Deena J. Tampi, MSN, MBA-HCA

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.

1. Reich DS, Lucchinetti CF, Calabresi PA. Multiple sclerosis. 

2. Paparrigopoulos T, Ferentinos P, Kouzoupis A, et al. The neuropsychiatry of multiple sclerosis: focus on disorders of mood, affect and behavior. 

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

6. Filippi M, Bar-Or A, Piehl F, et al. Multiple sclerosis. Nat Rev Dis Primers. 2018;4(1):43. Published correction appears in 

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

9. Murphy R, O’Donoghue S, Counihan T, et al. 

Neuropsychiatric syndromes of multiple sclerosis

10. Lo Fermo S, Barone R, Patti F, et al. Outcome of psychiatric symptoms presenting at onset of multiple sclerosis: a retrospective study. 

11. Asghar-Ali AA, Taber KH, Hurley RA, Hayman LA. Pure neuropsychiatric presentation of multiple sclerosis. 

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. 

17. Feinstein A. An examination of suicidal intent in patients with multiple sclerosis. 

18. Carta MG, Paribello P, Anastasia A, et al. 

Pharmacological management of depression in patients with multiple sclerosis

19. Fiest KM, Walker JR, Bernstein CN, et al. Systematic review and meta-analysis of interventions for depression and anxiety in persons with multiple sclerosis. 

20. Edwards LJ, Constantinescu CS. A prospective study of conditions associated with multiple sclerosis in a cohort of 658 consecutive outpatients attending a multiple sclerosis clinic. 

21. Carta MG, Moro MF, Lorefice L, et al. The risk of bipolar disorders in multiple sclerosis. 

22. Jefferies K. The neuropsychiatry of multiple sclerosis. 

23. Korostil M, Feinstein A. Anxiety disorders and their clinical correlates in multiple sclerosis patients. 

Articles

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

Neuropsychiatric Symptoms of Multiple Sclerosis

Diagnostic and Statistical Manual of Mental Disorders

, 5th edition (DSM-5) classifies attention-deficit/hyperactivity disorder (ADHD) as a neurodevelopmental disorder characterized by a persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development.

 There is growing evidence that symptoms of ADHD can persist into adulthood and can cause significant impairments in social, academic, and occupational functioning. In addition, there is emerging evidence for the existence of a different variant of adult ADHD (aADHD) where ADHD symptoms emerge for the first time in young adulthood without any symptoms being 

 In this article we review various aspects of adult ADHD (aADHD) and suggest possible treatments.

The prevalence of ADHD in childhood is between 

 Emerging evidence indicates that ADHD symptoms may persist into adulthood in approximately 

 to suggest that adult ADHD (aADHD) is not just a continuation of childhood onset ADHD (cADHD), as many individuals do not have a history of this 

 It is postulated that there may be 2 distinct subtypes of aADHD: the first with childhood onset and the other with onset exclusively in adulthood. A meta-analysis evaluating the risk markers that predicted the persistence of ADHD from childhood into adulthood found that the severity of ADHD (odds ratio (OR) = 2.33, 

 < 0.001), treatment for ADHD (OR = 2.09, 

 = 0.037), comorbid conduct disorder (OR = 1.85, 

 = 0.030), and comorbid major depressive disorder (OR = 1.8, 

 = 0.019) emerged as predictors for childhood ADHD persisting into adulthood.

A meta-analysis by Simon et al, found the conservative pooled prevalence rate for adult ADHD (aADHD) to be 

 This study also found that the proportion of individuals with ADHD decreases with age, and the prevalence rates were equal among men and women. This data is in contrast to cADHD, where boys had 3 to 10 times greater prevalence rates when compared to girls. The authors also opined that the true prevalence rate of adult ADHD may be an underestimate, as some children with ADHD do not outgrow the disorder but outgrow the current diagnostic criteria (

Adult ADHD results in significant impairments in the individual’s personal, social, and professional life.

 Individuals with aADHD tend to have poor self-esteem and reduced quality of interpersonal and professional relationships. These individuals are twice as likely to be divorced, when compared to age-matched controls. They also have significant educational difficulties with lower grades, greater rates of academic suspension and dropout rates, and are less likely to graduate than students without ADHD. Individuals with aADHD have greater rates of traffic violations and motor vehicle accidents, and higher rates of emergency room visits and hospital admissions. They also have lower life expectancies and higher risk for death, including accidental deaths. Individuals with aADHD are more likely to be unemployed and have a greater likelihood of being involved in criminal behaviors. The overall national annual incremental costs of ADHD ranges from $143 to $266 billion.

 Most of these costs were incurred by adults ($105 billion to $194 billion) compared to children ($38 to $72 billion), and the largest cost category in this group was productivity and income losses of $87 billion to $138 billion. 

Approximately 80% of aADHD cases present with at least 1 lifetime psychiatric comorbidity.

