ADHD and Comorbidities: An Evidence-Based Overview of Diagnosis, Treatment, and Clinical Integration

Oppositional defiant disorder (ODD)

• ODD is the most common comorbid disorder in children that can persist into adulthood. ODD is characterised by wilfully oppositional or defiant behaviours, i.e. deliberately refusing to comply with the rules and exhibiting spiteful and vindictive characteristics towards others. [Canadian ADHD Practice Guidelines]
• ODD symptoms that overlap with ADHD include reactive, irritable, and aggressive symptoms; however, according to the DSM-5, mood-related, provocative or vindictive symptom clusters can differentiate ODD from ADHD.
• The combination is associated with greater symptom severity, daily impairment, and a more at-risk prognosis than either disorder alone.
• As the symptoms of ADHD can progress to ODD, ADHD treatment should be optimised to prevent the reactive and irritable dimensions of ODD from developing later. [Harvey et al., 2016]

Management of ADHD and ODD: 

• Address core symptoms of ADHD and augmentation with other treatments to address the ODD.
• Psychostimulants, alpha-2 agonists, and atomoxetine can be beneficial for disruptive and aggressive behaviours in addition to core ADHD symptoms; however, psychostimulants generally provide the most benefit. [Pringsheim et al., 2015]
• Methylphenidate has the best evidence, followed by atomoxetine, guanfacine SR and clonidine for ADHD with behaviour problems. [Ghosh et al., 2017]
• Psychosocial management via parental management training, functional family therapy, cognitive behaviour therapy either in individual or group format are treatment approaches that can be used with pharmacotherapy options. [Ghosh et al., 2017]

Mild:

• May respond to behaviour management alone
• Monotherapy with stimulant medication or atomoxetine.

Moderate to severe:

• Combination pharmacotherapy (e.g. stimulant and clonidine) and behaviour management.

Severe or refractory cases

• May require the introduction of an atypical antipsychotic such as risperidone. [Hazell, 2010]

Conduct disorder/aggression (CD)

• CD is often preceded by ODD but is characterised as a more severe and persistent form of ODD whereby the patient exhibits higher levels of callousness and cruelty and an absence of remorse or empathy towards others. [Harpold et al., 2007]
• It is characterised by symptoms of aggression toward people or animals, destruction of property, deceitfulness or theft, and serious violations of rules.
• Aggressive behaviour, lying, stealing, fire-setting, and running away from home and school are the most frequent manifestations of CD. They are often accompanied by hyperactivity, impulsive behaviour, explosiveness, cognitive and learning problems, and poor social skills.
• Moreover, patients with CD are more than likely to develop antisocial personality disorder in adulthood and substance abuse disorders and depression. [Barkley et al., 2004]

Management of Comorbid Conduct Disorder and ADHD: 

• The most effective approach to treatment requires a multimodal strategy that incorporates stimulant/non-stimulant pharmacotherapies in conjunction with individual and family psychosocial interventions. [Canadian ADHD Practice Guidelines]
• Psychostimulants are highly recommended. [Lillig, 2018]
• Other drugs that may be useful include atomoxetine antidepressants (imipramine, desipramine, Selective Serotonin Reuptake Inhibitors (SSRIs), atypical antipsychotics such as risperidone, or mood stabilisers including lithium.  [Turgay, 2005]
• Risperidone may benefit patients with conduct disorder who have severe aggression or explosive anger after comorbid ADHD is treated.
• Some ADHD medications could increase irritability and aggressive symptoms; hence monitoring is needed.

Antisocial personality disorder (ASPD)

• ASPD symptoms are characterised by deceitfulness and disrespectful, manipulative or reckless behaviour without regard for oneself or others. The patient is often irritable and aggressive with confrontation and physical fights, a persistent and repeated characteristic.[Canadian ADHD Practice Guidelines]
• Patients with CD are more likely to develop ASPD; however, patients with ADHD are unlikely to develop ASPD. [Storebø and Simonsen, 2013]
• Therefore, the development of ASPD with ADHD is a complex issue that may require specialised interventions.
• Interventions include stimulants; however, ASPD is often associated with drug-seeking behaviours, and therefore clinicians should be wary of considering these treatments. [Biederman et al., 1995]
• The provision of non-stimulant therapies has not been adequately researched at present.

