Jennifer A. Reinhold, PharmD, BCPS, BCPP

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The clinical presentation and functional impacts of ADHD in adults vary greatly from their child and adolescent counterparts.

6 Challenges in Assessing ADHD in Adult Patients

To recognize the clinical presentation of adult ADHD as well as the associated challenges of assessment and treatment.

At the end of this CE activity, participants should be able to:

• Understand the difficulties associated with making an objective assessment of adult ADHD

• Identify the psychiatric conditions frequently comorbid with adult ADHD

• Distinguish which intervention to use when treating an adult patient with a diagnosis of ADHD

This continuing medical education 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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Jennifer A. Reinhold, PharmD, BCPS, BCPP, has no disclosures to report.

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The inattentive and the hyperactive-impulsive subtypes of ADHD are particularly evident in adults. This inherent heterogeneity complicates the diagnosis and contributes to the lack of uniformly recognized criteria in the adult population. Historically, the diagnostic criteria that were developed based on the traditional childhood presentation have been applied to adult patients. Practitioners have attempted to adapt these criteria to adults in practice, and DSM-5 has also modified some of the qualifiers in order to facilitate the utilization of the criteria in adults. However, the clinical presentation and functional impacts of ADHD in adults vary greatly from their child and adolescent counterparts.

As patients mature and their roles and responsibilities evolve, the functional impairments and symptom presentation evolve in response, thereby presenting a barrier to fulfilling diagnostic criteria. Adults are exposed to a variety of social and professional situations that can provide an opportunity for previously unnoticed symptoms to manifest. Inattentive symptoms may present as difficulty in completing tasks, poor time management, difficulty in sustaining attention in work-related activities, distractibility and forgetfulness, and poor concentration. Occupational performance and professional interpersonal relationships can suffer, and ultimately result in frequent job changes, unemployment, failure to live up to one’s occupational potential, and lower salaries. Moreover, deficits in global performance in the adult patient’s life role, follow-through, and memory can have pervasive effects that extend to those who depend on him or her (eg, children, spouses, employers, friends).

Perhaps the most significant evolution of symptoms occurs in the hyperactivity-impulsivity domain. It is often assumed that these symptoms fade or resolve entirely in adults as they grow older. However, maturation results in a shift in this symptom cluster, and it evolves from behavioral to cognitive-adult patients feel restless as opposed to running around and being disruptive in school. Approximately 90% of adult patients have symptoms of inattention.

Challenges in assessing ADHD in adult patients

There are many challenges associated with a diagnosis of ADHD in adults. Objective assessment is difficult because of many factors, including the extensive degree of symptom overlap with other psychiatric diagnoses (eg, psychiatric comorbidities, adaptive compensatory mechanisms, difficulty in assessing functional impact).

The most contemporary multidimensional approach to a relatively objective diagnosis in children and adolescents are DSM-5 criteria, which assess symptoms in all 3 domains. Until the release of DSM-5, there was very little consideration for the assessment of adult patients because DSM criteria had not been validated in the adult population. DSM-5 adapted the previous set of diagnostic criteria to be more accurately applicable to adult symptom presentation. The nomenclature has evolved to reflect more adult-specific situations, such as having difficulty focusing during lectures, avoidance of reviewing lengthy papers, and forgetfulness related to paying bills or keeping appointments.

Revisions that facilitate the application of the criteria to adults are the decrease in the number of required symptoms for adults to fulfill criteria as well as an increase in the age of initial presentation. Previously, adult patients needed to satisfy at least 6 of the 9 inattentive criteria, which is consistent with diagnosis in the pediatric and adolescent population. In DSM-5, adults need to satisfy only 5 of the 9 criteria and children and adolescents still need to satisfy 6 of the 9 inattentive criteria. DSM-IV required that symptoms present before age 7-a challenging retrospective for adult patients who had not previously sought an intervention.

Even with the new criteria, practitioners need to make a retrospective evaluation of the presence of ADHD in childhood in order to establish a diagnosis in adulthood. This was cited as one of the most problematic components of the criteria because many patients could not recall childhood symptoms or they could not produce documentation substantiating a childhood diagnosis. Because ADHD is considered a developmental disorder, the presence of current symptoms as well as a history of previous symptoms (in childhood) needs to be established. Patients with ADHD, however, have impaired short- and long-term memory; therefore, recall bias can affect the accuracy of assessments. The practitioner is faced with the challenge of determining whether this was an established childhood diagnosis, a missed diagnosis in childhood, or a late-onset adult ADHD.

There are a host of validated rating scales for assessing adult patients with suspected ADHD, although each has inherent limitations. The Adult Self-Report Scale (ASRS) is an 18-item screening tool that is based on DSM-IV criteria. Patients rate the items based on the frequency and degree to which they occur. A 6-item version of the ASRS captures abnormalities in the domains related to follow-through, memory, organization, procrastination, restlessness, and hyperactivity.

The Conners Self-Report Scale is a multidimensional assessment scale that both the patient and an observer complete. The long version of this scale has 66 items that assess symptoms consistent with inattention and memory deficits, impulsivity and emotional lability, hyperactivity and restlessness, and problems with self-conceptualization.

 Having multiple perspectives is ideal in that the observer can contribute critical data that the patient may be either unaware of or not willing to disclose. One of the most significant limitations of self-report scales is that they are generally not sufficient independently to establish a diagnosis in the absence of more objective data or documentation. A 30-item version of the Conners Adult ADHD Self-Report Scale can also be used.

