Comorbid ADHD and Depression: Assessment and Treatment Strategies

In both clinical and community settings, the clinical significance of ADHD and depressive disorders is substantial when they co-occur.¹ ADHD is a chronic disorder that often persists into adulthood; it is also among the most common psychiatric disorders. In DSM-5, the more lenient criteria for age of onset and lower required number of symptoms for adult ADHD will likely increase the rates of ADHD diagnoses.

In adults, episodes of MDD cause significant morbidity and mortality, but when they occur with ADHD, such episodes are more prolonged, more likely to result in suicidal behaviors and hospitalizations, and more likely to convert from unipolar to bipolar mood disorders.^2,3 The impact of comorbid depression on ADHD response has not been assessed, but studies of patients with bipolar disorders suggest that ADHD treatment may exacerbate untreated mood disorders.⁴ Because ADHD typically begins several years before the first unipolar depressive episode, earlier identification and treatment of ADHD may affect the risk of depression.

Significance for the Practicing Psychiatrist

TABLE 1. Overlap of ADHD, depressive, and bipolar mania symptoms

TABLE 2. Pharmacological trials related to ADHD and depression

Developmental and other etiological factors

Knowing the genetic and environmental risk factors for comorbid depression in patients with ADHD could potentially help inform strategies for earlier prevention, detection, and treatment. ADHD is among the most heritable psychiatric conditions.⁵ Family members of patients with ADHD are at higher risk for ADHD or depression, but environmental rather than genetic factors are the stronger predictors of which ADHD patients become depressed. Such environmental factors may include exposure to early abuse and other traumatic exposures, family or peer conflicts, and poor academic or other achievement, and may be influenced by patient behavior.⁶

Earlier pharmacological treatment of ADHD is associated with a lower risk of MDD.⁷ Rates of depression are equivalent across genders before adolescence but become twice as frequent in females as in males during adolescence.⁸ Moreover, hyperactive-impulsive symptoms in particular have been linked with a lifetime history of suicidal behaviors in females but not in males.⁹ On the other hand, pharmacotherapy for ADHD or depression may increase the risk of bipolar episodes in patients already at high risk because of factors such as a history of psychosis, medication-induced or subthreshold levels of mania, or a family history of bipolarity.⁴

Assessment challenges and strategies

The evaluation of any patient for potential ADHD requires gathering information about the frequency and severity of ADHD symptoms, and verifying the age of onset of symptoms, their chronicity, and associated impairment in multiple domains of function (eg, school, work, interpersonal and family relations). Because ADHD is highly heritable, patients with ADHD will often have other family members with the disorder.⁵ Ideally, evidence of symptoms and impairment is sought from collateral sources.

There are many ADHD rating scales useful for gathering collateral history regarding potential ADHD symptoms in children. Validated self-report rating scales are also available to screen for adult ADHD including the Conners’ Adult ADHD Rating Scales, the Brown Attention-Deficit Disorder Scale for Adults, the Wender Utah Rating Scale, the ADHD Rating Scale-IV, and the Adult ADHD Self-Report Scale-v1.1 Symptom Checklist.

Diagnosing ADHD and other comorbidities often requires having to weigh potentially contradictory reports. For example, while adolescents typically are more reliable reporters of depressive symptoms than their parents, the same is not true for adolescents with ADHD.¹ Parents and teachers are generally more reliable informants of ADHD and other externalizing behaviors. However, parents of children with ADHD are more likely to have depressive disorders themselves, and depressed parents tend to over-report their child’s symptoms and impairment.^5,10 Adults with ADHD often present with chief complaints of mood, anxiety, or substance use disorders, rather than ADHD.⁴ The key to diagnosing ADHD in patients who have depression is to carefully consider their childhood history to determine whether symptoms of inattention, hyperactivity, and impulsivity were evident before the depression.

As seen in Table 1, another challenge in correctly diagnosing co­morbid ADHD and depression is the overlap of their symptoms. The symptoms that best discriminate a true comorbid MDD in a pediatric patient with ADHD are depressive cognitions (eg, guilt, worthlessness, hopelessness, morbid or suicidal thoughts), severe anhedonia, and psychomotor retardation. In contrast, symptoms such as irritability, poor concentration, anergia, sleep problems, and psychomotor or appetite changes are less helpful, because they overlap with ADHD, the side effects of ADHD medications, and other frequent comorbidities (eg, oppositional defiant or conduct disorders, anxiety disorders).¹¹

The risk of bipolar disorders, as well as the conversion from unipolar depressive to bipolar disorders, is increased with ADHD.³ Getting an accurate history of a previous manic episode is challenging. Manic episodes in pediatric bipolar disorders are typically mixed or rapid cycling.¹² In adults they are predominantly depressive rather than mixed or manic.⁴ As with depressive disorders, many mania symptoms overlap with those of ADHD, other common comorbid disorders, or side effects of ADHD medications.^4,12

Several validated measures in the public domain may also be helpful in screening for bipolar symptoms over time, including parent-reports of bipolar symptoms in their children and self-reports of such symptoms in adults. An accurate diagnosis requires a careful clinical interview and close follow-up over time to identify signs and symptoms of depression, mania, or hypomania that are clearly distinct from the patient’s usual state.

