DOSAGE ADJUSTMENT IN SPECIAL POPULATIONS

Depression and Anxiety Newsletter _______Series 2,Issue 1, 2007

DOSAGE ADJUSTMENT IN SPECIAL POPULATIONS

Michael Menaster, MD, MA Private Practice of Psychiatry, Adjunct Professor of Psychology, Golden Gate University, San Francisco, Calif

OVERVIEW

Special consideration may be necessary when prescribing pharmacologic therapy for depression and anxiety disorders in certain populations of patients. These populations are diverse in demographics and symptomatology. As a result, discussions of the special considerations their comorbid conditions require tend to be outside of the mainstream literature. This article discusses 3 special populations: patients with traumatic brain injury (TBI), patients with HIV or AIDS, and Asian Americans. When prescribing pharmacologic therapy for depression to patients in these special populations, clinicians must perform thorough patient assessments, maintain a high index of suspicion for comorbidities, and proceed with slow and gentle titration of medications.

TRAUMATIC BRAIN INJURY TBI is a significant cause of death and disability, particularly in children and young adults, and is associated with changes in milieu of several neurotransmitters, including dopamine (eg, diffuse axonal injury associated with reduced dopamine turnover), acetylcholine, and serotonin (5-HT), particularly 5-HT1A receptors.1-3 Mood disorders, including depression; behavioral problems such as personality changes, amotivation, psychosis, agitation, and aggression; impaired memory and sleep; and cognitive dysfunction are common sequelae of TBI, and neuroprotection is an important treatment goal.4,5 The loss of consciousness has a significant dose-response relationship to cognitive impairment; these symptoms are generally associated with frontal lobe dysfunction.6 Aggression and cognitive impairment, two of the more serious psychiatric symptoms of TBI, are most often treated with methylphenidate and amantadine, which often leads to improved attention and motor performance.3,7-9 Other studies have found that low-dose bromocriptine, a dopamine (D2) agonist, improved executive function and dual-task performance.10 Anticonvulsants such as topiramate, carbamazepine, and valproic acid offer the dual benefit of seizure protection and mood stabilization. Other medications in this category, including phenobarbital, phenytoin, ethosuximide, lamotrigine, tiagabine, and oxcarbazepine, offer additional neuroprotective effects.1112 Intuitively, neuron cell loss and injury would predispose patients with TBI to a greater sensitivity to any medication, thus requiring lower dosages for efficacy and minimization of adverse effects. Clinicians cannot overlook the physical sequelae of TBI when selecting medications and dosages. For instance, one study found markedly altered protein-binding and phenytoin-binding in children within the first 10 days after a TBI.13 Antipsychotics can also be used to treat agitation and aggression in these patients. However, if indicated, second-generation antipsychotics (eg, quetiapine) are preferred, as their lower affinity to the D2 receptors and faster dissociation compared to first-generation medications (eg, haloperidol [Haldol]) lead to comparatively improved cognition and lower rates of extrapyramidal symptoms.

