage, blood levels, underlying disease, comedications, clinical response, and age of the patient.

Drugs have been reported to be the primary cause contributing to cognitive impairment in approximately 10% of patients evaluated for dementia (30). Polypharmacy increases the risks, with relative odds increasing from 2.7 with two or three drugs, to 9.3 with four or five drugs, to 13.7 with more than six drugs. Among the 188,284 adverse drug reactions recorded by the French PharmacoVigilance Database during a decade, there were 519 cases of memory loss (09). Using a case (reports in database)/noncase (literature) method, the study confirmed an association between memory disorders and some drugs, such as benzodiazepines and anticonvulsants. Significant association with memory disorders were found for other drugs, such as benzodiazepine-like hypnotics, newer anticonvulsants, serotonin reuptake inhibitor antidepressants, isotretinoin, and ciclosporin, which were poorly documented in the literature.

Prevention

• Avoidance of drugs known to cause memory disturbances (if possible) • Avoidance of polypharmacy • Careful use of psychotropic drugs in elderly subjects

The best method of prevention of drug-induced memory loss is avoidance, if possible, of drugs known to cause memory impairment, such as benzodiazepines and anticholinergic drugs. Polypharmacy should be avoided as some drugs in a large list are likely to have adverse effects on memory. Caution should be exercised in use of antipsychotics in the elderly as their brains are more sensitive to the adverse effects of drugs. Drugs with shorter duration of action are safer, and memory tests may be done after initial dose to determine any adverse effect. For systemic disorders, drugs with potential neurotoxicity should be avoided if they cross the blood-brain barrier easily.

In cases of alcohol, substance abuse, and drug addiction, appropriate measures should be directed to manage these problems for prevention of memory loss.

Differential diagnosis

Confusing conditions

Table 3 lists conditions associated with amnesia in which drug-induced memory disturbance should be considered in the differential diagnosis. History of intake of suspected drugs is an important feature for differential diagnosis. Differentiation may be difficult in a condition such as epilepsy, where the disease, the manifestation (seizures), and the drugs used for the treatment may all cause memory disturbances. Regarding forensic medicine, a specific type of amnesia, amnesia automatism or amnesic complex automatism, is implicated in drug-facilitated robbery or sexual assault. It has significance in forensic medicine.

Oral provocation testing with drugs to detect anaphylaxis is a stressful experience. In one case, oral challenge with COX 2 inhibitor rofecoxib (withdrawn from U.S. and other markets due to adverse effects) resulted in acute anterograde and retrograde amnesia, which lasted several hours although the patient did not show symptoms of anaphylaxis (23). This type of memory disturbance associated with drug administration is not due to demonstrable effect of the drug on the brain and should be differentiated from drug-induced memory loss.

Table 3. Differential Diagnosis of Drug-Induced Memory Disturbance

• Alcoholism:
	- Wernicke-Korsakoff syndrome
• Alzheimer disease
• Benign forgetfulness of aging
• Cerebral hypoxia:
	- Carbon monoxide poisoning - Cardiac arrest and resuscitation
• Cerebrovascular diseases:
- Transient ischemic attacks - Vascular dementia
• Dementia with Lewy bodies
• Epilepsy
• General medical disorders:
- Hypoglycemia - Hypothyroidism
• Head injuries:
	- Cerebral concussion - Chronic traumatic encephalopathy - Posttraumatic stress disorder
• Hypnotic amnesia
• Insufficient sleep
• Malingering and hysteria
• Neuropsychiatric paraneoplastic syndromes in cancer patients
• Normal pressure hydrocephalus
• Psychiatric disorders:
	- Depression anxiety and stress - Schizophrenia - Electroconvulsive therapy
• Transient global amnesia

Diagnostic workup

Key tests and procedures

	• History of drug use
	• Blood level of suspected drugs
	• Memory tests

The history of intake of drugs known to be associated with memory disorders is important. Blood levels of these drugs may be determined by appropriate laboratory tests. Neuropsychological tests with emphasis on tests of memory should be routine. Other diagnostic procedures should be done according to suspected or known concomitant illnesses.

Management

	• Discontinuation of the medication causing memory disturbance usually suffices.
	• Antidotes for anticholinergic-induced memory impairment should be used cautiously as some of them can further impair memory; for example, scopolamine-induced memory deficits can be ameliorated by anticholinesterase physostigmine but not a benzodiazepine antagonist.

Discontinuation of the medication causing memory disturbance is usually sufficient and the patient may recover spontaneously. Memory training exercises may accelerate the recovery, but no controlled studies on patients with drug-induced memory disturbances exist.

Use of a nonsedating dose of diazepam (5 mg in an adult) can relieve anxiety by effects on attentional vigilance and startle responsivity--the underlying mechanism of anxiolytic effect--without impairing memory (32). Overdose of benzodiazepine, on the other hand, can produce severe amnesia due to sedative and hypnotic effects. Flumazenil, a competitive benzodiazepine antagonist, is indicated in the management, but its role in the routine reversal of endoscopic conscious sedation has not been defined.

Uses of antidotes in anticholinergic-induced memory deficits are somewhat tricky because they are neurotransmitter-specific. Amphetamine can reduce the sedative effect of scopolamine but makes the memory deficits worse. Scopolamine-induced memory deficits can be ameliorated by anticholinesterase physostigmine, but not by a benzodiazepine antagonist.

Switching from lipophilic to hydrophilic statins may resolve cognitive impairment. However, due to rarity of this event, discontinuation of statins is not recommended as the vascular benefits and putative cognitive benefits outweigh the risk of cognitive impairment associated with statin use (40).

Drug-induced memory impairment has been suggested as a mechanism that aggravates the loss of control over drug use. According to this concept, histaminergic compounds such as H3 receptor antagonists may improve the treatment of addiction by reversing drug-induced memory deficits and, thus, the reinforcing properties of addictive drugs (04).

Special considerations

Anesthesia

Anesthetics can impair memory. Although inhalational anesthetic agents are among the most potent drugs that cause temporary amnesia, their effect on human emotional memory processing is not clear and is being studied. A study using glucose PET has shown that 0.25% sevoflurane blocks emotional memory by suppressing amygdala-to-hippocampal effective connectivity (02).

Diazepam-induced amnesia has been used therapeutically in combination with analgesic medications to reduce painful memories of endoscopic procedures.

Intravenous ketamine is used for relief of pain and is associated with cognitive impairment, which may vary according to the isomer of the drug. A controlled study in volunteers showed that immediate recall, retention in primary memory, and short-term storage capacity were less reduced after the isomers than after equianalgesic small-dose racemic ketamine.