Adolescent and adult patients with ADHD are also likely to have other comorbid disorders, such as anxiety, post-traumatic stress, obsessive compulsive, intermittent explosive, personality, and alcohol or substance use disorders. The co- occurrence of multiple disorders along with the ADHD and depression is especially common in tertiary clinical settings.¹³ Once again, the symptoms of these disorders overlap with those of depression or ADHD and need to be carefully considered and ruled in or out. If the primary problems are mood and/or these other disorders, verifying a suspected diagnosis of co-occurring ADHD might require observation over time to see whether the potential symptoms of ADHD persist after the other disorders improve with treatment.

Pharmacotherapy

Stimulant pharmacotherapy is generally the first-line treatment for uncomplicated ADHD.¹⁴ Methylphenidates and the amphetamines are FDA-approved for ADHD and have formulations with varying durations of effect. Immediate-release formulations include methylphenidate, dexmethylphenidate, dextroamphetamine, and mixed amphetamine salts. Intermediate-release stimulants include methylphenidates, dexmethylphenidate, and dextroamphetamine Spansules. Several extended-release formulations are now available for methylphenidate and 2 are available for the amphetamines-mixed amphetamine salts and lisdexamfetamine.

In patients of all ages, the extended-release stimulants offer the advantage of potential once-daily dosing, and less risk of abuse or diversion. Atomoxetine is the first non-stimulant FDA-approved for ADHD in children and adults. One trial suggested atomoxetine was useful for treating ADHD that is comorbid with MDD.¹⁵ There is also evidence for the efficacy of bupropion and tricyclic antidepressants for ADHD.¹⁴ One open-label trial in adolescents suggested that bupropion is effective for comorbid ADHD and depression.¹⁶ Tricyclic antidepressants and bupropion are not FDA-approved for pediatric depression or for ADHD at any age. Two extended-release alpha-agonists-guanfacine and clonidine-are FDA-approved for ADHD but have not been studied in comorbid ADHD and depression.

Regarding antidepressants, there is growing evidence for the efficacy of SSRIs for pediatric depression; fluoxetine and escitalopram are both FDA-approved for pediatric MDD.¹⁷ Sertraline, fluoxetine, and fluvoxamine are FDA-approved for treating pediatric obsessive compulsive disorder. These and other SSRIs are widely used off-label to treat other anxiety disorders and depression in children and adolescence.

Table 2 summarizes the studies that have examined these and other pharmacological treatments specifically in youths with depressive disorders and ADHD. While many of these studies are limited by their open-label designs, small sample sizes, or use of post hoc analyses, they offer preliminary evidence that monotherapy with stimulants, atomoxetine, fluoxetine, or bupropion is a reasonable treatment for ADHD and comorbid depression.

A trial of methylphenidate in pediatric patients who have subsyndromal depression and ADHD has demonstrated significant reductions in ADHD and depressive symptoms over 12 weeks of open-label treatment.¹⁸ Improvements in depressive and ADHD symptoms were highly intercorrelated, and depressive response was inversely correlated with baseline depressive severity. This study suggests that stimulant monotherapy may be a reasonable treatment for ADHD and milder depression.

Only one study of pediatric ADHD and comorbid MDD has used a placebo-controlled design. A significant difference in atomoxetine relative to placebo for ADHD was seen, but not for depression, because of the high level of depressive response to placebo.¹⁴

The Texas Children’s Medication Algorithm Project (CMAP) offers treatment algorithms for comorbid pediatric MDD and ADHD.^13,14 First, the clinician determines which of the 2 conditions is more severe, then step 1 for that specific condition is selected while monitoring any effects of treatment on the other. If ADHD is to be targeted first, the ADHD algorithm recommends initial treatment with a stimulant. Should only the ADHD improve but not the depression, then an SSRI can be added to target depression.

