Rajesh R. Tampi, MD, MS, DFAPA

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

The goal of this activity is to learn about the neuropsychiatric symptoms of multiple sclerosis (MS) and to recognize them in patients.

1. Appreciate the basic epidemiology of MS

2. Understand the prevalence of comorbid neuropsychiatric disorders and MS

3. Track the complex relationship between MS and the various psychiatric disorders and symptomology

4. Consider treatment strategies for patients with MS who present with neuropsychiatric disorders

This continuing medical education (CME) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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Physicians’ Education Resource®, LLC designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical education purposes only and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic or treatment options for a specific patient’s medical condition.

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 inflammatory disease of the central nervous system (CNS).

 Additionally, it is the most frequent demyelinating disease of the CNS among individuals of European heritage.

 MS is also recognized as the most common nontraumatic cause of disability due to neurological disease among young and middle-aged adults in Europe and North America.

The prevalence of MS appears to be increasing and is now considered a truly global problem.

 The prevalence of MS is highest in North America, Western Europe, and Australasia (> 100 cases per 100,000 population), whereas it is the lowest in eastern sub-Saharan Africa, central sub-Saharan African, and Oceania (< 4 cases per 100,000 population). It is 

 that more than 2 million individuals worldwide have the illness, including approximately 400,000 cases in the United States.

 for MS, one of which is female sex, as approximately three-fourths of the individuals with MS are women.

 First-degree relatives have a 2% to 4% risk of developing MS when compared with approximately a 0.1% risk among the general population. The concordance rates among monozygotic twins is approximately 30% to 50%. The genome-wide association studies have identified HLA DRB1*1501 haplotype as the most important gene variant that increases the risk for developing MS; it confers 3 times the risk for MS. Other risk factors include being from a temperate climate, exposure to tobacco, obesity, and a previous episode of infectious mononucleosis.

 of MS based on the clinical course of the illness.

 Relapsing-remitting type of MS (RRMS) affects approximately 85% of individuals with MS; patients with RRMS experience flare-ups (ie, relapses or exacerbation that are followed by periods of remission). In the secondary progressive type of MS (SPMS), the illness course continues to worsen with or without periods of remission or stabilization of symptoms (plateaus). Approximately 10% of patients with MS have the primary progressive type of MS (PPMS), in which the symptoms continue to worsen gradually from the onset of illness. In this form of the illness, plateaus may be seen but there are no relapses or remissions. Finally, up to 5% of individuals experience the progressive-relapsing type of MS (PRMS). Patients with PRMS have intermittent flare-ups or worsening symptoms with no periods of remission from the onset of illness.

The pathological hallmarks of MS are inflammation with demyelination and astroglial proliferation (gliosis) and neurodegeneration. The damage to tissues is restricted to the CNS, whereas the peripheral nervous system is 

 The 2 pathologies are present among all individuals with MS across the continuum of the disease. Although MS can affect any part of the CNS, the white matter tracts in the cerebral hemispheres, optic nerves, brainstem, cerebellum, and the spinal cord tend to be preferentially affected.

The clinical features of MS depend on the location of the demyelinating lesions in the CNS. In approximately 85% of the cases, the onset of the illness is characterized by an initial clinical attack, which consists of demyelinating lesions in the optic nerve, spinal cord, brainstem, or the cerebellum. This results in acute unilateral optic neuritis, a partial myelitis, or a brainstem syndrome.

 The initial attack may be followed by additional clinical episodes known as relapses. These attacks may have acute or subacute onset over hours to days, with maximal deficits within 4 weeks of onset and spontaneous remission.

 that neuropsychiatric symptoms are not uncommon among individuals with MS.

 Current evidence indicates that approximately 60% of the individuals with MS 

It has also been noted that in a minority of the cases (2.3%), neuropsychiatric symptoms may present at the onset of the illness, and the burden of these symptoms may remain over the course of illness.