Borderline personality disorder (BPD)

• ADHD and BPD are common comorbid disorders with a lifetime prevalence of 34% in ADHD patients. [Dowson et al., 2004]
• ADHD and BPD also share similar core symptoms, including impulsivity, mood lability, and emotional dysregulation.

The relationship between ADHD and BPD is multifaceted. [Storebø et al, 2014], [Ditrich et al, 2021]

• ADHD may be an early developmental stage of BPD
• The same genes lead to two distinct disorders (genetic pleiotropy)
• BPD and ADHD are overlapping, e.g. they are different presentations of the same underlying disorder
• ADHD is associated with a higher risk of developing BPD.
• They may be separate disorders co-occurring.

To distinguish patients with BPD from those with ADHD, BPD patients have rapid changes to self-identity and self-image and an elevated risk of heightened rejection sensitivity, suicidal threats, self-injury, depression, and anxiety. [Canadian ADHD Practice Guidelines]

Management of ADHD and BPD: 

• Psychotherapy is the primary treatment option for BPD, with dialectical behavioural therapy the most common. [van den Bosch et al., 2005]
• Medications that target specific core symptoms such as impulsivity, which both ADHD and BPD share, are helpful.
• Treatment of ADHD should always be considered when treating comorbid personality disorders as patients are more likely to engage and benefit from psychological treatment programs for BPD when comorbid ADHD is treated. [Asherson et al., 2014]
• Systematic reviews and meta-analyses have shown Methylphenidate (MPH) as beneficial in treating emotional dysregulation in adult ADHD alone.
• BPD-ADHD patients receiving MPH treatment showed a significantly improved response to DBT treatment for Trait-State Anger scores, motor impulsiveness, depression severity, and ADHD severity compared with those without stimulant medication. [Prada et al., 2015]
• MPH may improve decision making in patients with BPD by addressing ADHD symptomatology. [Gvirts et al., 2018]

Substance use disorder (SUD) 

• Substance abuse is a significant risk factor in patients with ADHD, and vice versa, with 50% of patients with SUD also diagnosed with ADHD. [Wilens et al., 2005]; [Molina et al., 2007]
• Patients with ADHD-SUD comorbidity show more complex and chronic patterns of substance use, including more polysubstance use, than adults with SUD without comorbid ADHD and, have more difficulties remaining abstinent and report a reduced quality of life. [Crunelle et al., 2018]
• They have more significant psychiatric comorbidity, such as antisocial personality disorder, borderline personality disorder, anxiety disorders, bipolar disorders and/or post-traumatic stress disorders.
• The Conners’ Adult ADHD, Diagnostic Interview for the DSM-IV (CAADID) is often used as the gold standard for diagnosing adult ADHD in patients with SUD.

Eating Disorders (EDs)

• The prevalence of ADHD in EDs ranges between 1.6% and 18%. Comorbid ADHD was more often reported in the AN-binge eating/purging subtype and BN than in the AN restrictive subtype. ADHD is also closely associated with Binge Eating Disorder (BED) with overlapping clinical (impulsivity) and neurobiological correlates. [Nickel et al., 2019]
• Females with ADHD are 3.6x more likely to develop an eating disorder than females without ADHD. [Canadian ADHD Practice Guidelines] Eating disorders such as bulimia nervosa and anorexia nervosa (purging subtype) are the most commonly diagnosed.
• ADHD and EDs may share common neurobiological mechanisms with dopamine dysregulation in frontostriatal areas underpinning both disorders. [Levin et al.,2016] 
• ADHD is also a risk factor for obesity unless the patient has compensatory behaviours such as excessive exercise, purging, fasting, or misuse of laxatives, diet pills or other medications. [Cortese et al., 2016]
• ADHD symptoms are inversely correlated with recovery in ED. [Svedlund et al., 2018]
• Lisdexamfetamine (LDX) is FDA approved to treat moderate to severe Binge Eating disorder (BED) in adults.
• Clinicians also need to be aware that some patients may feign ADHD to acquire stimulant medications to aid their weight loss. [Canadian ADHD Practice Guidelines]