Psychiatric comorbidity and symptom overlap

Another challenge in the evaluation of adult ADHD is the symptom overlap between ADHD and mood and anxiety disorders. Patients with ADHD tend to have high rates of comorbidity with anxiety, depression, and substance abuse disorders, with prevalence rates that are more than double those observed in patients without ADHD.

 In a 2006 study, 87% of adult patients had at least one psychiatric comorbidity and 56% had two.

 Determining whether ADHD is present alone or whether it is comorbid with another psychiatric disorder is critical-a mood or anxiety disorder may be responsible for the ADHD-like symptoms.

Compared with patients who have a depressive disorder, those with ADHD tend to have more occupational or functional impairment, organizational deficits, and impulsivity issues. The distinction between ADHD and bipolar disorder can be especially challenging, since the manic and hypomanic features of bipolar disorder are similar to the hyperactive and impulsive symptoms associated with ADHD. In patients with ADHD, these symptoms tend to be constant, but in bipolar disorder there is a waxing and waning of manic symptoms interrupted with periods of depression. Patients with bipolar disorder tend to be goal-directed and are usually productive, while patients with ADHD are less able to complete tasks.

Substance use disorders are more common in patients with ADHD, and the clinical course of ADHD tends to be more challenging in this patient population. In patients with an opiate or cocaine addiction, the prevalence of ADHD is as high as 35%; and for alcohol-addicted patients, the ADHD prevalence exceeds 70%.

 Alcohol and certain prescription and illicit drugs can produce symptoms that mirror those of ADHD, which may artificially inflate the prevalence of ADHD in patients with an addiction problem and may not be reflective of the true prevalence.

Adult patients may develop and depend on compensatory mechanisms in order to overcome some of the functional impairments associated with ADHD.

 Patients who are highly functioning with higher than average IQs tend to develop useful coping mechanisms to overcome symptoms or to hide them from others. Some patients become compulsive list makers or develop a highly structured daily routine in order to complete tasks and to minimize forgetting details or losing belongings.

They may unknowingly rely on coworkers or family members to an inappropriate extent for reminders or assistance in completing tasks or fulfilling responsibilities. Although compensatory mechanisms are generally therapeutic for the patient, they may cloud the clinical picture particularly in cases where the patient does not self-suspect ADHD but rather a family member or the practitioner suspects ADHD.

Engaging in compensatory mechanisms such as relying significantly on others or forgoing sleep to finish tasks may mask the symptoms of ADHD or suggest that a patient is adequately coping when he or she is not. In any case, the use of appropriate compensatory mechanisms should also be taken into consideration when determining whether drug therapy is indicated. Some patients can manage without a clinically significant functional impact by relying on compensatory mechanisms and are able to avoid drug therapy.

Among the DSM criteria is an item that evaluates the degree of clinical impact of ADHD symptoms on life domains. For a diagnosis of ADHD, there must be clear evidence of significant clinical impact, which can be especially difficult to objectively assess. Failure to demonstrate significant clinical impact precludes a diagnosis of ADHD even if all other criteria are satisfied. Examples of true clinical impact include disciplinary action at work, risk of job loss, relationship discord, or frequent automobile accidents or accidents in the home.

Given the high degree of psychiatric symptom overlap, the realistic possibility of feigning ADHD symptoms, and a general fear of enabling drug addiction or diversion, the underdiagnosis versus overdiagnosis of ADHD in practice has been called into question. There are no available data to quantify this concern, and therefore no support can be lent to the argument of failure to recognize ADHD or misdiagnosis of ADHD. A psychiatric comorbidity and the point of entry into the health care system (primary care versus a psychiatrist) may influence whether ADHD is overdiagnosed or underdiagnosed. The most frequent point of entry into the health care system and the most common place for ADHD to be evaluated and diagnosed is in the primary care setting, where it may be overdiagnosed. However, when patients are seen by a psychiatrist, it usually is the comorbid psychiatric diagnosis that is treated and not ADHD. Thus, ADHD may be underdiagnosed when patients present to a psychiatrist. Given the assertion that ADHD is overdiagnosed in primary care and underdiagnosed by specialists, the true prevalence of ADHD theoretically lies somewhere in between.

Prescription drug abuse and drug-seeking behavior

According to the most recent survey by the National Institute on Drug Abuse, adults between the ages of 18 and 25 are statistically the most likely to abuse prescription drugs.

 Adults between the ages of 18 and 22 are the most likely to abuse stimulant medications, with rates in college students double those in non-college students.

 The majority of adult patients who present with self-suspected ADHD are between the ages of 18 and 24; therefore, the unfortunate but realistic risk of drug seeking must be considered.

A definitive statistic that quantifies the risk and rates of stimulant medication abuse is elusive owing to patient unwillingness to admit abuse or diversion. However, multiple studies have attempted to capture this rate through anonymous surveys and emergency-department visits. Generally stimulants with a rapid onset of effect and shorter half-life are more likely to be abused, since there is a more narrow window between ingesting the drug and realizing the perceived reward. Variability exists within the therapeutic class in terms of abuse potential: rates of abuse of amphetamine salts exceed those of methylphenidate.

Establishing a meaningful comparison of the rates of abuse of stimulant medications compared with prescription drugs for other indications is also challenging. Considering the physiologic consequences of abusing stimulants, opioids, or sedative-hypnotics, it may not be surprising that accidental death due to abuse of a prescription drug is by far the highest for the opioids. Prescription opioid-related accidental deaths were more frequent than cocaine, heroin, and stimulant overdoses combined.