 The National Comorbidity Survey found that aADHD was significantly comorbid with mood disorders (OR = 2.7 to 7.5), anxiety disorders (OR = 1.5 to 5.5), substance use disorders (SUDs, OR = 1.5 to 7.9), and intermittent explosive disorder (OR = 3.7).

 aADHD was also associated with greater disability in both basic functioning (self-care, mobility, and cognition) and instrumental functioning (days out of role), productive role functioning and also on social role functioning). Only 10.9% of these individuals with aADHD received treatment for ADHD in the preceding 12 months.

Available evidence from family, twin, and adoption studies indicates that ADHD tends to run in families, with a high heritability rate of 74%.

 In addition, a third of ADHD’s heritability is due to a polygenic component, indicating many common variants with each having small effects. The heritability of aADHD and cADHD appear to be very similar, although family studies indicate that there may be an increased familial liability for aADHD when compared with cADHD.

 Twin studies that are based on self-rated symptoms among a sample of adult population show a moderate heritability rate at 30% to 40%.

Current evidence indicates that some of the same genes that may be involved in cADHD may also be involved in aADHD.

 Linkage studies have identified LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In a systematic review and meta-analysis of candidate gene association studies, pharmacogenetic and biochemical (metabolomics) studies performed among individuals with aADHD found an association between aADHD and the gene brain-specific angiogenesis inhibitor 1-associated protein 2.

 They also found lower serum docosahexaenoic acid (DHA) levels among aADHD individuals.

There is evidence from neuroimaging studies that among individuals with ADHD there is a dysfunction of dopamine pathways that are involved in attention, executive function, and motivation and reward.

 Additionally, dysfunctions are also noted in noradrenergic pathways, especially those projecting into the prefrontal cortex, the central region for executive function.

A simultaneous electroencephalography and functional magnetic resonance imaging (fMRI) study found that aADHD individuals had increased medial/lateral frontal and parietal activity during the voluntary selection task on fMRI.

 A meta-analysis found that right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in cADHD.

 Additionally, these changes and alterations in limbic regions like anterior cingulate cortex and amygdala were more pronounced among non-treated individuals and these appeared to diminish over time from childhood to adulthood.

In a study that sought to delineate the neural correlates of component-specific inhibitory deficits in aADHD using fMRI, brain activation was assessed during 3 stages of behavioral inhibition, ie interference inhibition (Simon task), action withholding (Go/no-go task), and action cancelation (Stop-signal task).

 Individuals with ADHD were impaired in all tasks. It was noted that impaired interference inhibition was associated with hypoactivation in parietal and medial frontal regions. During action withholding and cancelation, individuals with ADHD displayed hypoactivation in a fronto-striatal network. These findings indicate that at least 2 disturbed neural circuits in aADHD differentially associated with deficits in separate inhibitory subcomponents. Frontal brain responses were reduced among individuals with aADHD when compared to controls during free responses, whereas parietal brain functions seemed to be unaffected. These results appear to indicate that selection processes are related to dysfunctions, predominantly in frontal brain regions among individuals with ADHD. 

A study that investigated neural and behavioral correlates of visual encoding during a working memory (WM) task among young adults with aADHD found that there was ineffective allocation of attentional resources involved in encoding of information in WM.

 It has been noted that individuals with aADHD have significantly lower sensory gating than controls, suggesting an impaired ability to filter incoming information.

 Additionally, increased connectivity between the default mode network and a region within left lateral prefrontal cortex (PFC) has been noted. Furthermore, greater levels of resting state activity within that area of PFC was noted to be associated with reduced performance on attentional tasks.

 A common reason for this under-diagnosis is the nature of the illness, as it shares many clinical characteristics with common psychiatric disorders. These disorders include major depression, bipolar disorder, anxiety disorders, SUDs, and personality disorders. Given this overlap in symptomatology, it is recommended that aADHD should be evaluated using a dimensional rather than a categorical approach.

 Katzman et al recommend asking about long-standing and consistent problems with attention and distractibility. Additionally, inquire about complaints from the last 10 to 20 years, conceptualizing how the individual would have been as a child in a classroom. Early diagnosis and treatment of comorbid disorders appear to improve the outcomes among individuals with aADHD. 

It is also recommended that the focus of the evaluation in an adult presenting with symptoms of ADHD should be on the individual’s mental state, as it adds immediate and greater clinical value than the use of cognitive or neuroimaging information.

 Additionally, certain symptoms like physically restless, emotional dysregulation, excessive mental wandering, and sleep-onset insomnia may suggest a diagnosis of aADHD. It is also prudent to exercise caution when evaluating individuals with aADHD, as some individuals may feign ADHD symptoms in order to obtain stimulant medications for diversion to non-medical use.

To meet the DSM-5 diagnostic criteria for ADHD among adults, the individual needs to have 5 or more of the 9 symptoms of inattention and/or of hyperactivity and impulsivity.