 Additionally, these symptoms may occur without any other physical manifestations of the illness.

Although there may be overlap, neuropsychiatric symptoms of MS can be divided into 2 broad categories: those associated with cognition and those associated with mood, affect, and behavior.

 In 1 study, depressive symptoms were the most common neuropsychiatric symptom seen among individuals with MS (

Figure 1. Prevalence of Common Neuropsychiatric Symptoms in MS

 neuropsychiatric disorder seen among individuals with MS.

 The lifetime prevalence of MDD is approximately 25% to 50%, which is approximately 2 to 5 times more common than in the general population.

 As there is significant overlap in symptoms between MDD and MS (including fatigue, reduced appetite, poor concentration, memory deficits, and insomnia), a diagnosis of MDD can often be missed in these individuals.

 The most commonly observed symptoms among individuals with MS and MDD are persistent low mood, anhedonia, diurnal mood variation, pessimistic thoughts, suicidal ideation, and impaired functioning that is out of proportion to the associated physical disability from the MS. Symptoms like apathy, social withdrawal, feelings of worthlessness, guilt, and poor self-esteem are less likely to be seen.

The relationship between MDD and MS remains a very 

 Available evidence indicates that both biological and psychosocial factors play a role in the development of MDD among individuals with MS.

 It is still unclear whether MDD occurs due to the neuropathological process associated with MS and/or as a consequence of the psychosocial stress associated with being diagnosed with MS.

Biological factors that contribute to the development of MDD among individuals with MS include lesions in the left arcuate fasciculus, prefrontal cortex, anterior temporal lobe, and parietal lobe.

 Additionally, atrophy in the frontal, parietal, and occipital lobes is associated with the development of depression among individuals with MS. Neuroendocrine factors like hypothalamus-pituitary-adrenal axis dysfunction has been noted among individuals with MS who have MDD. These individuals have non-suppression of cortisol when administered the dexamethasone suppression test, and this finding is correlated with greater number of lesions in the brain.

 The use or sudden discontinuation of corticosteroids, baclofen, dantrolene, and tizanidine among individuals with MS 

 Although there is no clear association noted between the use of interferon and the development of MDD among individuals with MS, patients receiving interferon should be routinely screened for the development of MDD.

 Interestingly, depression severity has been found to be higher among individuals with MS who use escape-avoidance and emotional respite coping strategies, and less severe among individuals who use planful problem-solving and cognitive reframing.

Suicidal ideation is not uncommon among individuals with MS. One study showed that the lifetime prevalence of suicidal intent was 28.6% in individuals with MS, and 6.4% of individuals with MS had attempted suicide.

 In this study, suicide intent was strongly associated with major depression, alcohol abuse, and social isolation.

Available evidence indicates that MDD in MS is often poorly diagnosed and treated, with as many as two-thirds of patients not receiving appropriate depression treatment.

 Screening tools such as the Beck Depression Inventory, the Beck Fast Screen for Depression in Medically Ill Patients, and the Hospital Anxiety and Depression Scale have been successfully used for screening in this patient population. Although there are only a limited number of controlled studies, available 

 indicates the following for the treatment of MDD among individuals with MS: selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressant (TCAs), mirtazapine, selective serotonin and noradrenergic reuptake inhibitors (SNRIs), and bupropion.

 Electroconvulsive therapy has also been used for the treatment of MDD among individuals with MS with good efficacy and minimal adverse effects.

The good news is appropriate treatment can be helpful for these patients. In a meta-analysis, Fiest et al found 21 articles that reported data on 13 unique clinical trials for the treatment of depression in MS.

 The investigators found that depression severity improved in 9 psychological and 3 pharmacological trials of treatments for depression.

The prevalence of bipolar disorder among individuals with MS is 0.3%.

 When compared with controls, individuals with MS had greater lifetime prevalence of bipolar I disorder (P = .05), bipolar 2 disorder (P <.0001), and cyclothymia (P =.0001).