Anxiety disorder

• Individuals with ADHD have higher rates of anxiety (up to 50%) than the general population. [Katzman et al., 2017]
• Patients with ADHD are often forgetful, which can cause excessive over-compensatory mechanisms (e.g. checking and rechecking) that can induce a state of anxiety about forgetting something important. [Canadian ADHD Practice Guidelines]. This can give the impression of a primary anxiety disorder.
• In childhood, the presence of generalised anxiety disorder (GAD) could prevent the typical inhibitory dysfunction present in ADHD. In adolescence it may increase the deficit of working memory. In adulthood it may enhance the presence of sleep problems.
• Individuals with anxiety disorders who have comorbid ADHD tend to have more severe anxiety symptoms, earlier age of onset of anxiety, and more frequent additional comorbid psychiatric diagnoses and substance use than those who do not have ADHD. [Katzman et al., 2017]
• The combination of ADHD and anxiety is associated with a very high risk of bipolar disorder. [Meier et al., 2018]
• However, some signs and symptoms are distinct to ADHD that differentiate from anxiety. For example, ADHD symptoms such as inattention and restlessness occur in the absence of an emotional state, unlike what that with an anxiety disorder. Patients with anxiety will also exhibit physical symptoms such as elevated heart rate, nausea, and shortness of breath, all of which are usually absent in patients with ADHD. [Canadian ADHD Practice Guidelines]

Management of Anxiety and ADHD:

• Treatment of anxiety and ADHD requires a strategy that treats the most impairing condition.
• Individuals with comorbid ADHD and anxiety disorders would benefit from adjunctive psychosocial or adjunctive pharmacotherapy interventions to cognitive behavioural treatment. [D’Agati et al., 2019]
• Individuals with ADHD can experience distress and state anxiety during cognitive tasks. MPH can reduce state anxiety and improve cognitive performance. [Bloch et al., 2017]
• Psychostimulants can also increase anxiety and should be titrated upward slowly until symptoms are stabilised.
• Some studies that evaluated MPH in anxiety showed that patients could respond less well and get more unpleasant arousal side-effects.
• Low dose aripiprazole treatment in adolescents and adults may also provide benefits. [D’Agati et al., 2019]

Management of Anxiety and ADHD in children. 

• Treating ADHD with stimulants can lead to improvement in ADHD-related anxiety symptoms.
• Treating anxiety can reduce anxiety-related attentional problems and executive functioning.
• Atomoxetine and alpha agonists may be suitable treatments that address both ADHD and anxiety.
• Behavioural treatment should be part of the plan for ADHD co-occurring with anxiety disorders. [Janiczak et al.,2020] 

Major depressive disorder (MDD)

• Patients with ADHD are at an increased risk of developing MDD with ADHD-MDD comorbidity, also increasing illness severity and functional impairments. [Miller et al., 2007]
• Loss of motivation, restlessness, and irritability are common symptoms of both MDD and ADHD; however, feelings of sadness, hopelessness, tiredness and suicide indicate MDD rather than ADHD.
• A clinician is encouraged to ask “since when?” if MDD-specific symptoms are reported. [Canadian ADHD Practice Guidelines]

ADHD and Comorbid MDD in children: 

True comorbid MDD is differentiated by :

• Depressive cognitions (e.g., guilt, worthlessness, hopelessness, morbid or suicidal thoughts)
• Severe anhedonia
• Psychomotor retardation.

