Treatment Considerations for Comorbid BD and OCD

Obsessive compulsive disorder symptoms that present only during episodes of depression may be secondary to the mood episode.^5,9 The patient in Case 1 is taking a mood stabilizer and a selective serotonin reuptake inhibitor (SSRI) antidepressant without any improvement in depressive or OCD symptoms. There is limited evidence for the efficacy of medications in the treatment of comorbid BD and OCD. Case reports and case series have suggested lithium, anticonvulsant mood stabilizers, olanzapine, risperidone, quetiapine, or aripiprazole for this comorbidity.^5,9 Serotonergic antidepressant medication should only be used in combination with appropriate effective mood stabilizer treatment to avoid decompensation of bipolar symptoms.⁵ A systematic review of the treatment of BD and OCD reported a high rate of nonresponse to pharmacologic treatment, common use of polypharmacy, and a risk of manic/hypomanic mood switch if conventional treatment for OCD, such as SSRI therapy, was used.¹⁰ Mood stabilizer monotherapy is unlikely to be effective for both disorders; combination treatment with a mood stabilizer and a second-generation antipsychotic (SGA) or 2 mood stabilizers is recommended.^10,11 A case series reported on 3 patients with comorbid BD and OCD taking a mood stabilizer and adjunctive aripiprazole 15 mg to 25 mg daily.¹² A decrease in the Yale Brown Obsessive Compulsive Scale (YBOCS) score was observed for all patients. All 3 patients tolerated aripiprazole with no reported side effects, including akathisia. In a placebo-controlled study of adjunctive quetiapine in patients with treatment-refractory OCD (n = 40), the YBOCS score decreased by ∼25%.¹³ A comparison trial of aripiprazole (n = 6) and quetiapine (n = 12) as augmentation treatment in refractory OCD resulted in more participants moderately responding to quetiapine (∼55%) than aripiprazole (∼28%) with similar decreases in YBOCS scores (P = .01 for quetiapine, not statistically significant for aripiprazole).¹⁴

In the case of the 28-year-old patient with continuing symptoms of bipolar depression and OCD, medication changes are warranted. Lithium is recommended as third-line therapy in the Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations.⁵ Table 2 provides a review of the recommendations from the CANMAT task force.⁵ Selective serotonin reuptake inhibitor drug therapy should not be used without effective mood stabilizer therapy; sertraline is not effective for either depressive or OCD symptoms for this patient. The case does not clarify if the patient has taken other SSRI antidepressant therapy, therefore a switch to a different SSRI may be an option. Aripiprazole, risperidone, and quetiapine have evidence of efficacy as augmentation agents for SSRI treatment for OCD symptoms specifically in randomized controlled trials of OCD without BD.^13-15 Other SGAs that have been studied for bipolar depression, such as lurasidone or olanzapine, may be considered although clinical evidence is limited for effectiveness for OCD symptoms. For this patient, options include transition to another SSRI or to an atypical antipsychotic while continuing lithium treatment. If the patient prefers another SSRI, paroxetine may help with sleep. It can be initiated either by direct switch or cross-titration as tolerated by the patient. If the patient prefers an atypical antipsychotic, then the sertraline should be tapered over 1 to 4 weeks, as tolerated, while initiating either quetiapine (if sedation desired) or aripiprazole (if sedation is not desired). Combination treatment with either an SSRI and mood stabilizer or SGA and mood stabilizer were most commonly used in a systematic review of the treatment of BD and OCD.⁵

TABLE 2 Canadian Network for Mood and Anxiety Treatments task force recommendations for the management of patients with mood disorders and comorbid anxiety disorders⁵

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The use of psychotherapy in comorbid BD and OCD has been shown to be effective in clinical trials. Interpersonal therapy, cognitive behavioral therapy (CBT), mindfulness-based CBT, and relaxation therapy may be employed in combination with medication treatment.^15-17 Psychoeducation is not effective, and CBT is more effective for OCD symptoms when the patient is euthymic.^18,19 Comorbid OCD can have a significant impact on recovery for both bipolar and OCD symptoms, with a decreased social quality of life, higher risk of rapid cycling, suicide attempts, alcohol use, and a decreased likelihood of remission of bipolar symptoms in the first year of treatment with mood stabilizers.^18-20