 Manic symptoms can either precede the occurrence of neurological symptoms of MS or may occur during the exacerbation of MS symptoms.

 One-third of individuals with MS experience drug-induced mania, which tends to occur early in treatment and is dose dependent.

 Manic symptoms also occur more commonly among individuals with a family history of bipolar disorder. Additionally, manic symptoms may be seen among individuals with greater volume of brain lesions, especially in the bilateral temporal horn.

Lithium has been found to be effective in the treatment of manic symptoms among individuals with MS. For drug-induced manic symptoms, lithium, olanzapine, and phenytoin are effective treatments.

 Symptom control can be achieved without reduction in doses of the offending drug.

Available evidence indicates the prevalence rate for anxiety disorders among individuals with MS is approximately 36% (

Individuals with anxiety disorders were more likely to be women, have a history of depression, drink alcohol to excess, report higher social stressors, and have contemplated suicide. In a majority of these cases, the diagnosis of an anxiety disorder had been missed, and therefore they had not received any treatment. 

Figure 2. Prevalence and Types of Anxiety Disorders in MS

There are no RCTs that have evaluated pharmacotherapy for anxiety disorders among individuals with MS, but available evidence indicates efficacy for SSRIs, SNRIs, pregabalin, gabapentin, and beta-blockers.

 The use of benzodiazepines should be restricted to cases of anxiety that are acute and severe, and the prescription should be only be given for a short duration of treatment. Nonpharmacological management strategies that are beneficial in cases of anxiety disorders in MS include stress management and cognitive behavioral therapy.

 are seen in approximately 2% to 4% of individuals with MS.

 This rate is 2 to 3 times than that among the general population. It has also been noted that in 90% of these cases, psychotic symptoms occur in individuals after the onset of symptoms of MS.

 A systematic review found that the mean age of individuals having psychotic symptoms was 34.4 years, and there was a female predominance.

 In the majority of cases, the individuals did not have a prior history of psychiatric disease. Additionally, a majority of cases could be classified as a psychotic disorder or a mood disorder with psychotic features.

In this review, most of the individuals received some type of antipsychotic medication, with variable success. About a quarter of these individuals were treated with corticosteroids in the acute phase of their psychotic symptoms, and the majority responded favorably. In the 60% of individuals with imaging data, predominantly frontotemporal lesions were noted; most had contrast enhancing lesions. Data available from these case reports indicate that hallucinations and delusions (mostly paranoid) were the most common symptom, followed by irritability/agitation, sleep disturbance, grandiosity, and several others (

Figure 3. Psychosis Symptoms in MS (Percentages Approximate)

Psychotic symptoms are thought to occur in individuals with MS via 3 mechanisms: through a shared common pathophysiological process with the MS; due to the regional demyelination that occurs in synchrony with the course of MS; and as a side effect or as an exacerbation of the effect of the medications used to treat MS.

Available evidence indicates efficacy for low-dose atypical antipsychotic agents, including risperidone, ziprasidone, clozapine, aripiprazole, quetiapine, and olanzapine.

 Clozapine is often prescribed for treatment-resistant psychosis due to the risk for agranulocytosis. Prophylactic use of lithium along with corticosteroids and low doses of chlorpromazine have also shown benefit in the treatment of psychotic symptoms in MS.

 19% of individuals with MS have misused psychoactive substances or alcohol within the past month.

 Substance use tends to occur more commonly among younger individuals, those individuals who are still employed, and among those individuals who have less severe symptoms.

 One study found that 43% of individuals with MS had used cannabis at some time during the illness.

 Of these, 68% of individuals had used cannabis to alleviate symptoms of MS. A total of 18% of the individuals had used cannabis in the last month, of whom 12% had used it for symptom relief. Being married or having a long-term partner, smoking tobacco, and increasing disability were independent risk factors for MS-related cannabis use. When compared with individuals who could walk unaided, cannabis use was more likely in those who were chair-bound (adjusted odds ratio [OR] = 2.47) or only able to walk with an aid (adjusted OR = 1.56). Pain and spasms were common reasons for cannabis use. Interestingly, 71% of individuals with MS who had never used cannabis said they would try the drug if it were available on prescription.