Symptoms such as irritability, poor concentration, anergia, sleep problems, and psychomotor or appetite changes have overlap with ADHD and other frequent comorbidities. They may be associated with the side effects of ADHD medications. [Daviss, 2016]

Management of ADHD and Comorbid MDD.

• Treat the most severe or functionally impairing condition first. [Daviss, 2016].[McIntosh et al., 2009]

If Depression is more severe:

• If moderate-severe MDD is the most pressing clinical issue, then treatment for Depression should be initiated first. [McIntosh et al., 2009]
• Option to add a stimulant if the depressive but not the ADHD symptoms respond to the antidepressant. [Daviss, 2016]
• Once the depression has improved, the patient should be re-evaluated for symptoms of ADHD, and if necessary, treatment for ADHD should be initiated.
• If the patient does not respond adequately to antidepressant medication, consideration should be given to re-evaluating both the Depression and ADHD diagnosis and, if appropriate, initiating ADHD treatment.
• Consider concomitant psychotherapy.

If ADHD is the primary condition

• Treat ADHD first with long-acting psychostimulant as first-line treatment
• Atomoxetine and bupropion are indicated if a stimulant trial is contraindicated or has failed, or when a non-stimulant is preferred
• Reassess if depressive symptoms are present and if AD is required.
• Antidepressants may not always be needed.
• Consider concomitant psychotherapy.

Management of ADHD and Comorbid MDD in Children and adolescents: [Turgay et al., 2006]

ADHD symptoms more prominent: 

• Treatment with psychostimulants for at least two weeks
• If depressive symptoms do not improve, add SSRI.
• Continue stimulant medication if the ADHD and depressive symptoms improve.
• If the ADHD and/or depressive symptoms worsen, the stimulant should be discontinued.
• Combining SSRI with psychostimulants can be considered when the risk of suicide and/or serious self-injurious behaviour is high. [Hughes et al., 1999]
• Atomoxetine is also effective in treating ADHD in pediatric patients with ADHD and comorbid symptoms of depression or anxiety.

Depressive symptoms more prominent: 

• Start with AD
• If no response, switch to a different class of antidepressants.
• Add psychostimulants if depressive symptoms improve with antidepressants, but ADHD symptoms do not respond.
• Bupropion is a recommended antidepressant as it addresses both symptoms of Depression and ADHD.

Important Tips in Management

• Antidepressants such as SSRIs can be combined with stimulant or non-stimulant medications for ADHD.
• However, fluoxetine and paroxetine are potent inhibitors of the CYP450/2D6 liver isoenzyme, and caution is advised when co-administering amphetamines or atomoxetine for ADHD as they can increase levels.
• Children and adolescents, and patients should be monitored for indicators of potential suicidal ideation

Bipolar disorder (BD): 

• ADHD often co-occurs with BD and BPD, characterised by symptoms that overlap with ADHD. [Asherson et al., 2014]
• Approximately 20% of patients with BD or BPD will have comorbid ADHD, with research suggesting that this is true comorbidity that goes beyond the complexity of just symptom overlap. [Milberger et al., 1995]

The following table can help differentiate ADHD from Bipolar disorder:

Management of ADHD and Comorbid Bipolar Disorder: 