Psychostimulants remain the drug class of choice in treating adults and children with ADHD. Most product formulations available are derived from one of two parent molecules: methylphenidate or amphetamine (

). Pharmacologically, the stimulants inhibit the reuptake of dopamine and norepinephrine, thereby increasing concentrations in the presynaptic cleft. Amphetamines also directly stimulate the release of dopamine and norepinephrine. About 14 products are currently available in the US: some of them are immediate-release and others are extended-release formulations. It is generally recommended that drug therapy, particularly in adults, should consist of an extended-release product in order to maximize compliance and minimize the risk of abuse. Stimulant medications mitigate traditional ADHD symptoms and have demonstrated utility in improving interpersonal relationships, self-esteem, and cognition, as well as alleviating symptoms of comorbid anxiety disorders.

 Stimulants are arguably the most effective in resolving ADHD symptoms and comorbid psychopathology; however, because of the risk of adverse effects and abuse potential, these agents may be underprescribed for adult ADHD.

Common, transient adverse effects include sleep disturbance, appetite suppression and associated weight loss, agitation, and nervousness. These are typically minimized by taking the drugs with food and using an extended-release formulation. Serious concerns exist regarding cardiotoxicity. Patients can experience palpitations, tachycardia, and elevations in blood pressure. Serious cardiovascular effects include rhythm disturbances and cardiomyopathy, which precludes use in patients who have an existing cardiovascular abnormality.

Owing to their less impressive effectiveness compared with stimulants, the nonstimulant medications tend to be prescribed less frequently among all age groups. Generally, practitioners do not initiate drug therapy with a nonstimulant unless the patient has a contraindication to stimulants (cardiac abnormalities, previous or current substance abuse) or is intolerant to or has failed a trial of a stimulant. Currently, the nonstimulant therapeutic class includes atomoxetine, immediate- and extended-release guanfacine, clonidine, and bupropion 

Atomoxetine’s efficacy and safety have been demonstrated in adults and children; however, its associated rates of response are less impressive than those of the stimulants. It remains an appropriate option in patients who have contraindications to stimulants or who have a comorbid anxiety disorder, as anecdotal evidence suggests some level of anxiolytic activity.

Bupropion has been evaluated in a small number of studies involving children, adolescents, and adults, in whom its efficacy compared with placebo or with an active stimulant comparator has been established. This is not an approved indication for bupropion in any age group, however. Bupropion may be a therapeutic alternative in adults who have contraindications or are intolerant to stimulant medications, or in patients who have a comorbid depressive illness.

Guanfacine and clonidine are typically reserved for children who also have a hyperactive component. Of the newer extended-release formulations, only extended-release clonidine has an indication for the treatment of adult ADHD.

A 42-year-old woman presents to a primary care clinic for an evaluation of her attention issues. Alice’s symptoms became apparent in early grade school, but with extra effort she managed to get good grades throughout elementary school, high school, and college. Lately she has had increasing difficulty in remembering appointments and completing her projects; she has also been losing her belongings, avoiding tasks, getting distracted at meetings, and failing to listen to people when they speak to her. Her direct superior has brought this to her attention and has mentioned possible disciplinary action. Symptoms occur all day, regardless of setting. Her past medical history includes dyslipidemia, anxiety, and gastroesophageal reflux disease. Prescription medications include 20-mg atorvastatin daily, 10-mg escitalopram daily, and 20-mg omeprazole daily. Evaluations for mood and anxiety disorders reveal no additional diagnoses. There is no documented history of or current issues with substance abuse.

Does this patient fulfill DSM-5 diagnostic criteria for ADHD?

. She reports at least 5 symptoms of inattention (remembering appointments, finishing projects, losing belongings, task avoidance, easy distraction, failing to listen to others in conversation). The symptoms (per patient report) began before age 12, occur both at work and at home, and have resulted in functional impairment (evidenced by her supervisor’s threat of disciplinary action). Given her age, it would be difficult to collect collateral supporting information from a teacher or parent, and so the patient report alone will need to be the only account of symptoms. The clinician’s judgment about the validity of these claims will also need to be taken into consideration. If possible, an attempt could be made to discuss these issues with the patient’s husband or work supervisor in order to acquire different perspectives and additional supporting information. Other psychiatric diagnoses and substance abuse issues are ruled out; therefore, the ADHD symptoms are not better explained by another psychiatric disorder.

Is this patient a candidate for a pharmacotherapeutic intervention?

 Current treatment guidelines recommend initiating drug therapy in adults as a first-line treatment.

Is this patient a candidate for non-drug therapy?

 There is no treatment guideline that specifically recommends non-drug therapy for adult patients because there is a lack of efficacy data to support it. However, if the patient complains of specific symptoms that may be behavior-mediated (such as time management or procrastination-related symptoms), counseling or other workshop-based interventions may help her to manage these symptoms more effectively and may eventually reduce her dependence on drug therapy for the monotherapy of ADHD.

What pharmacotherapeutic intervention(s) would be most appropriate?

 Consistent with the domestic guidelines for the management of ADHD in children, the National Institute for Health and Care Excellence guidelines in Europe recommend initiating a stimulant medication as first-line therapy. None of the stimulants are considered superior with regard to safety or efficacy in adults or children. However, a long-acting formulation is generally preferred because of the reduced likelihood of abuse. This patient has no history of substance abuse, but use of longer-acting formulations will minimize any risk.

