The patient is a 32-year-old woman who was first diagnosed with major depressive disorder (MDD) and obsessive compulsive disorder (OCD) at 15 years. Her obsessions and compulsions were composed primarily of trichotillomania and pathological skin picking. A few months later, those behaviors also assumed an impulsive pattern (sometimes her skin picking and trichotillomania were egosyntonic and pleasurable). At 17 years, she began to experiment with illicit drugs, including alcohol, cocaine, and opioids. She had a history of three previous inpatient hospitalizations for depression and suicide attempts by overdosing on drugs. She had also received inpatient detoxification and rehabilitation from alcohol, cocaine, and opiates. She was diagnosed with viral hepatitis C at 30 years, remained asymptomatic, and received no treatments. Otherwise, her medical history was unremarkable.
The patient presented to our inpatient acute psychiatric unit 1 month after completing inpatient substance abuse rehabilitation. Over the preceding 2 weeks, she had become progressively more depressed despite being medication compliant and had begun to experience suicidal ideation with a plan to again overdose on drugs. Her skin picking and, to a lesser extent, her hair pulling intensified at about the same time. She said she was ashamed and embarrassed to appear in public because of her skin and hair picking. About a week after the onset of her depressive symptoms, she again relapsed into cocaine and alcohol abuse. Her most recent drug use was 3 days before her admission, but she did not manifest any physical signs of withdrawal throughout the entire hospital stay. The patient was given fluoxetine 60 mg/d, suboxone 8 mg/2 mg daily, and trazodone 100 mg at bedtime.
For the first 4 days of admission, she refused to leave her room or take a shower. She would only eat when other patients were not there. The patient continued to express suicidal ideation and pick on her skin and facial hair. She had extensive skin ulcerations on her face, ears, anterior chest wall, forearms, hands, torso, and legs. Because of her sense of shame and embarrassment about her appearance, she refused nonpharmacological interventions for her condition, as she refused to be seen for individual therapy. She remained depressed and suicidal despite fluoxetine being titrated to 80 mg/d and trazodone being switched to quetiapine at 100 mg at bedtime (upon her request, because of previous superior hypnotic response). She was unable to tolerate higher doses of suboxone and had a history of poor response to naloxone. Furthermore, she refused to take higher doses of quetiapine because she was concerned about regaining weight.
It was hypothesized that the presence of concurrent pathological skin picking, trichotillomania, and depression were suggestive of glutamatergic dysfunction.1–3 It was also thought that the introduction of a glutamatergic agent may have resulted in the treatment of the pathological skin picking and trichotillomania4–6 and may have helped to shorten the time to response for remission of her depression.1–3 However, the glutamatergic agent may have not provided any significant effects for her substance abuse.1,4 The decision to explore a trial of a glutamatergic agent was made easier by the patient’s refusal of other augmentative agents. The patient’s concern for primary indications, dosing, and side-effect profile narrowed the selection to a trial of memantine. Dosing was begun at 5 mg/d and increased to 10 mg/d 1 week later.
Her initial Hamilton Depression Rating Scale (HAM-D) score was 23 on admission and 18 at the beginning of memantine augmentation. She scored 18 on the skin-picking treatment scale at the outset. Her hair pulling was less extensive or distressing compared with the skin picking. Because she had no access to tweezers or other hair pulling devices and because she had bitten her nails to the point where her fingers were no longer effective at pulling her hair, it was decided not to rate this particular symptom but to monitor her reports of thoughts and urges.
By day 10 of admission (5 days after onset of memantine augmentation), she reported feeling less depressed. She said she was able to leave her room, attend group sessions and interact with her peers, shower daily, and wear clean clothing. Her HAM-D scores decreased to 13, and her skin picking treatment scale score decreased to 6 from 18. She reported that she no longer felt the urge or compulsion to pull at her hair. Her skin condition dramatically improved as her lesions began to heal, and she could then appear outside of her room with little or no facial makeup. Her clinical global improvement scores were much improved to very much improved, and she attributed her gains to the addition of memantine. She said it was the first time she could remember being free from urges or desires to pick at her skin. Her symptoms of depression, skin picking, and trichotillomania continued to improve, with no switch to mania or hypomania. However, the patient continued to experience cravings for alcohol and cocaine. Her final HAM-D score 2 weeks after initiation of memantine was 6, and skin picking score was 2. She eventually signed herself out of the hospital and was subsequently lost to follow-up.
