CNS Spectr. 2008;13:5(Suppl 8):1-20

An expert panel review of clinical challenges in psychiatry

This activity is jointly sponsored by the Mount Sinai School of Medicine and MBL Communications, Inc., and supported by an educational grant from Shire Pharmaceuticals Inc.

Accreditation Statement

This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. 

Credit Designation

The Mount Sinai School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s)^TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement

It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer reviewed and approved by Eric Hollander, MD, Chair and Professor of Psychiatry at the Mount Sinai School of Medicine. Review Date: April 23, 2008.

Statement of Need and Purpose

Although attention-deficit/hyperactivity disorder (ADHD) has traditionally been considered a pediatric disorder, up to 65% of children with a diagnosis of ADHD continue to display behavioral problems and symptoms of the disorder into their adult lives. Adults with ADHD demonstrate functional impairments in multiple domains, often including poor educational performance, occupational problems, and relationship difficulties. Accurate diagnosis of ADHD in adults is challenging and requires careful consideration of other psychiatric and medical disorders that may mimic symptoms of the disorder. The majority of adults with ADHD exhibit at least one comorbid psychiatric disorder, which may confound a proper ADHD diagnosis. Comorbidity between ADHD and major depressive disorder has been reported from both epidemiologic and clinical studies of both children and adults. Stimulants and noradrenergic and dopaminergic antidepressants have been shown to be useful medical interventions for adult ADHD. Cognitive-behavioral skills training and psychotherapy are useful adjuncts to pharmacotherapy. Devising a treatment plan for comorbid adult ADHD requires careful consideration, and treating the depression may improve ADHD symptoms such as inattention and irritability. Education is needed to increase the detection and treatment of adult ADHD and research is necessary to determine whether effective treatment would reduce the onset, persistence, and severity of disorders that co-occur with adult ADHD.

Target Audience

This activity is designed to meet the educational needs of psychiatrists.

Learning Objectives

• Evaluate recent research on the genetic and biologic evidence for associations between attention-deficit/hyperactivity disorder (ADHD) and depression.
• Assess the treatments that would benefit patients with ADHD and comorbid depression and the risks of treating this patient subgroup.

Faculty Disclosures

Timothy E. Wilens, MD, is associate professor of psychiatry in the Department of Psychiatry at Harvard Medical School and director of substance abuse services in the Clinical and Research Program in Pediatric Psychopharmacology at Massachusetts General Hospital in Boston. Dr. Wilens is a consultant for Abbott, Cephalon, Eli Lilly, Ortho-McNeil, Merck, the National Institutes of Health (NIH), National Institute on Drug Abuse (NIDA), Novartis, and Shire; is on the speaker’s bureaus of Ortho-McNeil, Novartis, and Shire; and receives grant support from Abbott, Eli Lilly, Ortho-McNeil, Merck, NIH, NIDA, and Shire. Dr. Wilens’ presentation includes discussion of  unapproved/investigational uses of treatments for adult attention-deficit/hyperactivity disorder.

Andrew A. Nierenberg, MD, is associate director of the Depression Clinical and Research Program at Massachusetts General Hospital and professor of psychiatry at Harvard Medical School in Boston. Dr. Nierenberg is a consultant to or serves on the advisory boards of AstraZeneca, Brain Cells, Bristol-Myers Squibb, Eli Lilly, Jazz, Merck, the National Institute of Mental Health (NIMH), Novartis, and Schering-Plough; and receives research support from the NIMH and Pfizer.

Anthony L. Rostain, MD, is professor of psychiatry and pediatrics and director of the Adult ADHD Treatment and Research Program at the University of Pennsylvania School of Medicine in Philadelphia. Dr. Rostain has received honoraria from Eli Lilly and Ortho-McNeil; and serves on the advisory board of Shire.

Thomas J. Spencer, MD, is associate professor of psychiatry at Harvard Medical School and associate director of the Clinical and Research Program in Pediatric Psychopharmacology at Massachusetts General Hospital in Boston. Dr. Spencer is on the advisory boards of Cephalon, Eli Lilly, GlaxoSmithKline, McNeil, Novartis, Pfizer, and Shire; is on the speaker’s bureaus of Eli Lilly, GlaxoSmithKline, Ortho-McNeil, Novartis, and Shire; and receives research support from Cephalon, Eli Lilly, GlaxoSmithKline, Ortho-McNeil, Novartis, and Shire. Dr. Spencer’s presentation includes discussion of unapproved/investigational uses of atomoxetine, fluoxetine, paroxetine, and venlafaxine.

Acknowledgment of Commercial Support

Funding for this activity has been provided by an educational grant from Shire Pharmaceuticals Inc.

Peer Reviewers

David L. Ginsberg, MD, receives honoraria from AstraZeneca and GlaxoSmithKline.

Eric Hollander, MD, reports no affiliation with or financial interest in any organization that may pose a conflict of interest. 

To Receive Credit for this Activity

Read this Expert Roundtable Supplement, reflect on the information presented, and complete the CME posttest and evaluation on pages 19 and 20. To obtain credit, you should score 70% or better. Early submission of this posttest is encouraged. Please submit this posttest by May 1, 2010 to be eligible for credit. Release date: May 1, 2008; Termination date: May 31, 2010

The estimated time to complete this activity is 2 hours.

A related audio CME PsychCast^TM will also be available online in June 2008 at: cmepsychcast.mblcommunications.com and via iTunes.

Abstract

Major Depressive Disorder: Epidemiology, Course of Illness, and Treatment

Andrew A. Nierenberg, MD

Introduction

Understanding the epidemiology of major depressive disorder (MDD) and the neurobiologic theories behind depression and antidepressant treatment is vital for physicians who must identify and treat patients with this disorder. The epidemiology of MDD reveals that this disorder is widespread: the lifetime prevalence of MDD is estimated to be ~17%^1,2 and the 12-month prevalence is ≥7%, according to the National Comorbidity Survey Replication.² Epidemiologic studies suggest that in any 30-day period, 2% to 5% of the United States population meet criteria for MDD.³ In addition, nearly twice as many women as men (21% versus 13%, respectively) are affected by a depressive disorder during their lifetimes.¹ These numbers reveal a vast population of people affected by MDD, making depression a tremendous social and medical concern.

Disability and Comorbidity   

Depressive illness is a highly prevalent disorder associated with substantial morbidity and mortality. According to the World Health Organization, MDD is the leading cause of disability in the US and around the world.⁴ The annual costs associated with depression (both direct and indirect) in the US were estimated to be $43.7 billion in 1990.⁵

MDD is typically accompanied by comorbid psychiatric disorders. Anxiety disorders are the most prevalent; 60% to 70% of adult MDD patients experience a comorbid anxiety disorder, which worsens patient outcomes. Twenty percent to 25% of adult MDD patients suffer from substance abuse disorders, and ~30% of these patients have impulse-control disorders. Some patients with MDD experience two or three comorbid disorders simulaneously.⁶

Disturbing new evidence suggests a cohort effect in which younger populations have an increased likelihood of experiencing MDD. A study by Kessler and colleagues⁶ indicates the lifetime prevalence for people ≥60 years of age is ~14%. By comparison, people 18–29 years of age have a lifetime MDD prevalence of 25% (Slide 1). The methodology of this study was designed to minimize the effects of recall and recognition. The reasons for this dramatically increased prevalence among younger populations are unknown. Some theories posit that life is more stressful today. Another theory suggests the increased prevalence of MDD is related to decreased intake of omega-3 fatty acids and increased intake of omega-6 among younger adults. However, a clear cause remains to be identified.