Longer-acting products tend to have a smoother onset and offset of action compared with immediate-release agents, which produce a noticeable onset in most patients. A longer-acting product will reduce the pill burden and will require less frequent dosing-an advantage for someone who needs coverage throughout the day.

If this patient has a contraindication to stimulants, what is the next most appropriate intervention?

 Contraindications to stimulants generally include cardiovascular issues such as arrhythmias, uncontrolled hypertension, or concomitant administration of other drugs that can be arrhythmogenic. In the setting of a contraindication, the nonstimulants could be considered. Atomoxetine is generally used first because its efficacy data are more robust than that of clonidine, guanfacine, and bupropion.

If this patient had a comorbid diagnosis of depression or anxiety, how might the treatment plan for ADHD be different?

 Depending on the severity of symptoms, the practitioner may choose to treat the mood or anxiety disorder first. This depends on which symptoms are most distressing and which are causing the most functional impairment. Improvement in a comorbid mood and/or anxiety disorder may also indirectly improve ADHD symptoms because patients who are euthymic and not anxious may be better equipped to deal with the ADHD symptoms. Assuming that the comorbid diagnosis is depression, a stimulant and an antidepressant could be initiated, but not at the same time in order to gauge which drug resulted in the resolution of which symptoms.

Bupropion might be a possible intervention if a reduction in pill burden is important. Bupropion is not indicated for ADHD, but there is some evidence to support its use. Assuming that the comorbidity is anxiety, the initiation of a stimulant may or may not worsen symptoms. This is highly patient-specific and will depend on whether the anxiety is worsening the ADHD or vice versa. It may be advisable to initiate medication therapy for the anxiety first and once improved or resolved, initiate drug therapy carefully for the ADHD and monitor for worsening of anxious symptoms.

Historically considered a diagnosis of childhood, ADHD persists into adulthood for a vast majority of patients. Secondary to the absence of validated screening tools for adults, the pervasive symptom overlap with other psychiatric illnesses, frequent comorbidity with other psychiatric diagnoses, feigned ADHD, and the risk of drug diversion or abuse, diagnosis in adults has proven to be challenging. However, utilizing the available diagnostic criteria, gathering as much data as possible from as many sources as possible, considering the possible influence of other psychiatric comorbidities, and being diligent in assessing risk of abuse, the diagnosis of ADHD in an adult can be achieved responsibly and with minimal risk.

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Dr Reinhold is Associate Professor of Clinical Pharmacy in the department of pharmacy practice/pharmacy administration at The Philadelphia College of Pharmacy at the University of the Sciences in Philadelphia.

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 Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. 

 McGough JJ, Smalley SL, McCracken JT, et al. Psychiatric comorbidity in adult attention deficit hyperactivity disorder: findings from multiplex families. 

 Levin FR. Diagnosing attention-deficit/hyperactivity disorder in patients with substance use disorders. 

 Santosh PJ, Sattar S, Canagaratnam M. Efficacy and tolerability of pharmacotherapies for attention-deficit hyperactivity disorder in adults. 

 Fayyad J, De Graaf R, Kessler R. Cross-national prevalence and correlates of adult attention-deficit hyperactivity disorder. 

 Ginsberg Y, Quintero J, Anand E, et al. Underdiagnosis of attention-deficit/hyperactivity disorder in adult patients: a review of the literature. 

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 Substance Abuse and Mental Health Services Administration. Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings. 2013. 

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Articles

The clinical presentation and functional impacts of ADHD in adults vary greatly from their child and adolescent counterparts. Here: latest information on this complex topic.

Adult ADHD: A Review of the  Clinical Presentation, Challenges,  and Treatment Options 

Generalized anxiety disorder (GAD) is a highly prevalent, chronic, debilitating, relapsing, and often underdiagnosed anxiety disorder. Characterized by a waxing and waning episodic clinical course replete with periods of remission and relapse, GAD presents with excessive and pathological worry that is difficult to control. A diagnosis of GAD incorporates physical, psychological, and cognitive symptoms as well as potentially profound functional impairment.

The core symptom of excessive worry must be present for a minimum of 6 months and must occur in conjunction with at least 3 of 6 physiological arousal symptoms: restlessness, fatigue, muscle tension, irritability, concentration deficit, and sleep disturbance. The evolution of the diagnostic criteria from DSM-III through DSM-5 has seen changes only in the duration of the core worry component, which increased from a duration of 1 month in DSM-III to 6 months in DSM-IV and DSM-5.

[[{"type":"media","view_mode":"media_crop","fid":"31077","attributes":{"alt":"GAD","class":"media-image media-image-right","id":"media_crop_1657298906725","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"3281","media_crop_rotate":"0","media_crop_scale_h":"159","media_crop_scale_w":"160","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]The most commonly occurring anxiety disorder, GAD is unlike the other anxiety disorders. It is a disorder of adult onset, with the highest median age of onset of all the anxiety disorders-a pattern more consistent with MDD.

The pathological worry is typically based on extant dangers with an overestimated likelihood that such dangers will realistically occur (eg, a loved one is kidnapped). This then rapidly devolves into generalized worry that pervades multiple life domains. For some patients, this leads to avoidant behavior, and activities or places with perceived danger are avoided. If it is not treated, the patient’s sphere of comfort may continue to constrict until daily activities become limited and normal function is impaired.

