Treatment Guidelines for Bipolar Disorder and ADHD
Critical Treatment Principle: Stabilize Mood First
Bipolar disorder must be stabilized with a mood stabilizer before initiating any ADHD treatment, as treating unstabilized bipolar disorder with ADHD medications significantly increases the risk of mood destabilization and can trigger manic or mixed episodes. 1
Step 1: Achieve Mood Stabilization
First-Line Mood Stabilizers
- Initiate lithium or divalproex (valproate) as first-line agents for bipolar disorder stabilization 2, 1
- Lithium remains the most effective drug overall for bipolar disorder, though full remission occurs only in a subset of patients 3
- Maintain the mood stabilizer regimen for 12 to 24 months minimum before considering ADHD treatment 1
Alternative Mood Stabilizers
- Haloperidol is recommended for acute bipolar mania, with second-generation antipsychotics (quetiapine, aripiprazole, asenapide, lurasidone, cariprazine) as alternatives 2, 4
- Carbamazepine may be considered as an alternative mood stabilizer 2
Critical Monitoring for Lithium
- Regular monitoring of lithium levels, renal and thyroid function, and urinalyses once stable dose is obtained 1
- Over 90% of adolescents noncompliant with lithium relapsed, compared to 37.5% relapse rate for compliant patients 1
Step 2: Screen for Bipolar Disorder Before ADHD Treatment
Prior to initiating atomoxetine or any ADHD medication, screen patients for personal or family history of bipolar disorder, mania, or hypomania. 5
Step 3: Treat ADHD After Mood Stabilization
First-Line ADHD Treatment: Atomoxetine
Atomoxetine is the preferred first-line ADHD medication for patients with comorbid bipolar disorder, providing effective ADHD symptom control without exacerbating mood instability. 1, 6
Dosing Protocol for Atomoxetine
- Starting dose: 40 mg daily (or 0.5 mg/kg/day in children/adolescents under 70 kg) 6, 5
- Target dose: 80-100 mg daily (or 1.2 mg/kg/day in children/adolescents under 70 kg) 6, 5
- Titration: Increase after minimum of 3 days to target dose 5
- Maximum dose: 100 mg daily (or 1.4 mg/kg/day in children/adolescents, whichever is less) 5
- Time to full effect: 4-6 weeks at therapeutic dose 6
Advantages of Atomoxetine
- Provides "around-the-clock" symptom control without rebound/crash effects seen with stimulants 6
- Particularly useful when substance abuse history is present 2, 7
- Does not exacerbate mood instability 1, 6
Monitoring Requirements for Atomoxetine
- Assess effectiveness after 6-8 weeks at therapeutic dose using standardized ADHD rating scales 1, 6
- Monitor suicidal ideation, appetite and weight changes, and vital signs at each visit 6
Second-Line ADHD Treatment: Alpha-2 Agonists
- Extended-release guanfacine or clonidine extended-release may be considered as second-line treatment 6
- These agents address both ADHD symptoms and emotional dysregulation with minimal risk of triggering mood episodes 6
- Guanfacine and clonidine are particularly useful when sleep disturbances are present 2
Third-Line ADHD Treatment: Stimulants (Use with Extreme Caution)
Stimulants should only be considered after complete mood stabilization on a mood stabilizer regimen, and carry significant risks in bipolar disorder. 1, 6
When Stimulants May Be Used
- Once mood symptoms are adequately controlled on a mood stabilizer for at least 12-24 months 1
- Low-dose mixed amphetamine salts have been shown safe and effective for comorbid ADHD once mood is stabilized with divalproex 1
- Methylphenidate and lisdexamfetamine have large effect sizes for reducing ADHD core symptoms 2
Critical Precautions with Stimulants
- Never initiate stimulants before achieving mood stability 1, 6
- Stimulants may be regarded as unviable in substance use disorders due to dopaminergic activity in nucleus accumbens and striatum 2
- The use of stimulants for comorbid ADHD does not affect relapse rates when mood stabilizers are maintained 1
Step 4: Maintain Both Treatments Indefinitely
Continue the mood stabilizer regimen indefinitely while treating ADHD, as discontinuation significantly increases relapse risk. 1
- Maintenance treatment for bipolar disorder should continue for at least 2 years after the last episode 2
- Most youths with bipolar disorder require ongoing medication therapy to prevent relapse 1
- Pharmacological treatment should be provided in parallel with psychotherapeutic and psychosocial interventions 2
Multimodal Treatment Approach
Essential Non-Pharmacological Components
- Psychoeducation should be routinely offered to individuals with bipolar disorder and their family members/caregivers 2
- Cognitive behavioral therapy and family interventions can be considered if adequately trained professionals are available 2
- Behavioral therapy should be provided in parallel with pharmacological treatment for remaining symptoms and deficits in psychosocial functioning 2
Psychosocial Interventions
- Psychosocial interventions to enhance independent living and social skills should be considered 2
- Facilitation of supported employment may be considered if patients have difficulty obtaining or retaining normal employment 2
Special Dosing Considerations
Hepatic Impairment
- Moderate hepatic impairment (Child-Pugh Class B): Reduce atomoxetine initial and target doses to 50% of normal 5
- Severe hepatic impairment (Child-Pugh Class C): Reduce atomoxetine initial and target doses to 25% of normal 5
CYP2D6 Poor Metabolizers or Strong Inhibitors
- When using strong CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine) or in CYP2D6 poor metabolizers, initiate atomoxetine at 0.5 mg/kg/day (or 40 mg/day in adults) 5
- Only increase to usual target dose if symptoms fail to improve after 4 weeks and initial dose is well tolerated 5
Critical Pitfalls to Avoid
Never Treat ADHD Before Mood Stabilization
- Initiating ADHD treatment before achieving mood stability significantly increases risk of mood destabilization 1, 6
- Comorbid ADHD predicts poorer response to bipolar treatment, necessitating adequate mood control first 1, 6
Do Not Assume Single Medication Will Treat Both Conditions
- A single medication will not effectively treat both conditions 1
- Combination therapy is necessary, with mood stabilizer as foundation 1
Avoid Benzodiazepines
- Do not use benzodiazepines for anxiety management in this population due to heightened risk of behavioral disinhibition 6
Do Not Use Antidepressants as Monotherapy
- Antidepressants are not recommended as monotherapy for bipolar disorder 4
- If antidepressants are used for bipolar depression, they must always be combined with a mood stabilizer (lithium or valproate), with SSRIs preferred over tricyclics 2
Clinical Context and Prognosis
Prevalence and Impact
- Lifetime ADHD occurs in approximately 9.5% of adults with bipolar disorder (14.7% in males, 5.8% in females) 8
- Patients with comorbid ADHD have onset of mood disorder approximately 5 years earlier 8
- After adjusting for age of onset, those with ADHD comorbidity have shorter periods of wellness and are more frequently depressed 8
Increased Comorbidity Burden
- Patients with bipolar disorder and ADHD have substantially higher rates of anxiety disorders, alcohol abuse, and substance dependence 8
- More than 50% of patients with bipolar disorder are not adherent to treatment 4