Neurophysiologic and Psychological Effects of Stress

A stress diathesis model discussed by Shelton⁷ indicates that an individual subjected to an extreme stressor (ie, a relationship disruption, a personal loss, or an achievement-related setback such as job loss) will typically experience a transient decreased mood. Those without a propensity to develop MDD show resilience to the stressor and will bounce back. People with a propensity for depression lack this capacity to rebound. For these individuals, the depression incurred during stress can persist, accompanied by ruminations and other symptoms of MDD that can reinforce the depression.

Hasler and colleagues⁸ reviewed the neuroanatomical abnormalities in MDD (Slide 2). These range from increased amygdala activity and decreased amygdala volume to reduced hippocampal volume, reduced anterior cingulate volume, and decreased subgenual prefrontal cortex activity. Stress can negatively impact both the amygdala and the hippocampus; stress and neuroprotective factors are interrelated. Stress also impacts gene expression. Reduced hippocampal volume can decrease gene expression of brain-derived neurotrophic factor.

Hasler and colleagues⁸ also reviewed the neurochemical abnormalities seen in MDD. There is a relationship between increased stress sensitivity and gender, with women more affected than men. People who are prone to develop MDD have a mood bias toward negative emotions, impaired cognitive functioning, psychomotor changes, anhedonia, and impaired learning and memory. The neurochemical abnormalities range from serotonergic dysfunction to the dysregulation of the corticotropin-releasing hormone system, catecholaminergic dysfunction, and even rapid eye movement sleep abnormalities. Stress negatively impacts all of these systems.

It has recently become apparent that adults generate new neurons, particularly in the hippocampus. Hippocampal neurogenesis is a process in which neural progenitor cells proliferate, migrate, and produce newborn cells. Immature neurons and mature neurons form functional connections and functional synapses with other neurons, a vital process for adult brains.⁹ This process, too, can be negatively impacted by stress, and this negative impact is reversed by antidepressants.¹⁰

Although the model for gene-environment interaction is incomplete, it is intriguing. For example, people with a short-arm allele (s allele) in the promoter region of the serotonin transporter gene (5-HTTLPR) may be more sensitive to stressful life events. Poor parenting in conjunction with this allele may also lead to a higher risk of depression. Carriers of the s allele have a smaller area 25 near the subgenual prefrontal cortex. They also experience a decoupling of cortical limbic attenuation of negative affect, meaning that they cannot suppress negative affect.¹¹

Caspi and colleagues¹¹ found that the s allele of the 5-HTTLPR interacts with the environment such that greater numbers of stressful life events increase the probability of major depressive episodes (Slide 3). These data come from a longitudinal cohort of ~1,000 people who were followed from 3 years of age until 26 years of age. Thus, this study was able to record the stressful life events experienced by its subjects. In the absence of stressful life events, there was no gene association with depression. As subjects accumulated three or four stressful life events (eg, death, divorce, disasters); separation in the frequency of depression occurred between those with two copies of the s allele and those with one or no copies of the s allele. A much higher likelihood of experiencing depression was associated with being homozygous for the s allele. These results have been replicated in three separate studies but were not replicated in two other studies, outcomes that allow cautious optimism for the use of 5-HTTLPR gene variation to predict vulnerability to depression.

Pezawas and colleagues¹² used multimodal neuroimaging to demonstrate decreased coupling between the amygdala and the anterior cingulate in carriers of the 5-HTTLPR s allele. Here again, the s allele was related to decreased ability to extinguish negative affect. Hariri and colleagues¹³ used functional magnetic resonance imaging to flash threatening pictures at subjects in order to test amygdala reactivity. In subjects carrying the s allele of the 5-HTTLPR, the amygdala, which encodes fear, is more reactive. Johnstone and colleagues¹⁴ showed that carriers of the s allele experience dysregulation of suppression of negative affect. In an important follow up study, Pezawas and colleagues¹⁵ found that the effects of the 5-HTTLPR s allele on amygdala response to threat is protected by the presence of brainderived neurotrophic factor (BDNF) MET allele. The genetic story appears, of course, more complicated than originally thought.

In sum, the s allele of the 5-HTTLPR causes vulnerability to stress, higher likelihood of developing MDD when stressed, and decreased ability to dampen negative affect and that these effects of the s allele are mitigated by the presence of the BDNF MET allele. Carriers of this s allele are more reactive to threat and more likely to become and remain distressed. This is an intriguing model that may explain why some people become depressed and other people do not, under similar conditions of stress and loss.

Treatment Outcomes in Major Depressive Disorder

When experiencing stress, people progress from euthymia to the disorder (Slide 4).¹⁶ With acute treatment, these patients may respond and remit. However, they may also experience relapse, either during the acute treatment, which lasts 6–12 weeks, or during continuation treatment, which lasts 4–9 months. They may also experience recurrence during maintenance treatment, which lasts ≥1 year. Recurrence is considered a separate depressive episode.

For many people, MDD is recurrent. Lavori and colleagues¹⁷ followed a cohort of 359 MDD patients who had recovered from their index episode. Three years into study entry, ~50% of the group experienced another episode of depression. Fifteen years into study entry, nearly 90% of subjects experienced another episode of depression. Clearly, MDD can be a highly recurrent disorder. It can also be chronic, lasting for up to 2 years.

As a recurrent or chronic disorder, MDD will often require long-term treatment. Unfortunately, few people continue taking their depression medication. A study by McManus and colleagues¹⁸ showed that <40% of patients continued to receive antidepressant medication 6–8 months after initiation; this was true even of modern serotonin uptake inhibitors (Slide 5). Psychotherapy is also beneficial. Fava and colleagues^19,20 observed that well-being therapy (a modification of cognitive-behavioral therapy) prevented recurrent episodes of depression. Sessions were given for 30 minutes every other week, for a total of 10 sessions. This type of psychotherapy offered significant protection against depressive relapse for 6 years. Though this study has yet to be replicated, similar studies support the beneficial effects of structured psychotherapy.

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study was quite informative about depression treatments. In this study, patients received citalopram as an initial treatment and were carefully followed for symptoms and side effects. Those who did not do well with citalopram were either switched to bupropion, cognitive therapy, sertraline, or venlafaxine, or received augmentation with bupropion, buspirone, or cognitive therapy.²¹ Additional levels of progress evaluation and medication switching were built into the study design. At Level 1, with aggressive care using citalopram and even psychoeducation, patients experienced an overall remission rate of 32.9%.²² Of those who responded to citalopram but did not remit, approximately two thirds of the ultimate responders responded by week 6. Though response can take >6 weeks, most of the response will occur within the first 6 weeks. Half of ultimate remitters reached remission within 6 weeks, but remission can take an additional 6 weeks or more.

Some patients who did not remit with citalopram switched medications at Level 2. Of those switched to bupropion, sertraline, or venlafaxine, no difference was shown between response or remission rates.²³ At Level 2, ~25% of patients’ conditions improved regardless of which of the three medications they received. Other patients who did not remit with citalopram received augmentation with bupropion or buspirone. Here, ~30% of patients’ conditions improved, with no statistical difference between the groups.²⁴

Some patients failed to remit with either the Level 2 medication switch or the augmentation. These patients went onto Level 3, in which they were switched to either mirtazapine or nortriptyline. On these medications, 12% to 15% of patients’ conditions improved, with no difference between the groups.²⁵ Patients who did not respond to augmentation or switching were put on either lithium or thyroid. Fifteen percent to 25% of these patients experienced improvement, with no statistical significance between the groups.²⁶ Patients who still did not improve sufficiently were switched to tranylcypromine or to a combination of venlafaxine and mirtazapine, in Level 4. Thirteen percent of these patients experienced improvement, with no difference between the groups.²⁷ Overall, Level 1 treatment produced 33% remission. Level 2 was not much different. Levels 3 and 4 remitted approximately half the number of patients. In terms of augmentation combination, Level 2 produced more remission than augmentation at Levels 3 or 4 (Slide 6).