The close association of somatic complaints may complicate the diagnostic process, because patients with GAD generally present in primary care with a physical symptom seemingly unrelated to a mental health condition. Aside from the physical, psychological, and cognitive manifestations, social and occupational functioning are often impaired. The functional impairment sustained in GAD is comparable in magnitude to that of MDD. The robust association of GAD and psychiatric and physical comorbidity complicates the clinical course and is associated with reduced response and remission rates.

The diagnosis of GAD is initially made using DSM-5 criteria, which is generally coupled with the Hamilton Rating Scale for Anxiety (HAM-A) to assess severity, the Clinical Global Impression-Improvement (CGI-I) scale to assess overall improvement, and the Sheehan Disability Scale (SDS) to assess functionality.

Treatment response is defined as a 50% or greater improvement in HAM-A score and a “much improved” or “very much improved” rating on the CGI-I. Remission is defined as a HAM-A score of 7 or less, a CGI-I score of 1 (not ill at all), and an SDS score of 5 or less. Although at least half of the patients respond to treatment, remission is achieved by only about one-third to half of those who respond. Failure to remit fully confers a greater risk of relapse.

Treatment phases are delineated into an acute and a long-term phase, with slight variations in treatment goals. Acutely, the goal is to improve the presenting anxiety symptoms. Once target symptoms are improved or resolved, the focus shifts to long-term, or maintenance, therapy, the goal of which is to completely resolve symptoms and return the patient to a premorbid level of social and occupational functionality (remission). Coupled with the goal of remission is relapse prevention. Characterized by alternating periods of remission and relapse, a critical therapeutic challenge in treating GAD is preventing relapse or recurrence of symptoms. Symptomatic remission typically precedes functional remission, which underscores the need for deliberately longer courses of treatment to truly achieve remission.

 Customarily a single drug, generally an antidepressant, is initiated at a low dosage and is titrated according to clinical response and tolerability. A preliminary assessment of response can be gauged at 4 to 8 weeks. Patients who endorse some level of appreciable symptom resolution and are tolerant of the medication are considered to have achieved a durable remission. This is considered predictive of an eventual sustained remission that persists for several months beyond this acute treatment phase.

The absence of a response at the initial 4- to 8-week follow-up visit or intolerance of adverse effects may prompt either a reevaluation of the diagnosis or an adjustment in medication. Reasonable interventions include increasing the dosage of medication (if the initial drug was tolerated but the clinical effect was not of the magnitude desired), switching to a different drug within the same pharmacological class (if there was some level of improvement but questionable tolerability), switching to a drug outside of the pharmacological class (if there was lack of response and/or poor tolerability), or augmenting the initial drug (if the dose of the initial drug was already optimized but the full therapeutic effect had not been achieved).

The acute treatment phase is now considered the most therapeutically sound time to use a benzodiazepine, which is representative of a shift in philosophy from when drug therapy options were more limited.

 On resolution of the presenting anxiety symptoms, it is recommended that treatment be continued beyond initial symptom resolution for 12 months to minimize the risk of relapse. If a benzodiazepine was initiated concomitantly with an antidepressant during the acute phase, it is generally tapered during the maintenance phase.

Currently available pharmacotherapeutic options

The arsenal of recommended pharmacotherapeutic interventions has grown meaningfully in the past decade. Drug classes that were experimental for the treatment of GAD 10 years ago have risen to first-line options, and newer, novel drug products are now beginning to amass a litany of literature that serves as an evidence base for clinical practice. Secondary to the proposed neurobiological basis for pathological worry and anxiety syndromes, drug therapies with evidence for clinical utility tend to target serotonin, norepinephrine, Î³-aminobutyric acid (GABA), or combinations thereof. Internationally, the SSRIs, the SNRIs, and pregabalin are regarded as first-line options for GAD. US guidelines have not yet integrated pregabalin into the first-line tier, nor does the drug have FDA approval for this indication; however, it is considered an alternative therapy.

 These drugs are thought to mitigate anxiety symptoms by inhibiting the reuptake of serotonin in the synaptic cleft. While the 2- to 4-week delay until onset of therapeutic effect may be discouraging and may impact patient compliance, significant reductions in “anxious mood” have been documented as early as week 1 in paroxetine trials. Remission rates in paroxetine responders at 32 weeks are as high as 73%, with only 11% relapsing, a statistic that demonstrates much improvement over the spontaneous remission rate of 20% to 25%.

In patients with moderate to severe GAD, sertraline 50 to 100 mg/d has demonstrated superiority to placebo in improving HAM-A score. Clinical response criteria were met by 55% of patients in the sertraline group compared with 32% in the placebo group by week 12.

Escitalopram has been evaluated for the long-term treatment of GAD and prevention of relapse. Davidson and colleagues

 reported significantly superior improvements in HAM-A total score, HAM-A somatic and psychic subscales, and quality-of-life measures for escitalopram at every time point starting at week 1. By week 4, 50% of patients in the escitalopram arm had responded, and by week 8, 68% fulfilled response criteria. Remission was achieved by 36% of patients who received escitalopram compared with 16% of patients who received placebo (P < .01).

Pooled analyses further promulgate the sustained superior efficacy of escitalopram compared with placebo as early as week 1 with respect to HAM-A score and response and remission.

 The 24-week open-label extension study found that at 24 weeks, 92% of patients had responded and 60% of patients had remitted.