Unfortunately, the use of cannabis is associated with a number of adverse effects, including worsening cognitive functioning, worsening depressive symptoms, and/or psychosis.

 It is important to routinely screen for alcohol and/or psychoactive substance misuse among individuals with MS and, if present, refer these individuals for appropriate treatments.

 shows that 40% to 65% of individuals with MS have cognitive dysfunction.

 These individuals present with impairments in attention and information processing along with deficits in working, semantic, and episodic memory.

 Procedural and implicit memory, however, appear less impaired among individuals with MS. Patients also present with deficits in encoding memory when compared with retrieval functions. Additionally, these individuals have executive dysfunction, including deficits in concept formation, abstract reasoning, and verbal fluency. Cognitive impairment tends to occur early in the illness and tend to worsen as the illness progresses. Those individuals with RRMS do better than individuals with PPMS with regards to cognition.

There is a possible association noted between cognitive dysfunction and fatigue.

 Fatigue often impairs cognitive performance among individuals with MS, and cognitive dysfunction may increase fatigue levels. Fatigue and cognitive dysfunction appear to share a common pathophysiological substrate involving common frontal-subcortical pathways. It has been noted that the total lesion burden and regional lesion volume correlate with the extent of cognitive dysfunction.

 Ventricular enlargement that is correlated with cerebral atrophy is also associated with impaired cognitive functioning, especially in attention, verbal memory, and verbal fluency.

The most sensitive means to detect cognitive dysfunction among individuals with MS is neuropsychological testing. Unfortunately, the testing is time consuming, expensive, and not readily available. In such situations, brief screening instruments, such as the Minimal Assessment of Cognitive Function in MS, may be used to detect and monitor for the progression of cognitive impairment. Disease-modifying drugs, including beta-interferons and glatiramer acetate, may prevent or reduce the progression of cognitive dysfunction by containing the development of new cerebral lesions.

 However, clinical trials have provided inconsistent results, with neuropsychological effects documented only in 1 trial.

Pilot studies have tested symptomatic therapies for fatigue, which may share a common pathophysiological substrate with cognitive dysfunction. Small trials of amantadine, pemoline, 4-aminopyridine, and 3-4 aminopyridine have provided mainly negative results.

 Acetylcholinesterase inhibitors (AchEIs) used to treat Alzheimer disease—such as donepezil, rivastigmine, and galantamine—have recently been explored for individuals with MS, with the majority of pilot trials showing promising results.

 However, nonpharmacological interventions based on cognitive rehabilitation in general have provided limited results.

 (PBA) is seen in approximately 10% of individuals with MS.

 Individuals with PBA appear to have greater physical disability and are more likely to be in the chronic progressive stage of MS.

PBA, also known as pathological laughing and crying, emotional incontinence, pathological emotionalism, or involuntary emotional expression disorder, is considered a disconnection syndrome that results in the loss of cortical or 

 inhibition of a putative center for laughing and crying.

 Additionally, lesions in the brainstem and inferior frontal and parietal lobes, along with the involvement of the monoaminergic neurotransmitter systems, have been noted in individuals with PBA. PBA can be distinguished from a mood disorder by the dissociation between the affect and the underlying mood, which results in an incongruent emotional expression. This emotional expression is disproportionate to the underlying emotional experience. In addition, these symptoms are not associated with the neurovegetative symptoms associated with mood disorders, and they do not meet the duration criteria for the mood disorders.

 Center for Neurologic Study-Lability Scale is often used to screen for PBA.