Conclusion

In summary, MDD has a lifetime prevalence of ~17%. There is a cohort effect with the younger age of onset for reasons that are unclear. There is an evolving stress diathesis model showing that the s allele of the 5-HTTLPR gene may put people at risk of developing depression and being more sensitive to stress. MDD is highly recurrent, and the STAR*D study has shown that real-world outcomes may result in limited remission rates.

References

1. Blazer DG, Kessler RC, McGonagle KA, Swartz MS. The prevalence and distribution of major depression in a national community sample: the National Comorbidity Survey. Am J Psychiatry. 1994;151(2):979-986.
2. Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB. Sex and depression in the National Comorbidity Survey I: Lifetime prevalence, chronicity and recurrence. J Affect Disord. 1993;29(2-3):85-96.
3. Regier DA, Boyd JH, Burke JD Jr, et al. One-month prevalence of mental disorders in the United States: based on five Epidemiologic Catchment Area sites. Arch Gen Psychiatry. 1988;45(11):977-986.
4. Murray CJL. Rethinking Dalys. In: Murray CJL, Lopez AD, eds. The Global Burden of Disease: a Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020. Cambridge, Ma: Harvard University Press and the World Health Organization; 1996:6-43.
5. Greenberg PE, Stiglin LE, Finkelstein SN, Berndt ER. The economic burden of depression in 1990. J Clin Psychiatry. 1993;54(11):405-418.
6. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095-3105.
7. Shelton RC. The molecular biology of depression. Psychiatr Clin North Am. 2007;30(1):1-11.
8. Hasler G, Drevets WC, Manji HK, Charney DS. Discovering endophenotypes for major depression. Neuropsychopharmacology. 2004;29(10):1765-1781.
9. Duman RS. Depression: a case of neuronal life and death? Biol Psychiatry. 2004;56(3):140-145.
10. Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci. 2007;10(9):1110-1115.
11. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301(5631):386-389.
12. Pezawas L, Meyer-Lindenberg A, Drabant EM, et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci. 2005;8(6):828-834.
13. Hariri AR, Drabant EM, Munoz KE, et al. A susceptibility gene for affective disorders and the response of the human amygdala. Arch Gen Psychiatry. 2005;62(2):146-152.
14. Johnstone T, van Reekum CM, Urry HL, Kalin NH, Davidson RJ. Failure to regulate: counterproductive recruitment of top-down prefrontal-subcortical circuitry in major depression. J Neurosci. 2007;27(33):8877-8884.
15. Pezawas L, Meyer-Lindenberg A, Goldman AL, et al. Evidence of biological epistasis between BDNF and SLC6A4 and implications for depression. Mol Psychiatry. In press.
16. Kupfer DJ. Long-term treatment of depression. J Clin Psychiatry. 1991;52(suppl 5):28-34.
17. Lavori PW, Keller MB, Mueller TI, Scheftner W. Recurrence after recovery in unipolar MDD: an observational follow-up study of clinical predictors and somatic treatment as a mediating factor. Int J Meth Psychiatr Res. 1994;4:211-229.
18. McManus P, Mant A, Mitchell P, Dudley J. Length of therapy with selective serotonin reuptake inhibitors and tricyclic antidepressants in Australia. Aust N Z J Psychiatry. 2004;38(6):450-454.
19. Fava GA, Rafanelli C, Grandi S, Canestrari R, Morphy MA. Six-year outcome for cognitive behavioral treatment of residual symptoms in major depression. Am J Psychiatry. 1998;155(10):1443-1445.
20. Fava GA, Ruini C, Rafanelli C, Finos L, Conti S, Grandi S. Six-year outcome of cognitive behavior therapy for prevention of recurrent depression. Am J Psychiatry. 2004;161(10):1872-1876.
21. Rush AJ, Trivedi M, Fava M. Depression, IV: STAR*D treatment trial for depression. Am J Psychiatry. 2003;160(2):237.
22. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28-40.
23. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354(12):1231-1242.
24. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-1252.
25. Fava M, Rush AJ, Wisniewski SR, et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry. 2006;163(7):1161-1172.
26. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1519-1530.
27. McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1531-1541.

Adult ADHD and Depressive Disorders:  Prevalence, Significance, and Clinical Presentation

Anthony L. Rostain, MD

Introduction

Adult attention-deficit/hyperactivity disorder (ADHD) and the spectrum of depressive disorders have high overlapping prevalence rates. Rates of depression in adults with ADHD and rates of ADHD in depressed adults provide an important epidemiologic background for clinicians treating either or both of these populations. There is a distinctive phenomenology of ADHD and depression, and distinctive diagnostic issues that present with the coexistence of these two disorders.

Case Study   

A case study that exemplifies this phenomenon is Mr. B, a 30-year-old married man who visited the clinic at the insistence of his wife. She was concerned about his irresponsibility, lack of consideration for others, low self-esteem, and difficulty staying employed. Mr. B admitted to having changed jobs six times in the past 4 years, often having been fired for tardiness, inefficiency, trouble following directions, or arguing with his bosses. At the time of his evaluation, he was unemployed and looking for work. Mr. B’s past history was positive for childhood ADHD, combined type. Throughout his life, he had experienced prominent inattentiveness, poor impulse control, hyperactivity, and trouble with organization. He had been diagnosed with ADHD in the third grade and had been treated with stimulant medication through high school. Mr. B discontinued treatment when he entered college, and was pleased to graduate with a C average because he “did it on his own, without any help.”

During his evaluation Mr. B exhibited prominent ADHD symptoms, such as poor concentration, inefficiency, and restlessness. He confessed to feelings of failure, fear of the future, disinterest in activities he usually enjoyed, and, most recently, difficulty falling asleep. He reported extreme fatigue, as well as decreased appetite and sexual drive.

This case demonstrates the clear history and presence of ADHD as well as current mood disorder. The coexistence of these two disorders must be addressed since comorbidity affects the accuracy of diagnosis and the predictability of outcome. Comorbidities can influence complications, side effects, and treatment response, and may lead physicians to consider alternative treatments. Importantly, prognosis is less favorable and less certain with coexisting conditions.

Prevalence of Mood Disorders

Reported incidents of major depressive disorder (MDD) in adults with ADHD range from 16% to 31%.^1-4 Similarly, reported rates of dysthymia in adults with ADHD are between 19% and 37%.^3-6 Other coexisting conditions may also be seen in adults with ADHD, such as antisocial disorders, substance abuse disorders, and impulse-control disorders. Nevertheless, comorbid mood disorders are extraordinarily common, with an incidence rate of ~30%, with slightly higher rates of mood disorders in females versus males.^6,7

Barkley and colleagues⁸ found that rates of MDD in a group diagnosed with adult ADHD were comparable to those seen in a clinical sample (Slide 1). These rates were much higher than the occurrence of MDD in a community sample. Thirty-six percent of the adults in the ADHD group reported a history of MDD, which parallels the rates of depression in the clinical sample of patients without ADHD. These rates were four to five times higher than the community sample.