The adverse effects of SSRIs include weight gain, somnolence, GI sequelae, and agitation. Sexual dysfunction, often a presenting symptom in anxious patients, may be exacerbated or instigated. Another unfortunate pharmacological phenomenon of the SSRI class is its ability to cause agitation and jitteriness in the acute phase of treatment. This, coupled with the adverse-effect profile, might be responsible for early treatment failure with SSRIs.

 These agents inhibit the reuptake of serotonin and norepinephrine, although the selectivity and balance with respect to the extent of inhibition are variable among the SNRIs. Superior efficacy in improving anxiety symptoms as evidenced by reduction in HAM-A total scores was seen with 75 to 225 mg of venlafaxine XR daily compared with placebo.

 In addition, venlafaxine’s efficacy in treating anxiety symptoms in patients with comorbid depression as well as those with pure GAD has made it a commonly prescribed first-line drug.

The comorbidity of nonspecific somatic pain complaints is common in patients with GAD, and it negatively impacts quality of life, worsens outcomes, hampers symptom remission, and increases the risk of relapse. In a limited comparison of venlafaxine versus paroxetine, the improvement of HAM-A score and rates of response and remission did not differ between paroxetine and venlafaxine by week 8.

 evaluated the time to relapse by extending venlafaxine treatment to 6 and to 12 months in patients who had an initial response. After 12 months of treatment with venlafaxine, the relapse rate was 6.7% for the venlafaxine group and 32.3% for the placebo group. This study supports the use of venlafaxine for at least 12 months in patients who respond.

The inhibition of serotonin and norepinephrine is more balanced with duloxetine than with venlafaxine. Its dual effect on anxiety symptoms and somatic pain resulted in 53% to 61% of treated patients who achieved symptomatic remission and approximately 47% who achieved functional remission.

 A second study of similar design also supported the superiority of duloxetine 60 to 120 mg compared with placebo in terms of HAM-A score improvement but did not observe a difference in rates of response, although the maintenance of response was superior to that of placebo.

Early response to duloxetine within the first 2 weeks of therapy is predictive of a maintained response; therapy for 6 or more months is associated with functional remission and reduced risk of relapse. Duloxetine causes less sexual dysfunction than paroxetine.

The adverse effects are similar in scope and magnitude to those of the SSRIs; however, the risk of clinically meaningful increases in blood pressure have also been documented, particularly with venlafaxine.

. The anxiolytic properties of the benzodiazepines are attributable to the modulation of the GABA receptor and enhancement of GABA’s inhibitory effects with subsequent inhibition of monoamine reuptake. Benzodiazepines are indicated for the short-term management of the acute phase of anxiety (first 2 to 4 weeks) and for any subsequent exacerbations of anxiety during stable treatment with an antidepressant. Their rapid onset of action and tolerability make them conducive to alleviating anxiety symptoms when immediate anxiolytic effects are necessary.

Although more marked improvement is realized in the first 2 weeks of treatment with benzodiazepines, antidepressants consistently achieve the same efficacy and surpass it after 6 to 12 weeks of treatment. Although still a common practice, the use of benzodiazepines as long-term or as monotherapy is not recommended and is inconsistent with evidence-based guidelines. Benzodiazepines are most adept at alleviating somatic symptoms but have no effect, and may even have a somewhat detrimental effect, on the psychic symptoms of GAD.

. As a class, the TCAs have been limited by, and largely replaced as a result of, their adverse-effect profile. The anticholinergic and antiadrenergic effects, such as orthostasis, sexual dysfunction, sedation, and constipation, have markedly affected patient tolerability. The profound risk of toxicity in overdose coupled with these undesired effects has resulted in TCAs being replaced by newer, more tolerable, and possibly more effective drugs that are less toxic in overdose.

Of the TCAs, imipramine has the most compelling efficacy data relative to other drug therapies. In a landmark study by Rickels and colleagues,

 anxiolytic effects of imipramine, trazodone, diazepam, and placebo were compared in nondepressed patients with GAD. Imipramine resulted in moderate to marked improvement between weeks 2 and 8 of therapy in 73% of patients, compared with 69% for trazodone, 66% for diazepam, and 44% for placebo.

. This antianxiety agent is a partial agonist at the serotonin-1A receptors and a full agonist at the presynaptic serotonergic autoreceptors. Although buspirone’s effectiveness in treating GAD has been demonstrated inconsistently in several studies, its delayed onset of action, tolerability, and relative lack of efficacy with respect to most comorbid conditions (with the exception of MDD) has resulted in buspirone being used primarily as adjunctive therapy. Its effectiveness is comparable to but slightly weaker than that of diazepam, clorazepate, lorazepam, and alprazolam, but it has a clearly slower onset of action.

A randomized controlled trial in GAD patients without comorbid MDD compared buspirone and venlafaxine with placebo and found that both active treatments were superior to placebo.

 Buspirone’s utility is mainly associated with its propensity to relieve the cognitive aspects, but it lacks long-term efficacy-particularly in managing the behavioral and somatic manifestations.

. Pregabalin is a branched-chain amino acid and GABA analogue. The antinociceptive, antiseizure, and potentially anxiolytic properties of pregabalin-mediated through binding to the Î±2Î´ subunit of voltage-gated calcium channels within the CNS. Its action involves decreasing calcium influx at the presynaptic channel and subsequent inhibition of norepinephrine and glutamate.