Memantine, a glutamatergic agent, is a noncompetitive metabotropic antagonist of the N-methyl-D-aspartate acid (NMDA) receptor. It is approved by the Food and Drug Administration (FDA) only for the treatment of moderate-to-severe Alzheimer’s disease (AD).1 Accumulating evidence suggests that disturbed glutamate neurotransmission may be central to the neurobiology of diverse neuropsychiatric conditions, such as depression, anxiety, and impulse control disorders and substance abuse. Clinical trials have explored the role of memantine in these and other conditions.1
This appears to be the first reported case of memantine being used to treat pathological skin picking and trichotillomania. In a complex case, such as this patient, many factors may have been responsible for marked clinical response. Being an inpatient in a safe, structured, nurturing, non-judgmental and accepting environment, where she could be cared for, clearly played a role. It is possible that with more time for treatment, the fluoxetine alone may have been responsible for her clinical gains.
Pathological skin picking is characterized by dysfunctional, repetitive, and excessive manipulation of the skin, resulting in noticeable damage. It is listed under the Impulse Control Disorders-Not Otherwise Specified category in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM IV-TR). Affected patients are usually women, are in their early teens to mid-40s, and typically spend a lot of time picking at their facial skin. Skin picking arises from a sense of disfigurement, social isolation, shame, embarrassment, and resulting social, occupational, marital, and other interpersonal difficulties. Medical complications include skin lesions, infection, and cicatrization, and sometimes the need for cosmetic surgery. Skin picking runs a chronic course, may present either as an independent syndrome or be comorbid with (or a symptom of) OCD, body dysmorphic disorder, and borderline personality disorder. There is an increased incidence of eating disorder, substance abuse, and mood and anxiety disorder.5,6
The neurobiology of pathological skin picking and trichotillomania remains imprecise. Pathological skin picking has been proposed to be one of three bodily focused repetitive behaviors; the others are nail biting and trichotillomania.5,6 These disorders have similar demographics in terms of age of onset, gender distribution, and disability. Pathological skin picking and trichotillomania have also been considered as part of a spectrum of impulse control disorders that have as a common characteristic a failure to inhibit behavior motivated by reward from release of tension or from arousal.5,6 Finally, they have been considered as part of a spectrum of obsessive-compulsive disorders. Here, the primary premise is the avoidance of distress, not gratification, as in the impulse control spectrum.5,6
Glutamatergic dysfunction has been implicated in the etiology of impulse control disorders, and the glutamatergic agent N-acetyl cysteine has been reported to have some therapeutic benefits in pathological gambling, another impulse control disorder.5,6 The benefits of glutamatergic agents in OCD and of glutamatergic dysfunction in the corticostriatal, thalamicocortical loops as a neurobiological hypothesis of OCD have also been reported extensively. Riluzole and lamotrigine, both glutamatergic agents, have been reported to be beneficial in the treatment of pathological skin picking.5,6 There is currently no gold standard for the treatment of these conditions. Selective serotonin reuptake inhibitors (SSRIs) have been the most widely studied agents, but clomipramine, doxepin, the atypical antipsychotics olanzapine and palperidone, naltrexone, and the glutamatergic agents riluzole and lamotrigine, have all been reported to be beneficial.5,6 It is reasonable to propose that in this patient, the addition of the glutamatergic agent memantine may have shortened the time of response of her pathological skin picking and trichotillomania.