Barkley and colleagues⁸ also found that higher rates of dysthymia were found in patients being evaluated for ADHD (Slide 2): 25% met criteria for current dysthymia, which is approximately twice the rate found in the clinical sample and extraordinarily higher than the incidence found in the community samples. From these data, it is clear that MDD and dysthymia are very prominent among adults with ADHD.

Phenomenon of Comorbidity

A national epidemiologic study conducted by Kessler and colleagues⁹ investigated respondents who met criteria for ADHD. Mood disorders were very prominent in this group, occurring in ~40% of the sample (Slide 3).⁹ This confirms earlier studies largely conducted with treated and clinic samples. The Kessler study data are significant because they show the prevalence of depression among people with ADHD in a national survey. These authors also examined rates of ADHD among people responding primarily with mood disorders. Among those patients, 13% met criteria for ADHD (Slide 4),⁹ a rate approximately three times that of the general population. Notably, ADHD is more prevalent in groups with anxiety disorders, substance abuse disorders, or impulse-control disorders.

Adults with mood disorders experienced an incidence of ADHD three times that of adults without mood disorders, while adults with ADHD experienced over twice the prevalence of mood disorders as those without ADHD (Slide 5).⁹ This leads to an important question: How much of the coexistence of conditions is due to the overlap between symptoms of ADHD and those of MDD? These disorders overlap in only two areas: psychomotor disturbances and diminished concentration or attention. Otherwise, these diagnoses are distinct.¹⁰ Individuals with ADHD exhibit a different pattern of difficulty, including an inability to listen, a tendency to lose items, excessive garrulousness and forgetfulness, as well as the other ADHD symptoms. ADHD criteria do not include a mood component. Individuals with MDD exhibit a host of classic depressive symptoms, including depressed mood, feelings of worthlessness, insomnia, and fatigue (Slide 6). However, even after correcting for the overlapping symptoms of psychomotor agitation and trouble with concentration, it appears that the depression seen in individuals with ADHD is not an artifact of ADHD, nor is the ADHD seen in individuals with depression an artifact of depression. It is therefore clear that these disorders can be simultaneously present in the same patient.

The greatest distinctions between ADHD and MDD pertain to the presence of hyperactivity, talkativeness, and early school dysfunction (Slide 7). MDD does not present classically in childhood, whereas ADHD does. ADHD tends to be a constant condition, while mood disorders, though often chronic, tend to be cyclical. Irritability and depression are more often hallmarks of mood disorders. Substance abuse and global dysfunctions are found in both diagnostic groups. Finally, there is a strong prevalence of familial ADHD in probands with ADHD. Similarly, probands with MDD show high rates of familial depression. Family histories of depression are also seen in probands with ADHD, and vice versa.

Differential Diagnosis

When diagnosing comorbidities, clinicians should take a comprehensive approach, considering all facets of the presenting complaints. Clinicians should carefully investigate patient history and conduct a review of systems, looking both for medical problems and interferences with performance and/or concentration as well as symptoms such as sleep disorders. Structured rating scales are valuable tools to assist in this endeavor. ADHD scales include the Conners’ Adult ADHD Rating Scale, the Brown ADD Rating Scale, the Barkley Current Symptom Scale, and the Adult ADHD Clinical Diagnostic Scale. Physicians should be comfortable with a standardized scale for ADHD, regardless of which scale they select. All of these scales are helpful instruments that aid in documenting and quantifying ADHD symptoms. In preparing a treatment approach, clinicians should also document the extent of depressive symptoms using depression scales such as the Beck Depression Inventory, the Hamilton Rating Scale for Depression, or the Montgomery Asberg Depression Rating Scale.

One must obtain corroborating evidence when making a dual diagnosis, because often patients underreport their symptoms or have difficulty presenting a comprehensive picture of their condition. It is advisable that clinicians conduct some form of cognitive assessment depending on the presenting complaints and pertinent history. Clinicians should also create a description of the patient’s views of self, world, and future. Observations at the Adult ADHD Treatment and Research Program at the University of Pennsylvania School of Medicine indicate that patients with ADHD, and particularly those with comorbid depression, have very negative core beliefs and world views.¹¹ These patients may believe that common activities are too difficult for them to accomplish, which is associated with a schema of self-mistrust. Many feel they are failures or expect to be incompetent—thoughts that become self-fulfilling prophecies. A pervasive sense of inadequacy is also common. These patients feel that they are unable to live up to others’ expectations or to their own, and have a sense of being caught in a constantly chaotic and unstable world. It is important to tease apart these beliefs and schemas because they must be addressed individually in the comprehensive treatment approach.

Treatment

In preparing for treatment, clinicians must review the findings and diagnostic impressions. They must educate the patient about both ADHD and the comorbid mood disorder. Clinicians should consider both protective and risk factors, elicit patient preferences and priorities in drawing up a treatment plan, and emphasize a multimodal approach.

Clinicians should always be vigilant that patients with ADHD may be suffering from a depressive disorder and vice versa.  While the comorbidity of these disorders is common, treatment requires a long-range strategy, and outcomes may be compromised. 

References

1. Murphy K, Barkley RA. Attention deficit hyperactivity disorder in adults: comorbidities and adaptive impairments. Compr Psychiatry. 1996;37(6):393-401.
2. Biederman J, Faraone SV, Spencer T, et al.  Patterns of psychiatric comorbidity, cognition, and psychosocial functioning in adults with attention deficit hyperactivity disorder. Am J Psychiatry. 1993;150(12):1792-1798.
3. Roy-Byrne P, Scheele L, Brinkley J, et al.  Adult attention-deficit hyperactivity disorder: assessment guidelines based on clinical presentation to a specialty clinic. Compr Psychiatry. 1997;38(3):133-140.
4. Schubiner H, Tzelepis A, Isaacson JH, Warbasse LH 3rd, Zacharek M, Musial J. The dual diagnosis of attention-deficit/hyperactivity disorder and substance abuse: case reports and literature review. J Clin Psychiatry. 1995;56(4):146-150.
5. Murphy JM, Nierenberg AA, Laird NM, Monson RR, Sobol AM, Leighton AH. Incidence of major depression: prediction from subthreshold categories in the Stirling County Study. J Affect Disord. 2002;68(2-3):251-259.
6. Shekim WO, Asarnow RF, Hess E, Zaucha K, Wheeler N. A clinical and demographic profile of a sample of adults with attention deficit hyperactivity disorder, residual state. Compr Psychiatry. 1990;31(5):416-245.
7. Biederman J, Faraone SV, Spencer T, Wilens T, Mick E, Lapey KA. Gender differences in a sample of adults with attention deficit hyperactivity disorder.  Psychiatry Res. 1994;53(1):13-29.
8. Barkley R, Murphy KR, Fischer M. ADHD in Adults: What the Science Says. New York: Guilford Press;  2008.
9. 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. Am J Psychiatry. 2006;163(4):716-723.
10. Milberger S, Biederman J, Faraone SV, Murphy J, Tsuang MT. Attention deficit hyperactivity disorder and comorbid disorders: issues of overlapping symptoms. Am J Psychiatry. 1995;152(12):1793-1799.
11. Ramsay JR, Rostain AL. Cognitive Behavioral Therapy for Adult ADHD: An Integrative Psychosocial and Medical Approach. New York, NY: Routledge Press; 2008.

