The woman who wasn’t there

Which medications would you consider for Ms. A?

1. benzodiazepine plus a tricyclic antidepressant (TCA)
2. selective serotonin reuptake inhibitor (SSRI) plus a benzodiazepine
3. trazodone plus bupropion
4. atypical antipsychotic plus a benzodiazepine and a TCA

TREATMENT: Insufficient response

Ms. A’s previous psychiatrist prescribed various SSRIs and selective serotonin-norepinephrine reuptake inhibitors, including sertraline, escitalopram, citalopram, paroxetine, and venlafaxine, for depression and anxiety with little or no benefit. When she presented at our clinic, Ms. A was taking clonazepam, 0.25 mg as needed, and fluvoxamine, 50 mg/d, which she said helped her anxiety a little, but not depersonalization symptoms. She received supportive psychotherapy provided during biweekly 30-minute medication management visits.

We add aripiprazole, 2.5 mg/d, to augment fluvoxamine’s antidepressant effect and reduce her anxiety and dissociative symptoms. At the next visit 5 weeks later, she reports her depersonalization symptoms gradually lessened from 10 to 6 on a 10-point self-report scale.

We discontinue fluvoxamine after 5 weeks because it no longer significantly contributes to her recovery. We add amantadine, 100 mg/d, based on the belief that dopamine augmentation might help reduce her symptoms. Ms. A reports improved depersonalization symptoms over the next 4 weeks (5/10). However, a week later she says she feels her anxiety is worsening the depersonalization symptoms. We start buspirone, 7.5 mg/d titrated to 15 mg/d over 4 weeks, Ms. A reports feeling worse so we discontinue the drug.

Next Ms. A complains of excessive sleepiness, which seems to be related to amantadine, so we discontinue it. We start bupropion, 150 mg/d and titrate it to 450 mg/d, which we hope will reduce her fatigue, anxiety, depersonalization, and depression. Bupropion’s effect on norepinephrine and dopamine reuptake and a study of autonomic blunting in depersonalization⁹ justify our selection.

After 3 months, Ms. A stops taking aripiprazole because it is too costly. The following month she presents with severe anxiety and low-to-moderate depression. Clonazepam and bupropion are discontinued and replaced with diazepam, 20 mg/d, and clomipramine, 25 mg/d at bedtime titrated to 75 mg/d. Our decision is guided by a study on the efficacy of clomipramine in treating depersonalization¹⁰ and our desire to aggressively treat her anxiety and depression. After 2 weeks, Ms. A says her anxiety and depression have resolved completely but the depersonalization symptoms persist. We restart amantadine, 100 mg as needed, for anorgasmia.

Because of her persistent complaints of depersonalization, after discussion with Ms. A, we decide to return to what had helped her at the beginning of treatment and restart aripiprazole, 2.5 mg/d. Four months later, she reports her depersonalization symptoms have resolved completely. At this time, her regimen consists of clomipramine, 50 mg at bedtime, diazepam, 10 mg at bedtime, and aripiprazole, 2.5 mg/d.

Which neurotransmitter systems have been implicated in depersonalization disorder?

1. HPA axis
2. serotonin system
3. norepinephrine-dopamine system
4. dopamine-serotonin system
5. all of the above

The authors’ observations

The neurobiology of emotion processing is still unclear but some evidence indicates that the amygdala, anterior cingulate cortex, and medial prefrontal cortex might be involved in emotion regulation and integration.

Depersonalization disorder is associated with HPA axis dysregulation and patients with depersonalization disorder have a lower basal cortisol level compared with patients with MDD.^11,12 Simeon et al⁹ found a marked basal norepinephrine decline with increasing depersonalization severity.

Various SSRIs,^13,14 TCAs,^10,15,16 citalopram-olanzapine combination, naltrexone, citalopram-clonazepam combination,¹⁷ and fluoxetine-buspirone combination¹⁸ have been studied as treatment for depersonalization disorder. We present the first case report of aripiprazole to treat depersonalization disorder. A previous study¹⁹ of quetiapine—a low potency blocker of dopamine D2 receptors, which also has a high affinity for serotonin 5-HT2A receptors—suggested a potential role in improving emotional numbing symptoms in depersonalization/derealization disorder. The authors hypothesized that quetiapine may facilitate dopamine and serotonin neurotransmissions in the anterior limbic cortex and prefrontal cortex, which are involved in emotional experiences.

Other treatment options

The kappa opioid system also is implicated in depersonalization. Enadoline, a selective k-opioid agonist, has been shown to cause depersonalization symptoms in healthy subjects.²⁰ High doses of opioid antagonists, such as naltrexone, have been used successfully to treat depersonalization symptoms in patients with borderline personality disorder,²¹ PTSD,²² and depersonalization disorder.²³

Ketamine—which can produce depersonalization—increases glutamate transmission, which suggests that drugs that affect the glutamate system might be targets for future investigation. Similarly, smoking marijuana can induce depersonalization, which indicates that cannabinoid receptors might be another area for research. Hallucinogens, such as lysergic acid diethylamide, psilocybin, and dimethyltryptamine, can produce temporary depersonalization. These drugs are 5-HT2 agonists (HT2A, HT2C), which gives weight to using 5-HT2 antagonists to treat depersonalization.