It has been demonstrated in peripheral tissues and postmortem brain studies2,3 and by brain magnetic resonance spectroscopy2,3 that patients with MDD have alterations in regional extracellular glutamate levels (some subsets have higher levels; others have lower levels, and some have no demonstrable changes). Microarray gene expression studies in depressed patients have shown brain tissue with down-regulation of the gene that codes for glutamine synthetase2,3 and the genes that code for the glial excitatory amino acid transporters.2,3 One dose of Ketamine, a high-affinity, noncompetitive, NMDA receptor antagonist, was serendipitously found to induce a rapid and sustained improvement in depressive symptoms.2,3
More recent studies have replicated this finding. Animal studies have shown that NMDA antagonists possess antidepressant properties.2,3 It was, therefore, hoped that safer (low- to moderate-affinity agents, with fewer cognitive or perceptual side effects) NMDA modulating agents, such as memantine, could also result in rapid and sustained antidepressant action, either in monotherapy or as augmenting agents. Memantine has been reported to demonstrate rapid antidepressant activity in animal models and was found to augment fluoxetine in some animal studies.2,3 The rapid and sustained antidepressant response in the patient may therefore be in part a consequence of memantine augmentation. Ferguson and Shingleton reported, in an open-label study, eight patients with rapid (1 week) and sustained improvements in depressive symptoms. Muhonen et al. found that memantine had equivalent antidepressant effects with escitalopram in an outpatient setting. However, a double-blind, placebo-controlled study by Zarate et al. concluded that memantine did not have antidepressant effects in major depression.
Treatment of addictions has focused on stages of intoxication/withdrawal, relapse prevention, and use reduction. The glutamatergic agent acamprosate is FDA approved for the treatment of alcohol dependence. Ethanol has been reported to inhibit the NMDA receptor in a noncompetitive manner, and chronic alcohol exposure results in an up-regulation of those receptors. The central nervous system, therefore, becomes hyperexcitable in a state of acute and protracted alcohol withdrawal (as is the case with opioid withdrawal). This is the proposed explanation for why NMDA receptor antagonists, such as memantine, may be helpful with the treatment of withdrawal symptoms in both conditions.
The patient, however, did not manifest symptoms or signs of either alcohol or opioid withdrawal. There have been some promising but inconsistent reports on the effects of memantine in maintaining abstinence with alcohol and opioid abuse. Interestingly, memantine was reported to intensify the “highs” from cocaine use.4 The patient continued to experience cravings for alcohol and cocaine throughout hospitalization.
As glutamatergic dysfunction has been implicated in the etiology of many neuropsychiatric illnesses, early introduction of glutamatergic agents, such as memantine, may lead to more rapid and sustained remission.
Although many variables, including chance, may explain the patient’s clinical gains, it is possible that in some patients the addition of a glutamatergic agent, such as memantine, may shorten the time for response in the patient with a concurrent mood, anxiety, and substance-related disorder. Of course, more studies, including open- and closed-label trials, would be needed to replicate and validate this finding.
- Kavirajan H. Memantine: a comprehensive review of safety and efficacy. Expert Opin Drug Saf. 2009;8(1):89–109. doi:10.1517/14740330802528420 [CrossRef]
- Sanacora G. Do glutamatergic agents represent a new class of antidepressant drugs? Part 1. J Clin Psychiatry. 2009;70(10):1473–1475. doi:10.4088/JCP.09ac05680blu [CrossRef]
- Sanacora G. Do glutamatergic agents represent a new class of antidepressant drugs? Part 2. J Clin Psychiatry. 2009;70(11):1604–1605. doi:10.4088/JCP.09ac05757blu [CrossRef]
- Brewer JA, Potenza MN. The neurobiology and genetics of impulse control disorders: relationships to drug addictions. Biochem Pharmacol. 2008;75(1):63–75. doi:10.1016/j.bcp.2007.06.043 [CrossRef]
- Grant JE, Odlaug BL. Update on pathological skin picking. Curr Psychiatry Rep. 2009;11(4):283–288. doi:10.1007/s11920-009-0041-x [CrossRef]
- Chamberlain SR, Odlaug BL, Boulougouris V, Fineberg NA, Grant JE. Trichotillomania: neurobiology and treatment. Neurosci Biobehav Rev. 2009;33(6):831–842. doi:10.1016/j.neubiorev.2009.02.002 [CrossRef]