CASE: Refractory depression
Ms. W, age 38, is brought to the emergency department after her son finds her unresponsive and calls 911. Suffering from worsening depression, she wrote a note telling her children goodbye, and overdosed on zolpidem from an old prescription and her daughter’s opioids. After being evaluated and medically cleared in the emergency department, Ms. W was admitted to the psychiatric unit.
Ms. W has a history of recurrent major depressive disorder that developed after she was sexually abused by a relative as a teen. She also has bulimia nervosa, alcohol dependence, and posttraumatic stress disorder. She was hospitalized twice for depression and suicidality but had not previously attempted suicide. In the mid-to-late 1990s, she had trials of paroxetine, clomipramine, lithium, and bupropion.
She was seen regularly in our outpatient psychiatry clinic for medication management and supportive psychotherapy. Since being followed in our clinic starting in early 2005, she has had the following medication trials:
- fluoxetine, citalopram, venlafaxine XR, and duloxetine for depression
- atomoxetine, buspirone, liothyronine, risperidone, and aripiprazole for antidepressant augmentation
- lorazepam, clonazepam, and gabapentin for anxiety
- zolpidem and trazodone for insomnia
- nortriptyline for migraine headache prophylaxis.
Some medications were not tolerated, primarily because of increased anxiety. Those that were tolerated were adequate trials in terms of dose titration and length. High-dose fluoxetine (80 mg/d) augmented by risperidone (0.375 to 0.5 mg/d) produced the most reliable and significant improvement.
Ms. W had 2 courses of electroconvulsive therapy (ECT) totaling 30 treatments—most recently in 2007—that resulted in significant memory loss with limited benefit. Premenstrual worsening of depression and suicidality were noted. In collaboration with her gynecologist, Ms. W was treated with a 3-month trial of leuprolide to suppress her ovarian axis, which was helpful. In 2008 she underwent bilateral oophorectomy. She has not had symptoms of mood elevation or psychosis. Family history includes schizophrenia, depression, anxiety, and alcoholism.
In the months before hospitalization, Ms. W had been increasingly depressed and intermittently suicidal, although she did not endorse a specific plan or intention to harm herself because she was concerned about the impact suicide would have on her children. Weight gain with risperidone had reactivated body image issues, so Ms. W stopped taking this medication 2 weeks before hospitalization. Her depression became worse, and she began using her husband’s hydrocodone/acetaminophen prescription.
The authors’ observations
Approximately 40% of patients with major depression fail to respond to an initial antidepressant trial.1 An additional 50% of these patients will be treatment-resistant to a subsequent antidepressant.1 Patients may be progressively less likely to respond to additional medication trials.2
One of the most rapid-acting and effective treatments for unipolar and bipolar depression is sleep deprivation. Wirz-Justice et al3 found total or partial sleep deprivation during the second half of the night induced rapid depression remission. Response rates range from 40% to 60% over hours to days.4 Sleep deprivation also can reduce suicidality in patients with seasonal depression.5 This treatment has not been widely employed, however, because up to 80% of patients who undergo sleep deprivation experience rapid and significant depressive relapse.4
Sleep deprivation usually is well tolerated. Potential side effects include:
- headache
- gastrointestinal upset
- fatigue
- cognitive impairment.
Less often, patients report worsening of depressive symptoms and, rarely, suicidal ideation or psychosis.4 Mania or hypomania are potential complications of sleep loss for patients with bipolar or unipolar depression. In a review, Oliwenstein6 suggested that rates of total sleep deprivation-induced mania are likely to be similar to or less than those reported for antidepressants. Because sleep deprivation can induce seizures, this therapy is contraindicated for patients with epilepsy or those at risk for seizures.4
Researchers have successfully explored strategies to reduce the rate of depressive relapse after sleep deprivation, including coadministering light therapy, antidepressants, lithium (particularly for bipolar depression), and sleep-phase advance.4 Sleep-phase advance involves shifting the sleep-wake schedule to a very early sleep time and wake-up time (such as 5 PM to midnight) for 1 day, and then pushing back this schedule by 1 or 2 hours each day until the patient is returned to a “normal” sleep schedule (such as 10 PM to 5 AM). Researchers have demonstrated that sleep-phase advance can have antidepressant effects.7
TREATMENT: Sleep manipulation
Ms. W is continued on fluoxetine, 80 mg/d. We opt for a trial of partial sleep deprivation and sleep-phase advance for Ms. W because of the severity of her depression, her multiple ineffective or poorly tolerated medication trials, and limited benefit from ECT. This treatment involves instituting partial sleep deprivation the first night and subsequently advancing her sleep phase over the next several days (Table 1).