Pharmacotherapy of ADHD in Adults

Timothy E. Wilens, MD — Moderator

Introduction

There is a complex overlap between major depressive disorder (MDD) and attention-deficit/hyperactivity disorder (ADHD). The different therapeutic options for adult ADHD mirror those used for children with ADHD. Both stimulant and nonstimulant medications are used to treat the disorder.

Pharmacotherapeutic Options

Food and Drug Administration approval for ADHD treatments vary between pharmaceuticals used in adults and those used in children.¹ Dexmethylphenidate extended release (XR) is approved by the FDA for the treatment of childhood ADHD. Of the amphetamine compounds, mixed amphetamine salts XR are FDA approved. Lisdexamfetamine, the prodrug form of amphetamine, was recently FDA approved for adults. Atomoxetine is currently the only nonstimulant that is FDA-approved for treatment of ADHD in adults (Slide 1).¹

Prescribing Practices

Physicians must keep in mind a few key points when treating adults with ADHD. First, treating physicians must establish the diagnostic hypothesis, which requires that they fully understand how to make a diagnosis of adult ADHD. One should not expect that a patient’s response to pharmacotherapy is a good indicator of the accuracy of an ADHD diagnosis. Treating only those patients who respond to initial pharmacotherapy does not account for the nonspecificity of response to pharmacotherapy. There are many people who do not respond favorably to pharmaceutical treatment, and response is nonspecific—those without ADHD will also have somewhat of a response to medication. Second, when prescribing medication, one must be prepared to titrate to full doses of medication, or to tolerability. One may be able to titrate close to the upper limits of dosing, which may exceed FDA-approved dosing in some cases. Physicians must be prepared to monitor tolerability for side effects as well as other physiologic effects such as blood pressure.

Physicians should also consider how often they see patients. Many physicians choose to see patients through the first titration of the medication. Then, once the dosing is stable and tolerability and effectiveness are established, they taper visits during follow-up. Physicians should also be aware that electrocardiograms are now recommended prior to starting a stimulant medication in any age group.²

Stimulants   

Methylphenidate Products

There are perhaps more studies and longer experience with the use of methylphenidate than other medications for ADHD, even though both amphetamines and methylphenidates are FDA approved. The first methylphenidate product that has been FDA-approved for adults with ADHD is d-methylphenidate XR. A recent study by Spencer and colleagues³ offers evidence that this product reduces adult ADHD total Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition symptoms on the ADHD Rating Scale (ADHD-RS) (Slide 2). (The ADHD-RS measures change in ADHD symptom over time, with lower scores indicating improvement.) The 5-week study found a minor effect on placebo-response: d-methylphenidate XR 20 mg, 30 mg, and 40 mg exceeded the response found in placebo. There was no clear dose response between 20 mg and 30 mg, but there was some evidence that 40 mg worked better than the 20 mg dose and placebo. D-methylphenidate XR was well tolerated across all dosing ranges, with similar outcomes for relatively minor types of cardiovascular effects such as mild increases in heart rate. This study showed no appreciable changes in diastolic or systolic blood pressures correlated to use of d-methylphenidate. Patients had a very favorable response through the end of the study. This medication is currently approved at a dose of 20 mg/day.

Currently, three large studies have been conducted on OROS methylphenidate for the treatment of adult ADHD. OROS methylphenidate has not been approved by the FDA for the treatment of adult ADHD. A study by Biederman and colleagues⁴ showed symptom reduction with a mean dose of OROS methylphenidate 87 mg/day, which exceeds the FDA-approved dose of 72 mg/day for this medication (Slide 3). Biederman and colleagues⁴ looked at the percentage of subjects who respond favorably to treatment using three different definitions of treatment: 30% reduction in symptoms; 50% reduction in symptoms; and >30% reduction in ADHD symptoms as well as clinical level of ADHD. In other words, this study was designed to gauge clinical satisfactory response. Regardless of treatment definition, a significant number of responders were observed. Using the conservative definition of treatment—50% reduction in ADHD symptoms—subjects showed a relatively minimal placebo response while ~65% of subjects responded favorably to treatment. This is a fairly reasonable expectation when using stimulants for the treatment of ADHD in adults.

Amphetamine Products

Weisler and colleagues⁵ gathered short-term data on the treatment of adult ADHD with mixed amphetamine salts XR. Patient samples received doses of 20 mg, 40 mg, and 60 mg of medication. At week 4, when all patients had attained the dose assigned by the forced-dose escalation paradigm, evidence of dose response was observed. Patients experienced ADHD-RS total score improvement of 49%. Similar to the responses seen in children receiving this treatment, higher dosing of the stimulant medication correlated to better response rate. This was not always the case for individuals, but group data showed this trend relatively consistently.

The data are relatively limited on long-term outcomes in treatment of adult ADHD with pharmacotherapy. One of the few studies available was conducted by Biederman and colleagues.⁶ This study on oral-release osmotic system methylphenidate followed subjects for 24 months (Slide 4). This long-term open-label follow-up study demonstrated better effect. Part of outcome was an artifact of the open trial design compared to the placebo-controlled trials. However, there was also persistence in subjects’ response to the stimulant out to 24 months. This was also observed in 2-year follow-up studies of children and adolescents on these medications. Notably, there appeared to be no increase in the dose of medication necessary over the 24 months, indicating that tolerance does not develop over time.

The cardiovascular effects seen early in short-term studies were also sustained through the 24-month trial, but there was no increase or attenuation in the blood pressure or heart rate. Typically, mixed amphetamine salts can result in a 2–3 millimeter increase in systolic blood pressure and diastolic blood pressure, and a heart rate increase of ~2–4 beats/minute. There is one caveat: these test subjects were medically healthy individuals who passed a physical screening to participate in this study. It may not be possible to generalize these effects to individuals with relatively higher blood pressures at entry. That noted, few subjects of this study developed any issues with blood pressure, and there were no serious adverse cardiovascular outcomes.

Nonstimulants: Atomoxetine

Data about the nonstimulant medication atomoxetine is largely compiled from studies of the acute phase of treatment, controlled trials, and follow-up open-label studies out to 34 weeks (Slide 5).⁷ During the acute phase of the study, adult patients received up to 120 mg/day of atomoxetine; although, the preferred dose during titration was ~90 mg/day. Improvement on the Conners’ Adult ADHD Rating Scale was observed compared to placebo. In the acute phase and the extension phase, there tended to be a delay in the full onset of therapeutic action with these medications taking 6–10 weeks to see the full therapeutic benefit unfold. Atomoxetine should be maintained for 6–10 weeks to evaluate optimal outcome. In the longer term adult studies, atomoxetine continued to work out to 34 weeks and was relatively well tolerated.

Side Effects

The side-effect profiles of stimulants and atomoxetine have some similarities. Insomnia is commonly seen with the stimulants and occasionally with atomoxetine. Transient mood symptoms may also seen in both medications. Appetite loss may be seen with stimulants, though this tends to end after 6 months of treatment. In addition, all of the medications used for ADHD must be monitored for increases in blood pressure and heart rate as well as less common side effects such as sexual dysfunction. Both stimulants and atomoxetine should also be monitored for psychiatric symptomatology. 

Treatments without FDA Approval

There are also data on second- and third-line treatments for adult ADHD, which lack FDA approval. In a study by Wilens and colleagues,⁸ the antidepressant bupropion XL, titrated to 450 mg over 2 weeks, showed a response rate of ~50% to 55% (Slide 6). This response rate is lower than that seen with the stimulants, and perhaps greater than the response rate seen with atomoxetine versus placebo. The side effects in this trial were initial insomnia and some appetite reduction. The trial saw very few cardiovascular effects, though the subjects of this study were medically healthy and had been screened for cardiovascular problems. Bupropion was relatively well tolerated through the trials, and should perhaps be considered when the FDA-approved first-line agents are unsuccessful.