 A combination of dextromethorphan and quinidine is approved by US Food and Drug Administration (FDA) for the treatment of PBA. Symptoms of PBA also respond rapidly to low therapeutic doses of SSRIs. Efficacy has also been noted for SNRIs, mirtazapine, TCAs, levodopa, amantadine, and lamotrigine in the treatment of PBA.

Neuropsychiatric symptoms are not uncommon among individuals with MS. Although these symptoms may occur prior to the onset of MS symptoms, they commonly occur during the course of the illness. It is still unclear if the occurrence of neuropsychiatric symptoms indicates the level of severity of the underlying illness. However, the presence of these symptoms worsens MS outcomes. The management of the 

 among individuals with MS includes the optimal use of standard psychotropic medication regimen in conjunction with disease-modifying agents that are used to treat symptoms of MS. In addition, the use of appropriate psychotherapeutic interventions improves outcomes among these individuals. Ideally, neuropsychiatric symptoms in MS should be comanaged by a psychiatrist and a neurologist, with active collaboration between the providers and optimization of available services to care for these individuals.

is chairman, Department of Psychiatry & Behavioral Sciences, Cleveland Clinic Akron General, Akron, Ohio; chief, Section for Geriatric Psychiatry, Cleveland Clinic, Cleveland, Ohio; and professor of medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio. 

is co-founder and managing principal, Behavioral Health Advisory Group, Princeton, New Jersey.

is psychiatry clerkship site director, Cleveland Clinic Akron General, Akron, Ohio; clinical experiential director, Psychiatry Clerkship, Northeast Ohio Medical University, Rootstown, Ohio; clinical associate professor of psychiatry, Northeast Ohio Medical University, Rootstown, Ohio.

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3. GBD 2016 Multiple Sclerosis Collaborators. Global, regional, and national burden of multiple sclerosis 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. 

Treatment of multiple sclerosis: a review

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7. Brownlee WJ, Hardy TA, Fazekas F, Miller DH. Diagnosis of multiple sclerosis: progress and challenges. 

8. Marrie RA, Horwitz R, Cutter G, et al 

The burden of mental comorbidity in multiple sclerosis: frequent, underdiagnosed, and undertreated

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Neuropsychiatric syndromes of multiple sclerosis

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12. Diaz-Olavarrieta C, Cummings JL, Velazquez J, Garcia de la Cadena C. Neuropsychiatric manifestations of multiple sclerosis. 

13. Silveira C, Guedes R, Maia D, et al. Neuropsychiatric symptoms of multiple sclerosis: state of the art. 

Neuropsychiatric syndromes associated with multiple sclerosis

15. Chwastiak LA, Ehde DM. Psychiatric issues in multiple sclerosis. 

16. Mohr DC, Goodkin DE, Gatto N, Van der Wende J. Depression, coping and level of neurological impairment in multiple sclerosis. 

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Pharmacological management of depression in patients with multiple sclerosis

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Articles

Earn CME Credit by learning more about multiple sclerosis and how it affects patients. 

Neuropsychiatric Symptoms of Multiple Sclerosis

Available evidence indicates that benzodiazepines are commonly used to treat various disorders including anxiety, insomnia, agitation, alcohol withdrawal, and seizures.

 of benzodiazepine use among older adults in the United States is approximately 8.7%

; but it has been noted that approximately 44% of the prescriptions for benzodiazepine among older adults are potentially inappropriate.

2019 American Geriatrics Society Beers Criteria

 identifies benzodiazepines as potentially inappropriate medications for use among older adults.

) Factors associated with long-term use of benzodiazepines include the following: female sex, a diagnosis of Alzheimer disease (AD), schizophrenia, bipolar disorder, depression, coronary artery disease, and asthma/chronic obstructive pulmonary disease.

 is known to be associated with poor outcomes.

 One study found that benzodiazepine use was associated with greater risk for hospitalizations, emergency department visits, outpatient visits, and higher health care costs.