 These symptoms need to also have persisted for at least 6 months. In addition, several inattentive or hyperactive–impulsive symptoms should have been present prior to the age of 12 years. These symptoms should be present in 2 or more settings, including home, school, or work; with friends or relatives; in other activities. Furthermore, there should be clear impairment with/or reduced quality of social, academic, or occupational functioning. These symptoms should not occur due to another psychiatric disorder, especially due to psychotic, mood, or anxiety disorders; or due to substance intoxication or withdrawal. The DSM-5 also defines 3 clinical presentations of ADHD based on symptom profile: predominantly inattentive, predominantly hyperactive/impulsive, and a combined (inattentive and hyperactive and impulsive) presentation. The DSM-5 recommends that collateral information should be obtained, as adult recall of childhood symptoms tend to be unreliable.

As there is significant co-occurrence of many common psychiatric disorders with aADHD, these disorders should ideally be diagnosed and treated first.

 This will ensure that the best treatment can be chosen for the core aADHD symptoms. If that is not possible, co-treating these disorders may also be beneficial among individuals with aADHD.

Pharmacological agents are considered first line interventions for the treatment of aADHD.

 The medications that are approved for the treatment of adult ADHD include stimulants, such as amphetamines (amphetamine, dextroamphetamine, and lisdexamfetamine) and methylphenidate (methylphenidate and dexmethylphenidate); and non-stimulants (atomoxetine).

 Other medications that are used off-label include modafinil, guanfacine, venlafaxine, bupropion, and desipramine.

Both amphetamines and methylphenidate are available as immediate release preparations requiring multiple dosing each day and sustained release preparations for once or twice daily dosing.

 The amphetamines and methylphenidate have been found equally efficacious in the treatment of aADHD, with approximately 70% of individuals reporting immediate improvement in core symptoms within 1 hour after administration of the drug. The common adverse effects of these drugs include insomnia, dry mouth, decreased appetite, weight loss, headaches, depression, and anxiety. They are contraindicated among individuals with hypertension, psychosis, or tics, as the medications may worsen these conditions. These medications need to be used with caution among individuals with serious heart disease. Stimulant medications are classified by the Drug Enforcement Agency as Schedule II substances, as they have a potential for abuse especially among individuals with SUDs.

The only non-stimulant medication that is approved for the treatment of aADHD is atomoxetine.

 It appears to have lower potential for abuse than stimulant medications. It is also preferred for use among individuals with ADHD and comorbid substance use disorders, tics, anxiety, or psychosis. However, atomoxetine appears to be less effective than stimulant drugs in reducing core ADHD symptoms and requires 1 to 2 weeks of treatment to achieve full benefit.

Additionally, there is no convincing evidence that atomoxetineis safer than stimulants, and it needs to be used cautiously among individuals with cardiovascular and cerebrovascular disease. The common side effects of atomoxetine include dry mouth, insomnia, nausea, decreased appetite, constipation, decreased libido, dizziness, and sweating.

 Other non-stimulant medications that can be used off-label among individuals with aADHD include modafinil, guanfacine, venlafaxine, bupropion, and desipramine, but the evidence for their use is limited to a few small controlled studies of short duration.

In a meta-analysis that included data from 19 trials and studied 13 different drugs, the investigators found that although both stimulant and non-stimulant medications are effective treatments for aADHD, stimulant medications show greater efficacy for the short durations of treatment when compared to placebo.

 However, there were no significant differences noted between short- and long-acting stimulant medications.

A systematic review of 18 published studies found that that cognitive behavioral therapy (CBT) was the most effective psychological treatment for aADHD and the comorbid symptoms of anxiety and depression.

The National Institute for Health and Care Excellence recommends prescribing medications to adults with ADHD if their ADHD symptoms are causing a significant impairment in at least 1 

, after environmental modifications have been implemented.

 The guideline recommends using lisdexamfetamine or methylphenidate as first-line pharmacological agents for the management of aADHD.

Another recommendation is switching between the 2 medications for adults who have had a 6‑week trial of 1 medication at an adequate dose without significant benefit. Atomoxetine was recommended if the individual cannot tolerate lisdexamfetamine or methylphenidate or their symptoms have not responded to separate 6‑week trials with either medication. The guideline recommends using non-pharmacological treatments among individuals with aADHD who have made a choice not to use medications, had difficulty adhering to medications, or found medications to be ineffective or intolerable. The guideline also recommended considering non-pharmacological treatment in combination with medication for individuals with aADHD who have benefited from medications, but whose symptoms are still causing a significant impairment in at least 1 domain. The recommendation involves elements of or a full course of CBT.

Although normally associated with children, attention-deficit/hyperactivity disorder can also persist in adulthood, presenting challenges to both patients and clinicians. 

Deena J. Tampi, MSN, MBA-HCA

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