The pharmacologic armamentarium for adult ADHD also includes tricyclic antidepressants (TCAs). There are data on the use of TCAs in adults for ADHD, including desipramine. Data indicate that TCAs respond over 4 weeks with continued effectiveness, as demonstrated in children and adolescents who stay on their medication. These agents have issues regarding monitoring requirements, and have a side-effect burden that includes dry mouth and constipation and potential lethality in overdose.

Finally, there have been several positive results with modafinil, an arousal agent, in children.⁹ However, modafinil is not currently FDA approved in children because of concerns over Stevens-Johnson Syndrome. The evidence is currently not ample enough to recommend this agent in adults, although some who take modafinil seem to show some improvement in their ADHD symptoms.

There are also several agents currently being examined for the treatment of adult ADHD. These include alternative stimulant preparations.¹⁰ Nicotinic and cholinergic modulators are being examined for their pro-cognitive effects. Cholinesterase inhibitors do not appear to be effective for ADHD symptoms.

References

1. Wilens TE. Drug therapy for adults with attention-deficit hyperactivity disorder. Drugs. 2003;63(22):2395-2411.
2. Vetter VL, Elia J, Erickson C, et al. Cardiovascular Monitoring of Children and Adolescents With Heart Disease Receiving Stimulant Drugs. A Scientific Statement From the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing. Circulation. 2008. Epub ahead of print.
3. Spencer TJ, Adler LA, McGough JJ, et al. Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2007;61(12):1380-1387.
4. Biederman J, Mick E, Surman C, et al. A randomized, placebo-controlled trial of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2006;59(9):829-835.
5. Weisler RH, Biederman J, Spencer TJ, et al. Mixed amphetamine salts extended-release in the treatment of adult ADHD: a randomized, controlled trial. CNS Spectr. 2006:11(8):625-639.
6. Biederman J, Mick E, Spencer T, et al. An open-label trial of OROS methylphenidate in adults with late-onset ADHD. CNS Spectr. 2006;11(5):390-396.
7. Adler LA, Sutton VK, Moore RJ, et al. Quality of life assessment in adult patients with attention-deficit/hyperactivity disorder treated with atomoxetine. J Clin Psychopharmacol. 2006;26(6):648-652.
8. Wilens TE, Haight BR, Horrigan JP, et al. Bupropion XL in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled study. Biol Psychiatry. 2005;57(7):793-801.
9. Biederman J, Swanson JM, Wigal SB, et al. Efficacy and safety of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, flexible-dose study. Pediatrics. 2005;116(6):777-784.
10. Biederman J, Krishnan S, Zhang Y, Findling R. Efficacy and safety of lisdexamfetamine dimesylate in non-caucasian children aged 6 to 12 years with ADHD: a secondary analysis. In: Program and abstracts of the APA meeting; May 19-24, 2007; San Diego. Abstract NR 749.

Treatment of Adult ADHD and Comorbid Depression

Thomas J. Spencer, MD

Introduction

As a general principle, separate treatments are often needed for attention-deficit/hyperactivity disorder (ADHD) and comorbid psychiatric disorders. There are few treatments for mood disorders that also treat ADHD, and vice versa. This discussion will review the literature on agents that are effective for both disorders, or that may potentially be combined. Physicians must bear in mind that none of these agents is approved by the Food and Drug Administration for the treatment of comorbid ADHD and depression.

Pharmacotherapy of Depression and ADHD

Stimulants are a mainstay for ADHD treatment in both children and adults. Approximately 70% of individuals with ADHD will improve with stimulant treatment, and that percentage increases when several stimulants are tried. Although stimulants are not predictably effective for depression, in the past they were used (off label) in the treatment of geriatric depression because of their relative cardiac safety compared to tricyclic antidepressants (TCAs). However, controlled trials and literature reviews show that stimulants produce only a modest effect on mood disorders. They are also accompanied by a risk of inducing tolerance for the mood effect; this often prompts physicians to increase the dose, which raises the risk of medication abuse.

Stimulants are quite effective for ADHD simplex but may not be as effective for ADHD in the context of depression. A number of, but not all, studies^1-5 demonstrate that stimulants are somewhat less effective in the treatment of childhood ADHD with comorbid depression and/or anxiety.

Conversely, there are some antidepressants that have demonstrated efficacy in the treatment of ADHD. These agents work for both uncomplicated depression and uncomplicated ADHD. There are four positive studies of bupropion,^6,7 two of them double-blind.^8,9 One positive study of the old TCA desipramine has also been conducted.

Antidepressant Medication Studies in Adult ADHD

A randomized, double-blind, placebo-controlled study of desipramine in the treatment of adults with ADHD was conducted by Wilens and colleagues (Slide 1).¹⁰ In comparison to stimulant trials, many of which last ≤3 weeks, this 6-week trial was relatively long. The full dose was achieved by 2 weeks, and patient response continued to evolve until the end of the trial. Desipramine showed remarkable effectiveness, at a level equivalent to any nonstimulant including atomoxetine. Because of its QTc prolongation, desipramine is not used often in children, but it is a well-known pharmacologic treatment for depression in adults, though it requires sufficient screening for preexisting cardiac issues and monitoring of titration.

A multi-site study of bupropion extended release (XL) in adults with uncomplicated ADHD was conducted with doses up to 450 mg/day.¹¹ Approximately 55% of patients responded to the treatment. The dosing here is notable, as dosing of antidepressants for the treatment of ADHD is usually in the same range as that used in the treatment of depression. Early studies using lower doses of antidepressants found that the effect of these medications on ADHD often wore off.

Trials in Children and Adolescents

Literature on the treatment of child and adolescent ADHD informs the use of treatments for comorbid ADHD and depression in adults. Daviss and colleagues¹² conducted an open trial of bupropion sustained release (SR) in adolescents with comorbid depression. The aforementioned studies considered pharmacologic treatments for ADHD simplex only, whereas these investigators specifically set out to study the treatment of adolescent ADHD and comorbid depression. Twenty-four adolescents (11–16 years of age), with ADHD and comorbid depression were given bupropion SR, titrated up to a target of 3 mg/kg, with a mean of 2.2 mg/kg. The medication was well tolerated. Notably, 58% of patients experienced a response to both ADHD and depression, and 29% experienced a response to depression alone. Patients who did not experience a response to depression also did not experience a response to ADHD.

Bangs and colleagues¹³ conducted a large multi-site, double-blind study of atomoxetine in adolescents with ADHD and comorbid depression. Subjects were adolescents 12–18 years of age who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for both ADHD and major depressive disorder. Patients had ADHD Rating Scale (ADHD-RS) scores of 1.5 standard deviations above age and gender norms and Child Depression Rating Scale (CDRS) score of ≥40. Exclusion criteria included structured psychotherapy of ADHD and/or depression <1 month prior to trial entry. Patients were randomized to ~9 weeks of atomoxetine or placebo. The target atomoxetine dose was 1.2 mg/kg/day, though this was increased to 1.8 mg/kg/day (above the FDA maximum) for patients who did not respond adequately. The authors suspected that this comorbid population might require larger doses, but increasing atomoxetine doses to this level is not recommended. All daily doses were administered once daily.