When the depressive disorder at outset is more severe or when neither condition responds to stimulant monotherapy, CMAP recommends starting or switching to the depression algorithm, respectively. The first 2 steps of the depression algorithm are separate monotherapies with 2 SSRIs, while the third step is monotherapy with a non-SSRI such as bupropion. The clinician has the option to add a stimulant if the depressive but not the ADHD symptoms respond to the antidepressant. CMAP recommends changing only one medication at a time to make it easier to interpret responses to various treatments. Considering the limited available empirical evidence informing the treatment of comorbid ADHD and depression, the CMAP algorithms offer a reasonable clinical approach for patients of all ages.

As mentioned before, adults with ADHD typically present with primary concerns about other clinical comorbidities, such as mood symptoms or anxiety.⁴ Often these other conditions should be targeted first, perhaps with an SSRI or bupropion. Patients with an active substance or alcohol use disorder should also have that condition stabilized before ADHD can be safely and effectively treated. Persistent ADHD symptoms in patients with depression or other comorbidities can then be treated with an extended-release, once-daily stimulant or a non-stimulant ADHD treatment.

When the primary concern in adults with ADHD and depression is ADHD, the extended-release stimulants can be used first. Atomoxetine and bupropion are other monotherapies for such patients, especially if a stimulant trial is contraindicated or has failed, or when a non-stimulant is preferred for other reasons. Effective treatment of lifelong ADHD can improve the patient’s ability to function occupationally and interpersonally and reduce his or her depressive symptoms without the need to add an antidepressant.

Findings from an open-label study in 36 adults with bipolar disorders (mostly bipolar II) suggest that bupropion sustained-release is effective and safe for ADHD and mood symptoms.¹⁹ Only one patient converted to hypomania, although most patients (89%) were not taking concomitant anti-manic medication.

Even so, when using pharmacotherapy in patients with comorbid ADHD and depression, clinicians should monitor closely for unexpected or serious adverse effects, worsening moods, suicidality, and emerging manic or psychotic symptoms. In such cases, diagnoses of bipolar disorders or other conditions may need to be considered and treated instead.

Psychosocial interventions

Patients with comorbid ADHD and depression have significant academic, social, and occupational impairment, which can be targeted with psychosocial interventions. Parents of youths with both problems should be encouraged to request an evaluation for an Individualized Education Plan under the Individuals’ With Disabilities Education Act, to provide accommodations and extra support in school.

Patients with ADHD and depression may also benefit from concomitant psychotherapy. Cognitive behavioral therapy (CBT) and interpersonal therapies are available for pediatric and adult depressive disorders, though none have been specifically developed or tested in patients with comorbid ADHD and depression. A post hoc analysis of the Treatment of Adolescents with Depression study (TADS) suggests that responses to fluoxetine, CBT, or their combination were superior to placebo in the subgroup of subjects with comorbid MDD and ADHD.²⁰ However, youths with particularly severe and more chronic depressive symptoms at enrollment did best over time on the combination of CBT and fluoxetine and had a lower risk of emerging suicidality.^21,22 Such findings suggest that complex cases of MDD and ADHD may warrant the combination of CBT and fluoxetine.

Studies of individual or group therapies for ADHD have recently shown promising results, but primarily in adults rather than in youths with ADHD.²³ Using psychosocial interventions in combination with pharmacotherapy seems a reasonable approach for patients of all ages with comorbid ADHD and depression. Treatment of any co-occurring substance use disorders is usually the first priority, given the greater risks associated with such conditions.

Summary

Depressive disorders and ADHD commonly co-occur, and when comorbid are more impairing and challenging to assess and treat. Comorbid depression in patients who first develop ADHD may be related to a chronic history of functional deficits from the ADHD, along with adverse environmental and genetic factors. Despite the relative lack of randomized controlled trials, there is increasing evidence for the role of pharmacotherapy, including stimulants, SSRIs, atomoxetine, or bupropion, to target either or both disorders. There is also some suggestion for the potential benefit of concomitant psychosocial interventions to address the patient’s depressive and ADHD symptoms and any potential environmental factors contributing to such comorbid presentations.

This article was originally posted on 8/4/16 and has since been updated.

Disclosures:

Dr. Daviss is Associate Professor of Psychiatry, Dartmouth Geisel School of Medicine, Hanover, NH. Dr. Bond is a Psychiatric Resident at Dartmouth Hitchcock Medical Center, Lebanon, NH. They report no conflicts of interest concerning the subject matter of this article.

References:

1. Daviss WB. A review of co-morbid depression in pediatric ADHD: etiology, phenomenology, and treatment. J Child Adolesc Psychopharmacol. 2008; 18:565-571.

2. Biederman J, Ball SW, Monuteaux MC, et al. New insights into the comorbidity between ADHD and major depression in adolescent and young adult females. J Am Acad Child Adolesc Psychiatry. 2008; 47:426-434.