Two similarly designed randomized, placeboand active comparator–controlled, double-blind studies evaluated the efficacy of pregabalin versus lorazepam for the treatment of GAD. The pregabalin groups and the lorazepam group all experienced greater reductions in HAM-A score by week 4 compared with placebo, with no observed statistically significant differences among the active-treatment groups. Pregabalin at its highest study dose (600 mg) produced reductions in the psychic and somatic anxiety HAM-A subscale scores that were statistically superior to those produced with placebo, whereas lorazepam produced reductions that reached statistical significance versus placebo with respect to only the somatic subscale. The improvements in HAM-A score produced by the active-treatment groups were apparent by week 1 of the study.

The relative efficacy and early onset of effect of pregabalin versus commonly used benzodiazepines may represent a new therapeutic intervention for GAD as both a monotherapy (after failure of an initial monotherapy) and as an augmentation strategy. Pregabalin is renally excreted and therefore poses a low risk of drug-drug interactions, lacks withdrawal or physical dependence risk, is associated with minimal adverse effects (dizziness, weight gain, insomnia), and is safe and well tolerated. A potential role for pregabalin may be in patients who are tapering off long-term benzodiazepine monotherapy for GAD.

 is a novel compound that acts as an agonist of melatonergic (MT1, MT2) receptors and an antagonist of serotonergic (serotonin-2C) receptors. The antidepressant and anxiolytic effects of agomelatine appear to be mediated through the synergistic action at these receptors rather than through either one independently.

A 12-week, randomized, placebo-controlled study evaluated 25 to 50 mg of agomelatine used daily as monotherapy for GAD.15 HAM-A total score, CGI, Leeds Sleep Evaluation Questionnaire, and the SDS were used to assess response. By week 6, agomelatine was associated with a larger decrease in HAM-A score that persisted through study end. Responder rate in the agomelatine group separated from placebo by week 2 and persisted through week 12. By study end, remission rates were statistically significantly higher in the agomelatine group than in the placebo group. Subjective sleep parameters also improved to a greater extent in the agomelatine group. The most commonly reported adverse effects associated with agomelatine were dizziness and nausea.

A longer-term, randomized, placebo-controlled relapse prevention studied enrolled patients who had responded to an initial 16-week open-label treatment with agomelatine into a 26-week double-blind maintenance period, during which time to relapse was assessed.

 Patients either remained in the agomelatine group or were switched to placebo during the blinded maintenance phase. During this phase, 19.5% of patients in the agomelatine arm relapsed compared with 30.7% in the placebo arm (P = .046). The risk of relapse over time was reduced by 41.8% for the agomelatine group (hazard ratio = 0.582). The reduced risk of relapse was achieved in the severely ill group as well. Discontinuation of agomelatine did not precipitate withdrawal or discontinuation effects.

A 12-week international, multicenter, randomized, double-blind, placebo-controlled, active-comparator, parallel group study evaluated the efficacy of 25 to 50 mg of agomelatine daily compared with that of placebo or 10 to 20 mg of escitalopram daily.

 Both agomelatine and escitalopram were statistically superior to placebo in the reduction of HAM-A score by study end as well as in response rate and remission rate. This was also observed in the severely ill subset and was more pronounced in this group than in the full analysis set. Agomelatine has been established as a possible therapy for patients who endorse psychic and somatic symptoms and for patients who are considered more severely ill. It may be useful for treating patients for whom there is concern about drug interactions, dependence, or intolerance of adverse effects, since none of these issues are associated with agomelatine.

Vortioxetine is a multimodal antidepressant with potential anxiolytic effects. It acts as an inhibitor of serotonin reuptake by antagonizing the serotonin-3, serotonin-7, and serotonin-1D receptors, agonizing the serotonin-1A receptor, partially agonizing the serotonin-1B receptor, and inhibiting the serotonin transporter. Vortioxetine’s activity at multiple receptors results in modulation of the serotonergic, noradrenergic, dopaminergic, and histaminic systems, which results in antidepressant effects.

A 12-week relapse prevention study suggested that 5 or 10 mg of vortioxetine daily was efficacious in preventing relapse compared with placebo, and it was well tolerated.

 The most recent study, a randomized, double-blind, fixed-dose study, compared 2.5 and 10 mg of vortioxetine daily with placebo and found that there was no meaningful difference among any of the study arms.

Atypical antipsychotics differ from typical antipsychotics with respect to their ability to antagonize the serotonin-2A receptor and with their partial agonism of the serotonin-1A receptor. Modulating the serotonin-1A receptor yields the anxiolytic effects, while antagonism of the serotonin-2A receptor minimizes the development of extrapyramidal effects. The atypical antipsychotics, particularly olanzapine, risperidone, and aripiprazole, also have high affinity for histamine receptors, which further augments their sedative and anxiolytic effects.

Aripiprazole was evaluated in 4 open-label studies involving patients with treatment-resistant disease who were not adequately controlled with SSRI monotherapy.

 A retrospective analysis reported that at the end of 12 weeks, 59% of patients were considered “improved” or “very much improved” in terms of CGI-I, which equates to a response. Numerous patients experienced an early (weeks 1 to 5) as well as sustained response to augmentation with 15 and 30 mg of aripiprazole daily. Weight gain, sedation, and insomnia were among the most frequently reported adverse events. Two additional studies also supported the use of adjunctive aripiprazole, citing statistically significant improvements in HAM-A and CGI-I scores and appreciable rates of treatment response.