Over the 9-week period, patients showed little placebo response of ADHD symptoms. Among patients randomized to atomoxetine, scores on the ADHD-RS improved significantly (Slide 2). Depression scores on the CDRS improved for both placebo and atomoxetine treatment groups, but the change from baseline was not significantly different between groups (Slide 3). The incidence of treatment-emergent manic symptoms (a concern for all potentially antidepressant treatments) was not significantly different between groups. The incidence of nausea and decreased appetite occurred significantly more frequently in the atomoxetine treatment group.

Selective serotonin reuptake inhibitors (SSRIs) are not thought to be efficacious for ADHD.¹⁴ While these agents are helpful in the treatment of anxiety and depression, there is no clinical evidence supporting their efficacy on the core symptoms of ADHD, with or without depression. There does not appear to be direct interaction between the metabolism of stimulants and the metabolism of SSRIs. However, it should be noted that there are potential pharmacokinetic interactions between atomoxetine and the SSRIs fluoxetine and paroxetine, through the cytochrome P450 2D6 metabolic liver enzyme pathway. There are some open data reports¹⁵ supporting the effectiveness of venlafaxine in ADHD, but there are currently no controlled data to validate these observations.

Effect of ADHD on Response to Antidepressants

Birmaher and colleagues¹⁶ compared the antidepressants paroxetine and imipramine to placebo in a large double-blind, controlled trial in depressed adolescents (Slide 4). The percentage of patients who responded to depressive symptoms while taking paroxetine, imipramine, and placebo was significantly greater in subjects with uncomplicated depression. Paroxetine was particularly effective. In adolescents with both ADHD and depression, none of the treatments worked as well. In particular, paroxetine elicited the smallest response. The presence of ADHD seemed to mute the patients’ response of depressive symptoms to both antidepressants (as well as placebo).

An ambitious 20-week multi-site study by Weiss and colleagues¹⁷ examined 98 adults with ADHD, who were largely without comorbid conditions. These subjects were randomized to paroxetine or dextroamphetamine at doses of 40 mg and 20 mg BID respectively. Other patients received placebo, and all groups received some psychosocial treatment. Though subjects’ Hamilton Rating Scale for Depression (HAM-D) and Hamilton Rating Scale for Anxiety (HAM-A) scores were low at baseline, 50% of subjects had a history of mood or anxiety disorder.

In the study, dextroamphetamine was effective for ADHD while paroxetine was not. Dextroamphetamine plus or minus paroxetine was more effective than paroxetine alone or placebo. More patients on paroxetine were rated as mood and anxiety responders than patients on dextroamphetamine or placebo, even though HAM-D and HAM-A scores did not change significantly during the trial. Post-hoc analyses suggested that patients with a history of mood or anxiety disorders experienced a lower response in ADHD symptoms with dextroamphetamine.

Combination Pharmacotherapy

Common antidepressants and ADHD treatments that are potential candidates for combination pharmacotherapy of these comorbid conditions include bupropion, SSRIs, combined noradrenergic and serotonergic agents, TCAs, monoamine oxidase inhibitors, stimulants, catecholaminergic antidepressants, and alpha agonists (Slide 5). Two open studies examined combined treatments in children and adults.

Gammon and Brown¹⁸ studied a sample of 32 children with ADHD who had experienced inadequate response of ADHD symptoms to methylphenidate alone. Of the subjects, 78% had dysthymia and 18% had major depression. Doses of 17–60 mg methylphenidate were augmented with 5–20 mg fluoxetine. Thirty of the 32 patients experienced favorable response in their depressive symptoms, as measured by the Children’s Depression Inventory (CDI). Also observed were significant improvement in functioning as measured by the Children’s Global Assessment Scale (C-GAS) and significant improvement in ADHD symptoms as measured by the Conners’ Parent Rating Scale. Since the ADHD symptoms did not improve until the antidepressant was added, this underlines the suspicion that treatment of ADHD, in this case with methylphenidate, is difficult without also treating comorbid depression. These are promising data suggesting that the combination therapy is helpful.

A similar study by Findling¹⁹ investigated SSRI and stimulant treatment in 11 children and adults with major depression and ADHD. In this study, treatment started with SSRI therapy only. In this case, depression responded to the initial treatment of the SSRI, but ADHD did not. A stimulant was then added to the SSRI and the ADHD improved only with the addition of the stimulant. Again, it appears that it is difficult to treat ADHD without also treating comorbid depression. The combination of treatments was necessary  to  fully treat both conditions.

In both cases, these combined treatments were well tolerated. One adult experienced hypertension on methylphenidate monotherapy. Patients with borderline hypertension may develop hypertension by a small blood pressure increase due to the medication. In the Gammon study,¹⁸ one child experienced symptom exacerbation. 

Conclusion

Children with ADHD often develop depression, and both disorders also commonly co-exist in adults with ADHD. In the treatment algorithm for both disorders, physicians should prioritize the worst condition. Typically, depression is the worst condition, and it may have to be treated before ADHD will respond. Sometimes depression is so severe that patients and physicians are reluctant to treat the comorbid ADHD. Even though depression may temporarily divert attention away from the ADHD, treating physicians should not ignore this disorder. ADHD carries a host of additional academic, occupational, and cognitive symptoms. It may also cause social dysfunction and an inability to benefit from the psychosocial treatments that are needed both for depression or ADHD. Combined pharmacotherapy for ADHD and comorbid depression is often necessary and should be seriously considered by physicians whose patients present with these concurrent conditions.

References

1.  DuPaul G, Barkley R, McMurray M. Response of children with ADHD to methylphenidate: Interaction with internalizing symptoms. J Am Acad Child Adolesc Psychiatry. 1994;33:894-903.
2. Pliszka SR. Effect of anxiety on cognition, behavior, and stimulant response in ADHD. J Am Acad Child Adolesc Psychiatry. 1989;28:882-887.
3. Taylor E, Schachar R, Thorley G, Wieselberg HM, Everitt B, Rutter M. Which boys respond to stimulant medication?  A controlled trial of methylphenidate in boys with disruptive behaviour. Psychol Med. 1987;17:121-143.
4. Voelker SL, Lachar D, Gdowski LL. The personality inventory for children and response to methylphenidate: Preliminary evidence for predictive validity. J Pediatr Psychol. 1983;8:161-169.
5. Livingston R, Dykman R, Ackerman P. Psychiatric comorbidity and response to two doses of methylphenidate in children with attention deficit disorder. J Child Adolesc Psychopharmacol. 1992;2:115-122.
6. Wilens T, Prince J, Spencer T, et al. Bupropion SR for attention-deficit hyperactivity disorder in adults with bipolar disorder and AD/HD. NCDEU Poster Abstract No. 54;2000. Biol Psychiatry. 2003;54(1):9-16.
7. Wender P, Reimherr F. Bupropion treatment of attention-deficit hyperactivity disorder in adults. Am J Psychiatry. 1990;147:1018-1020.
8. Biederman J, Spencer TJ. Psychopharmacology of adults with attention-deficit/hyperactivity disorder. Primary Psychiatry. 2004;11(7):57-62.
9. Goodman D. In: Biederman J, ed. ADHD Across the Life Span: From Research to Clinical Practice—An Evidence-Based Understanding. Hasbrouck Heights, NJ: Veritas, Inc. In press.
10. Wilens TE, Biederman J, Prince J, et al. Six-week, double-blind, placebo-controlled study of desipramine for adult attention deficit hyperactivity disorder. Am J Psychiatry. 1996;153(9):1147-1153.
11. Wilens TE, Haight BR, Horrigan JP, et al. Bupropion XL in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled study. Biol Psychiatry. 2005;57(7):793-801.
12. Daviss WB, Bentivoglio P, Racusin R, Brown KM, Bostic JQ, Wiley L. Bupropion sustained release in adolescents with comorbid attention-deficit/hyperactivity disorder and depression. J Am Acad Child Adolesc Psychiatry. 2001;40(3):307-314.
13. Bangs ME, Emslie GJ, Spencer TJ, et al. Efficacy and safety of atomoxetine in adolescents with attention-deficit/hyperactivity disorder and major depression. J Child Adolesc Psychopharmacol. 2007;17(4):407-420.
14. Spencer TJ, Biederman J, Wilens TE, Faraone SV. Novel treatments for attention-deficit/hyperactivity disorder in children. J Clin Psychiatry. 2002;63(suppl 12):16-22.
15. Olvera RL, Pliszka SR, Luh J, Tatum R. An open trial of venlafaxine in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. J Child Adolesc Psychopharmacol. 1996;6:241-250.
16. Birmaher B, McCafferty JP, Bellew KM, et al. Comorbid ADHD and disruptive behavior disorders as predictors of response in adolescents treated for major depression. Poster presented at: Annual Meeting of the American Psychiatric Association; May 13-18, 2000; Chicago, IL. Abstract NR562:209.
17. Weiss M, Hechtman L. The Adult ADHD Research Group. A randomized double-blind trial of paroxetine and/or dextroamphetamine and problem-focused therapy for attention-deficit/hyperactivity disorder in adults. J Clin Psychiatry. 2006;67(4):611-619.
18. Gammon G, Brown T. Fluoxetine and methylphenidate in combination for treatment of attention deficit disorder and comorbid depressive disorder. J Child Adolesc Psychopharmacol. 1993;3:1-10.
19. Findling RL. Open-label treatment of comorbid depression and attentional disorders with co-administration of serotonin reuptake inhibitors and psychostimulants in children, adolescents, and adults: a case series. J Child Adolesc Psychopharmacol. 1996;6(3):165-175.