• The first goal of ADHD–BD treatment is mood stabilisation. In some cases, after mood is stabilised, some ADHD/BD patients may not fulfil diagnostic criteria for ADHD. [Salvi et al., 2021]
• In patients who complain of residual cognitive symptoms, clinicians can add ADHD medications such as MPH, atomoxetine or amphetamine salts.
• The use of stimulants in BPAD has been controversial, with the main concern being the risk of mania.
• A large study of 145000 children with ADHD showed that MPH treatment for more than one year reduced the risk of new-onset BPAD compared to those not treated. [Wang et al., 2016]
• Another study found no evidence for a positive association between MPH and treatment-emergent mania among those on concomitant mood stabilisers. However, those treated with MPH alone had a 6.7-times increased risk of manic episodes within three months of medication initiation. [Viktorin et al., 2017]
• Lisdexamfetamine also showed benefits on ADHD and depressive symptoms in a 4-week trial in adults with bipolar I/II disorder without inducing any treatment-emergent hypomanic or manic episode. [McIntyre et al., 2013]
• Lisdexamphetamine is also evidence-based as an add on treatment in the treatment of treatment-resistant Bipolar Depression. [McElroy et al., 2015]
• Bupropion SR may also be effective in ADHD/BD comorbidity without significant activation of mania. [Wilens et al., 2003]
• Atomoxetine has been associated with mania and hypomania or mood dysregulation or irritability in 33% of children with ADHD. Atomoxetine carries the risk of induction of (hypo) mania even in stabilised patients with BD. Caution is therefore warranted when using atomoxetine in ADHD/BD comorbidity. [Kumar et al., 2017]
• Alpha-2 agonists, such as clonidine and guanfacine, are useful agents in ADHD / BD comorbidity. Clonidine is also effective in the treatment of manic episodes. [Girard et al., 2017]

Disruptive mood dysregulation (DMDD)

• DMDD is characterised by chronic and severe irritability with frequent out-of-proportion outbursts of temper. [Canadian ADHD Practice Guidelines]
• There are many differential diagnoses, including BD, ODD, ADHD, and CD [Axelson et al., 2012]; however, patients with DMDD have an inter-episode mood that is still characterised as irritable/dysphoric. [Leibenluft et al., 2006]
• DMDD is a relatively new DSM-5 diagnosis, and therefore only approximate pharmacological and psychosocial treatments can be recommended.
• MPH treatment significantly improved mood and emotional symptoms associated with DMDD comorbid with ADHD. [Winters et al., 2018 ]

Obsessive-compulsive disorder (OCD)

• ADHD and OCD are both developmental disorders, and the comorbidity between these diagnoses is common despite inconsistent prevalence reports and their directly opposing neurobiology and clinical features. [Abramovitch et al., 2015]
• For example, impulsivity and disinhibition are core symptoms of ADHD (which can be treated with stimulants). In contrast, obsessiveness and compulsivity are the core symptoms of OCD (which can be treated with SSRIs and neuroleptics).
• Patients with OCD are very rarely impulsive and do not exhibit risk-taking behaviour. 75% of all individuals diagnosed with ADHD are diagnosed with the impulsive/hyperactive (combined) type, associated with significant impulsive behaviour.
• Individuals with OCD are able to perform accurate and repetitive rituals governed by very specific and complex rules, something that people with ADHD find difficult to do. [Abramovitch et al, 2013]

Management of ADHD and Comorbid OCD: 

• Treating OCD with SSRIs and cognitive behaviour therapy with exposure response prevention (CBT+ERP) improves attentional symptoms.
• Treating ADHD with stimulants improves comorbid obsessive-compulsive symptoms.
• Untreated comorbid ADHD diminishes treatment response on the OCD
• Clinicians can start with SSRIs for OCD and psychostimulants such as methylphenidate and dexamphetamine for ADHD.
• Medication should be introduced one at a time to assess response and improve tolerability. In addition, clinicians should be aware of the possibility of worsening OC symptoms with stimulants.
• TMS is also an effective option for treating comorbid ADHD and OCD [Cabarkapa et al., 2019] 

Tourette’s syndrome

• In a cohort study of Tourette syndrome patients, there were four subtypes identified: ‘pure’ Tourette syndrome (49.8%), Tourette syndrome and ADHD (22.2%), Tourette syndrome and OCD (21.5%), and Tourette syndrome, ADHD and OCD (6.5%). Rizzo et al., 2013]
• Tourette syndrome and Tourette syndrome with comorbid ADHD are distinct from both a neurobiologically perspective and a neurobehavioral perspective.
• For instance, patients with Tourette syndrome have prolonged prosaccade latencies, whereas patients with ADHD have impaired antisaccade accuracy. However, there are overlaps, including emotional lability.
• Tic disorders and ADHD can coexist as both disorders involve the frontostriatal circuits. [Neurobiology of Attention Deficit Hyperactivity Disorder (ADHD) – A Primer