Risk of Manic Switch: Use of Antidepressants in BD

Symptoms of anxiety disorders are regarded as chronic throughout treatment, often necessitating long-term medication treatment. The SSRI antidepressants are recommended as first-line drug therapy for the treatment of anxiety disorders. Selective serotonin reuptake inhibitors and bupropion are believed to have a lower risk of manic switch than serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants.^21,22 The risk of antidepressant treatment-emergent hypomania or mania (ATEM) has been a long-standing concern about the use of these medications to treat bipolar depression. The CANMAT task force recommendations for the treatment of anxiety disorders with comorbid BD suggest serotonergic antidepressants are second-line therapy, with the caution that patients should be taking effective mood stabilizer treatment as a foundational therapy.⁵ Predictors of manic switch were evaluated in a study using a sample of participants (n = 1720) in the Systematic Treatment Program for Bipolar Disorder trials.²³ According to this study, baseline variables for an increased risk of manic switch include younger age (17 to 22 years) at onset of BD, a previous history of rapid cycling, severe manic symptoms, suicide attempts, or amphetamine use.²³ A higher switch rate is possible if there is a history of manic switch using SSRIs in general and specifically with the use of fluoxetine, sertraline, or paroxetine.²³ A lower risk is conferred if the patient has a history of participation in psychotherapy.²³ The number of past manic episodes overall may also contribute to the risk of ATEM. A study of depressed bipolar patients (n = 1242) taking a mood stabilizer and a recently initiated antidepressant for 1 month observed 4.8% (n = 60) of study participants experienced a manic switch. Patients who had at least 4 lifetime manic episodes and a history of ATEM were at 2.84 times greater risk of manic switch.²⁴ Switch rates during a study of acute treatment comparing lithium monotherapy (n = 49), sertraline monotherapy (n = 45), and the combination (n = 48) were estimated to be approximately 14%, with no difference between the treatment arms.²⁵ Two studies focused on evaluating the correlates and rates of switch using a strict definition of ATEM.^26,27 Study participants who had ATEM (n = 44) had different baseline Young Mania Rating Scale (YMRS) scores compared to those who had and had not responded to antidepressant treatment but did not have ATEM (n = 128). The baseline YMRS scores for participants with ATEM was 3.7 versus those without ATEM (1.8 to 2.5). The YMRS scores for motor activity and speech were increased and the item for language-thought disorder was positive.²⁶ The authors²⁶ recommend evaluating patients for the presence of minimal baseline manic symptoms (specifically motor activation, pressured speech, and racing thoughts) to identify individuals at risk for ATEM prior to initiating antidepressant therapy. A study²⁷ (n = 210) using strict criteria for ATEM differentiated odds ratios (OR) of risk for ATEM based upon gender. For men (n = 95), increased risk was found for alcohol use/substance use disorder (OR 6.37), history of suicide attempt (OR 4.19), and increased number of depressive episodes per year (OR 1.71). For women (n = 125), history of thyroid disorder (OR 3.23), family history of BD I (OR 2.68), and depression as the first mood episode (OR 2.01) conferred greater risk of ATEM.²⁷

Treatment Considerations for Comorbid BD and GAD

The point prevalence for GAD with comorbid BD is estimated to be 12% with a lifetime prevalence of 15%.²⁸ This comorbidity leads to a more severe course of illness and increased suicidality.²⁸ Quality of life in patients with BD and comorbid anxiety disorders who are euthymic is poorer overall in both BD I and II, but the greater negative effect is found in BD I.²⁹ Olanzapine, lamotrigine, divalproex sodium, and olanzapine/fluoxetine combination have been found to be effective in the treatment of nonspecific anxiety symptoms that are comorbid with BD.^3,30,31 Lithium is not likely to be effective as monotherapy; augmentation of lithium with lamotrigine or olanzapine may improve efficacy.^3,30 Risperidone is not effective for nonspecific anxiety symptoms. Ziprasidone monotherapy was not associated with improved panic disorder or GAD symptoms in patients with BD (n = 49); increased abnormal involuntary movements were noted over the 8-week study.³² Benzodiazepines may be considered if the patient is not experiencing an acute depressive episode.^3,30

Quetiapine extended-release has been studied as monotherapy versus placebo and divalproex sodium extended-release, with conflicting results relative to effectiveness.^33,34 In a study³³ evaluating patients (n = 100) with acute bipolar I or bipolar II depression with comorbid GAD, quetiapine extended-release, at an average study dose of 276 mg/d, was not superior to placebo in treating anxiety symptoms. A trial³⁴ evaluating quetiapine extended-release monotherapy (n = 49), divalproex sodium extended-release monotherapy (n = 49), and placebo (n = 51) observed quetiapine extended-release, at an average study dose of 186 mg/d, provided rapid sustained improvement in anxiety symptoms (Hamilton Anxiety Rating Scale, P < .05 vs divalproex and placebo) in bipolar patients and was superior to both divalproex sodium extended-release and placebo.

Cognitive behavioral therapy has been shown to be beneficial for patients experiencing BD with comorbid GAD.³⁵ The Unified Protocol for Emotional Disorders was used as the basis for CBT developed to address common core symptoms of emotional lability and maladaptive attempts to control or avoid emotional experiences in patients with BD and comorbid anxiety disorders (n = 29). Greater reductions in anxiety (Hamilton Anxiety Rating Scale, P = .03) and depressive (Hamilton Depression Rating Scale, P = .01) symptoms were observed in study participants.³⁵