Question-and-Answer Session

Dr. Nierenberg: I believe this is variable. There seem to be people for whom ADHD does not greatly affect depression, and those for whom it does. ADHD seems to have a lesser impact on the treatment of depression if the psychosocial sequelae of ADHD are not severe. However, depressed patients with severe ADHD symptoms, such as persistent problems at work, chronic low esteem, and difficulty with relationships, do not seem to respond as well to antidepressants.

Dr. Rostain: In our program, we see many patients with ADHD and depression who are less depressed than when they first started treatment but are only in partial remission. Even psychotherapy may be hampered because these patients have sluggish cognitive tempo or are distracted as a result of their ADHD symptoms. Physicians can help these patients realize that some of their problems are not mood related. In these cases, we often suggest amplifying the antidepressant treatment with an agent that will combat some of the ADHD symptoms, such as the ability to focus. However, there are variable responses to these regimens, and there has not yet been a good, large randomized controlled trial studying the stepwise introduction of ADHD medications for patients treated for depression.

Q: Dr. Spencer discussed data showing that atomoxetine use in depressed children did not result in depression exacerbation. Are there data on the use of stimulants or nonstimulants in adults with ADHD and depression?     

Dr. Spencer: A rodent study¹ suggested that early treatment with methylphenidate led to greater levels of depression. However, Dr. Rostain explained that depression occurs in ADHD for reasons other than treatment. For example, Kessler and colleagues² showed that only 10% of ADHD patients were treated with any medication, in spite of huge rates of depression in that population-based sample. We have seen these treatments accused of causing childhood mania, among other issues, but these conditions often occur without treatment as well. While I do not believe ADHD treatments cause depression, there are acute dysphorias that can result from stimulants. However, it is important to note that these dysphorias are not depression. Depression is chronic, autonomous, severe, and devastating. Dysphoric reactions to stimulants are brief, remit when the stimulant is removed, and can occur at the peak of treatment or while the treatment is tapered off.  We have seen children become weepy or grumpy either at peak stimulant dosing or while the stimulant is washed away. This is likely because of the rapid onset and offset of these medications.

Q: Dr. Nierenberg discussed the effect of mood disorders on cognitive processing. ADHD affects the parts of the brain that enable people to make decisions and draw conclusions. This may affect the circuitry in a way that appears to be resistant to change and to intervention. How does this complicate treatment of depression?     

Dr. Spencer: Unfortunately, there are many theories, but no predictors. Anterior cingulate studies by Bush and colleagues^3-5 show that the cingulate is underactive in ADHD, and that it is normalized with 6 weeks of stimulant treatment. The issue of depression is also interesting. The anterior cingulate has cognitive features, such as controlling response inhibition, but also has emotional roles, such as emotional regulation, reward regulation, and error detection. Therefore, it may be a particularly vulnerable region that is affected by both depression and ADHD.

Dr. Nierenberg: I have never seen a neuroimaging study for major depressive disorder in which investigators also explicitly looked for signs of ADHD. It is possible that some of the imaging studies of people with depression have included people with comorbid ADHD that was simply not detected. There are no good studies, such as pre- or post-treatment studies, of depressed individuals in whom we might see neurophysiologic changes. This leads to another question: What are the predictors of treatment response when we have a comorbid individual with ADHD? At times I use algorithms. For example, if a patient is both dysphoric and anergic, and seems to have trouble moving around, I might prescribe a more stimulating antidepressant, whereas I would not use such a treatment in a depressed individual who seemed agitated or has trouble settling. Surprisingly, there are no data to support such a choice.

Q: Physicians who treat depression often say that patients with dysthymia plus depression require more time to treat and more complicated treatments. In my patients with both depressive episodes and history of chronic low mood and dysphoria, we use both medical and psychosocial interventions. These patients seem to take the most time to respond. Better ability to focus and increased energy do not seem to address the chronic sense of inadequacy and low self-esteem that many of these patients experience. Is this a common experience with depression and ADHD?  

Dr. Rostain: Yes. One needs to imagine what it is like to have depressive cognition, to persistently ruminate on problems, to feel anxious, and to have those issues coupled with repeated failures. These patients may have difficulty seeing themselves as anything but failures. They are repeatedly fired from work or reprimanded for bad performance; they don’t perform well in school, even if they are intelligent; they always fall short of expectations. Someone who is both chronically depressed and persistently underperforms may not seek help or may drop out of treatment before seeing results. For these patients, it is important to confirm that negative views and difficult experiences have a real basis. Helping them to reframe their perspectives and experiences may ease any discomfort they feel about obtaining treatment. Physicians should be careful to not add negativity to an already difficult situation.

References

1. Carlezon WA Jr, Mague SD, Andersen SL. Enduring behavioral effects of early exposure to methylphenidate in rats. Biol Psychiatry. 2003;54(12):1330-1337.
2. 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. Am J Psychiatry. 2006;163(4):716-723.
3. Bush G, Spencer TJ, Holmes J, et al. Functional magnetic resonance imaging of methylphenidate and placebo in attention-deficit/hyperactivity disorder during the multi-source interference task. Arch Gen Psychiatry. 2008;65(1):102-114.
4. Bush G, Frazier JA, Rauch SL, et al. Anterior cingulate cortex dysfunction in attention-deficit/hyperactivity disorder revealed by fMRI and the Counting Stroop. Biol Psychiatry. 1999;45(12):1542-1552.
5. Seidman LJ, Valera EM, Bush G. Brain function and structure in adults with attention-deficit/hyperactivity disorder. Psychiatr Clin North Am. 2004;27(2):323-347.