 Sedation, insomnia, and significant weight gain were observed in all 4 studies.

Adjunctive risperidone has improved the clinical picture in patients with either treatment-refractory GAD or residual anxiety symptoms. The separation from placebo occurs as early as week 2 of therapy with respect to statistically significant reductions in HAM-A score. Patients with more severe residual anxiety symptoms derived the most benefit; the magnitude of score improvement was greater for these patients than for patients with less serious symptoms at baseline.

 Adverse effects most frequently observed include weight gain, headache, and increased appetite.

Evidence suggests that monotherapy with extended-release quetiapine yields clinically and statistically significant improvements in HAM-A score and improved rates of remission compared with placebo. Three 10-week, multicenter, double-blind, placeboand active-controlled studies found that the reductions in HAM-A scores were statistically different from placebo for all active arms, with meaningful separation from placebo as early as week 1. Some improvements occurred as early as day 4. Somnolence, dizziness, and fatigue were reported more frequently in the active arms, yet sexual function improved slightly in the quetiapine groups.

Patients with MDD frequently endorse comorbid anxiety, and the addition of quetiapine to SSRIs or venlafaxine was shown to improve HAM-A score by week 2 and improve rates of response and remission.

 Quetiapine also has been shown to decrease symptom recurrence and improve sleep quality in patients during maintenance treatment.

 Evidence supporting the use of quetiapine as adjunctive therapy in patients who are classified as nonresponders or partial responders is inconsistent at best and is not currently recommended.

Medications prescribed for GAD, although relatively effective, are associated with adverse effects and are frequently discontinued by patients after an inappropriately brief duration. Premature discontinuation of medication or unrealistic expectations can result in ineffective treatment and the retention of residual symptoms. The presence of residual symptoms increases the likelihood of a relapse.

The first step in maximizing the effects of drug therapy is to provide patient education, specifically concentrating on adverse effects and when to expect them to arise, the expected delay in therapeutic effect when using antidepressants, and the importance of adhering to the regimen until an appropriate interval at which the efficacy and tolerability can be assessed. When a patient experiences lack of success with an initial monotherapy, additional medications can be used adjunctively to augment the first. This is becoming increasingly more common with the advent of anticonvulsants and antipsychotics being integrated into the treatment schema, particularly in treatment-resistant patients. Fortunately, there is momentum in developing newer, novel drugs in the hopes of mitigating some of the issues experienced with our current armamentarium.

Dr Reinhold is Associate Professor of Clinical Pharmacy in the department of pharmacy practice/pharmacy administration at the Philadelphia College of Pharmacy. She reports no conflicts of interest concerning the subject matter of this article.

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Treatment approaches to GAD, a highly prevalent, chronic, debilitating, relapsing, and often underdiagnosed anxiety disorder.  

Pharmacological Strategies for Generalized Anxiety Disorder

The Intricacies of Diagnosis and Treatment, by Thomas L. Schwartz, MD

Strategies for Assessing and Treating Comorbid Panic and Generalized Anxiety Disorder, by Kristalyn Salters-Pedneault, PhD

Can Anticonvulsants Help Patients With Anxiety Disorders? by Marco Mula, MD, PhD

SSRIs as Antihypertensives in Patients With Autonomic Panic Disorder, by Sean Hood, MBBS, MSc

Achieving Remission in Generalized Anxiety Disorder, by Laura A. Mandos, PharmD, Jennifer A. Reinhold, PharmD, and Karl Rickels, MD

Generalized anxiety disorder (GAD) is a prevalent, chronic, debilitating mental illness associated with marked impairment in daily functioning.

 An ongoing evolution of the definition of GAD has resulted in a bifurcation of the historical anxiety neurosis designation.

 A diagnosis of GAD currently implies chronic, excessive worry lasting at least 6 months and 3 of the possible 6 somatic or psychological symptoms (restlessness, fatigue, muscle tension, irritability, difficulty concentrating, and sleep disturbance).

 GAD typically presents in an episodic pattern of moderate improvement or remission and relapse characterized by a chronic and complicated clinical course.

Chronic worry, a core component of GAD, is consistently found in 10% of the population, and this subset reports a level of anxiety and tension so significant that it markedly impairs daily function. Epidemiological studies, however, suggest a lifetime GAD prevalence of 4% to 7%, a 1-year prevalence of 3% to 5%, and a current prevalence of 1.5% to 3%.4 Discrepancies between the incidence of anxiety-related symptoms and potential subsequent underestimation of GAD prevalence may be attributed to DSM-IV diagnostic criterion of 6 months’ duration of worry.

It is the robust association of GAD with psychological and physical comorbidities that potentially contributes to the complexity of the illness as well as the limited treatment success.

 More than 90% of patients with GAD present with an additional psychiatric diagnosis. The ancillary condition is major depressive disorder (MDD) in 48% of patients.

Generalized anxiety disorder (GAD) is a prevalent, chronic, debilitating mental illness associated with marked impairment in daily functioning.1 An ongoing evolution of the definition of GAD has resulted in a bifurcation of the historical anxiety neurosis designation.2 A diagnosis of GAD currently implies chronic, excessive worry lasting at least 6 months and 3 of the possible 6 somatic or psychological symptoms (restlessness, fatigue, muscle tension, irritability, difficulty concentrating, and sleep disturbance).3 GAD typically presents in an episodic pattern of moderate improvement or remission and relapse characterized by a chronic and complicated clinical course.