Management of ADHD and Comorbid Tics / Tourette’s Syndrome 

• Start with a non-stimulant agent such as guanfacine (long-acting preparations may be preferred) or clonidine, as they effectively alleviate both symptoms of TS and ADHD. [Rizzo et al., 2013]
• If the TS is not severe, but the ADHD is disabling, one should consider treating the ADHD with a stimulant. Monitor for worsening tics with a reliable TS rating scale, such as The Yale Global Tic Severity Scale (YGTSS). [Oluwabusi et al., 2016]
• According to the Tourette’s Syndrome Study Group, the combination of methylphenidate and clonidine is effective for ADHD in children with comorbid tics. Prior recommendations to avoid methylphenidate because of concerns of worsening tics are unsupported [Tourette’s Syndrome Study Group, 2002]
• Symptoms of ADHD and tics, including impulsivity, improve when stimulant and non-stimulant medications are used, including methylphenidate, guanfacine, clonidine, and a combination of methylphenidate and clonidine. [Osland et al, 2018]. 
• Methylphenidate and clonidine combination may be superior to either treatment alone in ADHD in children with comorbid tic disorders. [Osland et al, 2018]. 
• High-dose dexamphetamine (22.5 mg – 30 mg/day) in children with ADHD was found to worsen tics, with lower doses of 15 mg /day showing no worsening. [Osland et al, 2018]. 
• Overall, stimulants were not shown to worsen tics in the majority of patients.
• Atomoxetine and Aripiprazole are useful in some cases. [Rizzo et al., 2013]

Autism spectrum disorder (ASD)

• ASD was an exclusion criterion in the DSM-IV for ADHD; however, in the DSM-V, there is the possibility of a dual diagnosis. Analysis of the prevalence of ASD co-occurring with ADHD varies from 37% to 85%. [Gadow et al., 2006]; [Lee and Ousleey, 2006]
• ASD is characterised by social dysfunction and restrictive-repetitive behaviours, although these psychosocial issues can be exacerbated by comorbid ADHD. Both ADHD and ASD include a spectrum of difficulties associated with attention, communication, impulsivity, restlessness, and/or hyperactivity.
• Risperidone and aripiprazole are approved for the treatment of ASD, and both drugs effectively reduce irritability. Methylphenidate and atomoxetine are commonly administered for ADHD-related symptoms. However, there may only be an improvement in symptoms such as hyperactivity and impulsivity, which may not be associated with the patient’s ASD diagnosis. [Arnold et al., 2006]; [Arnold et al., 2012]
• ADHD and ASD are thought to be associated with (or defined by) executive dysfunction, although the specific executive domains that are negatively impacted may differ. For example, children with ASD have more planning, and cognitive flexibility difficulties and children with ADHD have more inhibition difficulties.
• Atomoxetine and methylphenidate show evidence for treating ADHD symptoms within individuals with ASD. However, effect sizes from the ASD population are somewhat smaller than the non-ASD population, and side effects are more common in the ASD population. [Antshel et al., 2013]
• ADHD and Autism Comorbidity: A Comprehensive Review Based on Expert Consensus Recommendations and Latest Research Findings

ADHD is associated with a high degree of comorbidity across the lifespan.

Comorbidities may make the diagnosis of ADHD challenging, and as a result, may delay diagnosis for some patients.

Comorbidities also confound treatment and may require other therapies beyond treatments for ADHD.  The presence of comorbidities is not a contraindication for the use of stimulants, even in conditions such as anxiety, SUD and Bipolar disorder.

In general, the more severe disorder should be addressed first.

Treating ADHD and comorbidities tends to have better outcomes than treating either disorder alone.