In the case of the 34-year-old patient with BD and comorbid GAD, the patient seems to be experiencing a hypomanic episode due to antidepressant treatment. Symptoms of depression and GAD are not well controlled on the combination of divalproex sodium extended-release and duloxetine. Duloxetine should be discontinued and the hypomanic symptoms evaluated for resolution. Discontinuation of duloxetine for this patient may be achieved via a dose taper over a few weeks since this patient is hypomanic. If this patient was manic and met criteria for hospitalization, duloxetine should be discontinued without a taper with monitoring for antidepressant discontinuation syndrome. The efficacy of divalproex sodium in the past should be evaluated. It would be useful to obtain another serum concentration of divalproex to evaluate adherence to medication and for possible dose adjustments. Since the patient has not had effective treatment of GAD and depression symptoms, an SGA such as quetiapine or olanzapine should be considered as adjunctive therapy. Quetiapine is the preferred choice for this patient, based on the limited clinical trial evidence for efficacy. The CANMAT task force recommends quetiapine as first-line treatment and the sedative side effect may be helpful for this patient. Olanzapine/fluoxetine is a second-line treatment recommendation and may be considered with caution if quetiapine is not effective.

With Anxious Distress Specifier

Table 3 provides the diagnostic criteria for the with anxious distress specifier.³⁶ This specifier was added to the Diagnostic and Statistical Manual for Mental Disorders, 5th edition³⁶ because of greater recognition that anxiety symptoms and disorders are common comorbidities in mood disorders. Anxiety symptoms lead to a greater burden of depressive symptoms, increased total number of depressive episodes, and a longer time to remission.⁵ The use of the with anxious distress specifier reminds health care professionals to evaluate anxiety symptoms and appropriate treatment in addition to evaluation of other mental health diagnoses.

TABLE 3 Diagnostic and Statistical Manual for Mental Disorders , 5th edition, criteria for the with anxious distress specifier³⁸

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Treatment Considerations for Comorbid BD and PTSD

Patients with comorbid BD and PTSD have a higher risk of psychosis upon hospitalization (13%, P < .001), personality disorder diagnosis (42%, P = 002), and suicide attempts (75%, P < .001).^6,37 Poorer quality of life, accelerated illness progression, and high rates of functional impairment also characterize patients with this comorbidity, with a higher symptom burden compared to either illness alone.^6,38,39

Non-adherence to treatment in BD increases the risk of rapid cycling, suicide attempts, current anxiety, and alcohol use disorder.⁴⁰ Non-adherence at 3 month follow-up is predictive of less improvement in bipolar symptoms than non-adherence at 12 month follow-up.⁴⁰ Patients with non-adherence to treatment for comorbid BD and PTSD may have childhood or other trauma that created a negative or distrustful impression of physicians, health care providers, and medication treatment.⁴¹ Traumatic outcomes resulting from dangerous behaviors that occur during a manic episode may trigger the reemergence of PTSD symptoms. Posttraumatic stress disorder nightmares could impact the sleep-wake cycle, leading to decreased sleep and a greater risk for a manic episode.⁴¹

The CANMAT task force recommendations recognize that there have been no clinical trials of drug therapy for comorbid BD and PTSD. The recommendations suggest initial medication therapy should be a mood stabilizer, followed by the combination of an SGA and an antidepressant.⁵ Once mood stabilizer treatment is initiated, then SSRI or SNRI antidepressant therapy may be used with caution for residual PTSD anxiety symptoms. Posttraumatic stress disorder may be less likely to respond to lithium treatment; therefore risperidone, lamotrigine, gabapentin, and oxcarbazepine may be considered.^11,30,42 The level of evidence for the efficacy of anticonvulsants and antipsychotics for the treatment of PTSD is limited. Mood stabilization remains the priority; once this is established, medication combinations including anticonvulsants, antipsychotics, and antidepressants may be considered.⁵ Benzodiazepines appear as a third-line recommendation in the CANMAT task force recommendations, but these medications are generally considered to be ineffective for PTSD and carry a risk of developing further PTSD symptoms after recent trauma, worsening psychotherapy outcomes, and developing substance use disorders in PTSD.⁴³ Divalproex sodium may be considered for the with anxious distress and general anxiety symptoms in BD.³⁰

In the case of the 38-year-old patient currently prescribed quetiapine extended-release and fluoxetine with questionable adherence to treatment, the patient should be asked about the reasons for not taking medications appropriately as well as the overall perception of medication therapy. A priority for this patient is to evaluate if this combination of medications has been effective in the past. If so, patient factors related to non-adherence should be addressed, and the patient should be encouraged to restart this medication regimen. Risperidone has positive evidence of effectiveness and may be considered if quetiapine is discontinued. If fluoxetine is discontinued, switching to an SNRI, such as venlafaxine, could be considered after mood stabilizer therapy has been established with increased monitoring for the risk of manic switch. The use of benzodiazepines should be avoided for this patient. Other common medications and treatments for PTSD, such as prazosin for nightmares and psychotherapy or CBT may also be considered. Studies evaluating CBT, including psychoeducation, coping skills, cognitive restructuring, and relaxation training, have included patients with comorbid BD and PTSD.¹⁸ While the results of these studies have preliminarily shown improvement in anxiety symptoms for CBT focused on PTSD with comorbid BD, retention rates in these studies has been low.¹⁸