Several important principles should be considered when treating patients with TBI for depression. When selecting an agent, strongly consider the impact of adverse effects, which can be used to treat comorbid symptoms (eg, use a sedating antidepressant to treat depression with insomnia).4 Start with monotherapy at low doses, and raise doses slowly.4,14 Consider maximizing the dose of a monotherapy agent before augmenting or changing medications.4 Alternatively, augment an agent with another agent that has a different mechanism of action.14 Reassess symptoms and consider using standardized scales like the Mini Mental State Examination (MMSE).14 Avoid benzodiazepines because of the risk of disinhibition.4,14 Limit the use of anticholinergic medications.4,14 Because of the possibility of intentional or accidental overdose, avoid prescribing large quantities of lethal medications.4 HIV and AIDS Determining pharmacologic treatment for patients with HIV or AIDS is challenging for numerous reasons, including the presence of a fatal illness, complicated medication regimens, medication noncompliance, drug-drug interactions, and comorbid medical and psychiatric conditions. For instance, the lifetime prevalence of depression in patients with HIV is as high as 45%.15 In this population, starting with low doses and increasing them slowly is prudent, except in cases of emergency. Antidepressants are effective in treating depressive disorders in patients with HIV. Tricyclic antidepressants (TCAs) have response rates as high as 89%, although adverse effects limit their use in patients with HIV and depression.15 One study found that patients who are HIV-positive take longer to respond to fluoxetine than do patients who are HIV-negative.16 In contrast, a study with imipramine found efficacy in patients with depression and HIV; no delay in response, difference in dose, or difference in adverse effects was found to be associated with HIV status.17 Citalopram (10-40 mg/d) was found to be efficacious in outpatients of Hispanic and non-Hispanic descent who had HIV, though 2 patients discontinued the study after experiencing rash and nausea and 4 other patients became noncompliant.18 Another study found no interaction between citalopram and ritonavir, a prototype cytochrome P450 (CYP) 3A4 inhibitor.19 Although venlafaxine has low to negligible drug-drug interactions at CYP2D6, CYP1A2, CYP2C19, and CYP3A4, venlafaxine and indinavir do interact such that venlafaxine resulted in a 28% decrease in the area under the concentration time curve (AUC) of plasma indinavir levels and a 36% decrease in the maximum plasma concentration of indinavir.20 Bupropion is also effective in treating depression in patients with HIV, particularly because of its tendency to increase energy.21 Nefazodone was efficacious in patients with HIV and depression with few adverse effects.22 However, nefazodone is associated with liver toxicity and may interact with protease inhibitors, such as indinavir, saquinavir, amprenavir, and nelfinavir. Psychostimulants have a role in treating depressed mood, impaired cognition, and fatigue.15 For instance, a double-blind study that compared desipramine and methylphenidate found them equally efficacious in treating depression and anxiety without a difference in onset of action.23 The highly active antiretroviral therapy (HAART) medications are the standard of care in treating patients with HIV. Fortunately, patients on HAART have improved attention, concentration, learning, memory, and psychomotor speed.24 Patients who are receiving psychiatric treatment and are newly diagnosed with HIV should consult with their primary care physicians or an HIV specialist about receiving HAART treatment. HIV infection is associated with hepatitis, in part because of comorbid viral hepatitis infections (A, B, and C). Moreover, HIV treatments are associated with hepatitis. Clinicians should obtain baseline and follow-up liver function tests before initiating nonemergent psychiatric treatment. When benzodiazepines are indicated for associated symptoms of insomnia or anxiety, lorazepam, oxazepam, and temazepam bypass CYP3A enzymes. ASIAN AMERICANS Mental illness in Asian Americans appears more severe and chronic, perhaps because treatment can be delayed and sought only by patients with the most severe illness.25,26 Countertransference issues surrounding the model minority myth27,28 may lead clinicians to underrecognize and underdiagnose mental illness, particularly eating disorders, mood disorders, and substance abuse, in Asian Americans.29 Additionally, when Asian Americans seek treatment, they typically initiate care with Eastern medicine providers (eg, acupuncturists, bone setters, psychics) and use homeopathic remedies (eg, teas, soups); their motivation for seeking these treatments may include a desire to preserve modesty.26,30-32 Typically, Eastern medicine involves only 1 treatment session; this may create patient expectations that conflict with Western medicine treatments. When Asian Americans use Western medicine services, they frequently also continue to use Eastern medicine treatments.26,30 Asian Americans tend to be more sensitive yet more responsive to lower dosages of medications.33 They may experience more frequent and more intense adverse effects from standard dosages of medications. For example, venlafaxine, which has a well-recognized association with elevated blood pressure, should be used with caution in Asian Americans, as it may be associated (through case reports) with dramatic increases in blood pressure.34 This underscores the need for obtaining a thorough informed consent before prescribing medications; in particular, clinicians should disclose the paucity of studies in Asian Americans and the risks for more frequent and intense adverse effects. Differences between the liver enzymes (eg, CYP3A system) of Asian Americans and those of European Americans may explain the higher sensitivities seen in Asian American patients.26 Asian Americans may also need lower than standard doses of lithium for bipolar disorder.26 Asians and some Asian Americans are more sensitive to psychotropic medications; this underscores the importance of considering ethnicity when determining starting dose and titration rates of all psychotropic medications.

REFERENCES

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