 Another study found the overdose death rate increased due to benzodiazepine use from 0.58 to 3.07 per 100,000 adults between 1996 and 2013.

 Benzodiazepines use is also associated with an increased risk of falls among older adults.

 Additionally, the use of benzodiazepines is associated with a 60% to 80% increase in the risk of traffic accidents.

 The co-ingestion of benzodiazepines and alcohol is associated with a 7.7-fold increased risk for traffic accidents.

Now, there is also emerging evidence that the use of 

 may increase the risk for developing dementia among older adults.

 This review evaluates the evidence from the literature on the association between benzodiazepine use and the risk for developing dementia.

A review of the literature indicates that there is a total of 15 studies that have evaluated the association between benzodiazepine use and the development of dementia.

 Four of the 15 studies were published prior to 2010

 and 11 of the studies were published since 2010.

Although there are no randomized controlled trials (RCTs) looking at the association between benzodiazepine use and the risk for dementia, 6 prospective cohort studies,

 and 1 retrospective cohort study18 explore the relationship. Two studies had both a prospective cohort and a case control component.

 Three of the studies were conducted in France,

 and 1 each in Sweden,14 the United States,

Of the 15 studies, 8 showed a positive association between benzodiazepine use and the development of dementia.

 Of these 8 studies, 2 were prospective cohort studies,

 had a prospective cohort and a case control arm to the study.

Four studies found benzodiazepines were not associated with the development of dementia.

 The negative studies included 2 case control studies,

 and 1 study that had a prospective cohort and a case control arm.

 One study found that previously using benzodiazepines was associated with the development of dementia, but current use was not.

 The other study found that short-term use of benzodiazepines was associated with the development of dementia, but long-term use was not.

 Finally, 1 prospective cohort study found that the use of benzodiazepines had a protective effect against the development of dementia.

More than half of the studies (8 out of 15, 53%) identified in the literature search showed a positive association between benzodiazepine use and the development of dementia. It is unclear whether there is any significant difference between men and women. This is true with higher doses; when the duration of use is shorter; for current users; for shorter-acting drugs; and study design (eg, cohort studies). (see 

Despite the evident association between benzodiazepine use and the development of dementia, a causality cannot be established, as none of the identified studies were RCTs.

Three important reviews have evaluated the association between benzodiazepine use and the development of dementia.

 In the first review, the investigators evaluated 3 studies that found an increased risk of cognitive decline among those using benzodiazepine, and 2 studies that found a lower risk of cognitive decline in former or ever users of benzodiazepines, and 2 studies that found no association between the use of benzodiazepines and the development of dementia.

 In another review that evaluated 10 studies, the investigators found that 9 studies showed an increased risk of dementia among those who used of benzodiazepines.

 The investigators opined that the risk of dementia increases with cumulative doses of medication, longer treatment duration, and when long-acting agents are used. In the third review that evaluated data from 11 studies, the investigators 

 positive association between benzodiazepine use and the development of dementia from 9 studies.

 One study found a protective effect for benzodiazepine use, and 1 study found no effect for benzodiazepine use and the development of dementia.

Three recent meta-analyses evaluated the risk of developing dementia among individuals who use benzodiazepines.

, which included data from 6 studies, the investigators found the pooled adjusted risk ratios (aRRs) for the development of dementia was 1.49 for those who have used benzodiazepines, 1.55 for those who recently benzodiazepines, and 1.55 for those who have previously used benzodiazepines, when compared with never users of benzodiazepines.

 The researchers stated the risk for dementia increased by 22% for every additional 20 defined daily doses of the drug per year (aRR=1.22).

that included data from 10 studies found the odds for developing dementia was higher by 78% among users those who were using benzodiazepines when compared to those who were not (OR=1.78)

 The investigators found a higher association when the studies were from Asia (OR=2.40), and a moderate association when the studies were from North America and Europe (OR=1.49).

 that included data from 12 prospective and retrospective cohort studies and case-control studies found that benzodiazepines can be a risk factor for the development of dementia (OR=1.38).