3. Chen MH, Chen YS, Hsu JW, et al. Comorbidity of ADHD and subsequent bipolar disorder among adolescents and young adults with major depression: a nationwide longitudinal study. Bipolar Disord. 2015;17:315-322.

4. Goodman DW, Thase ME. Recognizing ADHD in adults with comorbid mood disorders: implications for identification and management. Postgrad Med. 2009;121:20-30.

5. Faraone SV, Biederman J. Do attention deficit hyperactivity disorder and major depression share familial risk factors? J Nerv Ment Disord. 1997;185: 533-541.

6. Daviss WB, Diler RS, Birmaher B. Associations of lifetime depression with trauma exposure, other environment adversities, and impairment in adolescents with ADHD. J Abnorm Child Psychol. 2009;37: 857-871.

7. Daviss WB, Birmaher B, Diler RS, Mintz J. Does pharmacotherapy for attention-deficit/hyperactivity disorder predict risk of later major depression? J Child Adolesc Psychopharmacol. 2008;18:257-264.

8. Birmaher B, Ryan ND, Williamson DE, et al. Childhood and adolescent depression: a review of the past 10 years: part I. J Am Acad Child Adolesc Psychiatry. 1996;35:1427-1439.

9. Daviss WB, Diler RS. Suicidal behaviors in adolescents with ADHD: associations with depressive and other comorbidity, parent-child conflict, trauma exposure, and impairment. J Atten Disord. 2014;18: 680-690.

10. Shea K, Daviss WB. Caregiver depressive symptoms predict discrepancies between caregiver, teacher, and youth ratings of psychopathology in adolescents with ADHD. Presented at: 60th Annual Meeting of the American Academy of Child and Adolescent Psychiatry; October 22-27, 2013; Orlando, FL.

11. Diler RS, Daviss WB, Lopez A, et al. Differentiating major depressive disorder in youths with attention deficit hyperactivity disorder. J Affect Disord. 2007;102:125-130.

12. McClelan J, Kowatch R, Findling RL, Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2007;46:107-125.

13. Gao K, Wang Z, Chen J, et al. Should an assessment of Axis I comorbidity be included in the initial diagnostic assessment of mood disorders? Role of QIDS-16-SR total score in predicting number of Axis I comorbidity. J Affect Disord. 2013;148:256-264.

14. Pliszka SR, Crimon ML, Hughes CW, et al. The Texas Children’s Medication Algorithm Project: revision of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2006;45:652-657.

15. 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: 407-420.

16. Daviss WB, Bentivolglio P, Racusin R, et al. Bupropion sustained release in adolescents with comorbid attention-deficit/hyperactivity disorder and depression. J Am Acad Child Adolesc Psychiatry. 2001;40: 307-314.

17. Hughes CW, Emslie GJ, Crismon ML, et al. Texas Children’s Medication Algorithm Project: update from Texas Consensus Conference Panel on Medication Treatment of Childhood Major Depressive Disorder. J Am Acad Child Adolesc Psychiatry. 2007;46:667-686.

18. Golubchik P, Kodesh A, Weizman A. Attention-deficit/hyperactivity disorder and comorbid subsyndromal depression: what is the impact of methylphenidate on mood? Clin Neuropharmacol. 2013;36: 141-145.

19. Wilens TE, Prince JB, Spencer T, et al. An open trial of bupropion for the treatment of adults with attention-deficit/hyperactivity disorder and bipolar disorder. Biol Psychiatry. 2003;54:9-16.

20. Kratochvil CJ, May DE, Silva SG, et al. Treatment response in depressed adolescents with and without co-morbid attention-deficit/hyperactivity disorder in the Treatment for Adolescents with Depression Study. J Child Adolesc Psychopharmacol. 2009;19: 519-527.

21. Curry J, Rohde P, Simons A, et al. Predictors and moderators of acute outcome in the Treatment for Adolescents with Depression Study (TADS). J Am Acad Child Adolesc Psychiatry. 2006;45:1427-1439.

22. Emslie G, Kratochvil C, Vitiello B, et al. Treatment for Adolescents with Depression Study (TADS): safety results. J Am Acad Child Adolesc Psychiatry. 2006; 45:1440-1455.

23. Sonuga-Barke EJ, Brandeis D, Cortese S, et al. Nonpharmacological interventions for ADHD: systematic review and meta-analyses of randomized controlled trials of dietary and psychological treatment. Am J Psychiatry. 2013;170:275-289.

24. Gammon GD, Brown TE. Fluoxetine and methylphenidate in combination for treatment of attention deficit disorder and comorbid depressive disorder. J Child Adolesc Psychopharmacol. 1993;3:1-10.

25. 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;6:165-175.