 The investigators concluded that the current evidence lacks the power to differentiate between the risks for the development of AD versus vascular dementias (VD), the risks when using long-acting versus short-acting benzodiazepines, and the risks based on the duration and the doses of the drugs that are used.

 Carl Salzman, MD, provided a counterpoint to the question on whether benzodiazepines cause AD.

 Salzman stated that “there is little doubt that benzodiazepines like other sedative hypnotics may be associated with impaired cognition which is usually mild and dose-dependent.” He reported that the usual recommendations include only short half-life benzodiazepines at low doses and, if clinically possible, for brief periods of time. Salzman opined that future studies are needed regarding benzodiazepines’ and other medications’ possible associations with the development of late-life cognitive disorders. Until then, he advised that we must assume that the appropriate use of benzodiazepines will not lead to the development of AD. One caution with this editorial is that it cites a limited number of studies evaluating the association benzodiazepines and AD, and it is difficult to develop any definitive conclusions based on these studies.

The available evidence for the association between benzodiazepine use and the development of dementia should be evaluated based on the heterogeneity between the studies and limitations of each of these studies. These studies were conducted in different countries and had differing methodologies. In addition, many studies did not control for confounding variables including educational attainment, the presence of depression, anxiety, insomnia, and alcohol use. Also, 4 studies used the older DSM III-R criteria for the diagnosis of the dementia, causing concerns regarding the validity of the diagnosis. It is unclear whether the observed association between the use of benzodiazepines and the development of dementia is really a causal effect, or the result of unmeasured confounding variables, as none of these studies were RCTs.

 occurs when a pharmaceutical agent has been inadvertently prescribed for an early manifestation of a disease that has not yet been diagnostically detected. A prolonged lag phase between the first appearance of brain pathology associated with dementias, the development of clinical symptoms that may be risk factors for dementias including anxiety and depression, and the actual clinical diagnosis of dementia has led to investigators citing protopathic bias or “reverse causality” as the main area of controversy regarding the association between benzodiazepine use and the development of dementia.

 To prove a definitive association between benzodiazepine use and the development of dementia, the studies would have to be approximately 3 decades long given the prolonged life course of neurodegenerative disorders like dementias.

There are 3 possible mechanisms that have been postulated for the association between benzodiazepine use and the development of dementia.

 For one, benzodiazepines possibly decrease activity of β-amyloid precursor protein-cleaving enzyme 1 (BACE-1) and c-secretase activity, thus promoting β-amyloid accumulation in the brain. Secondly, astrocytes near the β-amyloid accumulation in the brain secreting γ-aminobutyric acid (GABA), thereby promoting the negative cognitive effects of benzodiazepines. Finally, benzodiazepines may reduce the cognitive reserves by lowering brain activation levels.

Available evidence indicates a positive association between the use of benzodiazepines and the development of dementia, although causality cannot be inferred from this data. Despite the lack of evidence proving causality, the association between benzodiazepine use and the 

 is a major cause for concern given the prevalence benzodiazepine use among older adults. The prescription of benzodiazepines to older adults must be carefully reviewed given the lack of data regarding their long-term efficacy and their significant adverse effects including the risk for developing dementia.

is the chairman of the department of psychiatry and behavioral sciences, Cleveland Clinic Akron General, Akron, OH.

is a psychologist in the Department of Psychiatry and Behavioral Sciences, Cleveland Clinic Akron General, Akron, OH

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

1. Lader M. Benzodiazepines revisited--will we ever learn? 

3. Dionne PA, Vasiliadis HM, Latimer E, Berbiche D, Preville M. Economic impact of inappropriate benzodiazepine prescribing and related drug interactions among elderly persons. 

Nearly half of the prescriptions for benzodiazepine among older adults are potentially inappropriate, so how best to do no harm?

Rajesh R. Tampi, MD, MS, DFAPA

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