Dr. Ginsberg is Vice-Chair of Clinical Initiatives in the Department of Psychiatry at New York University Medical Center in New York City.


Disclosure: Dr. Ginsberg receives honoraria for lectures, papers, and/or teaching from AstraZeneca and GlaxoSmithKline; and receives research support from Cyberonics.


 

Lithium-Induced Sinoatrial Block

For over 30 years, lithium carbonate has been a mainstay in the treatment of bipolar disorder. With a narrow therapeutic index, toxicity associated with lithium ranges from gastrointestinal complaints to marked neurologic impairment. Electrocardiogram (ECG) manifestations of lithium toxicity include prolonged QT interval, T wave flattening and inversion, first-degree atrioventricular conduction delay, and, rarely, ventricular tachycardia and fibrillation resulting in death.1-4

Sinoatrial block in association with lithium therapy was first reported in 1975.5 Subsequent reports cite reversible sinus node suppression as a consequence of chronic lithium therapy, even at therapeutic levels.6-8 The mechanism of action underlying this effect may be related to lithium’s competitive inhibition of calcium in the sodium-calcium exchange in cardiac cells.9 The following is a report of prominent bradycardia due to second-degree, type II sinoatrial block that resulted from toxic lithium levels.10

A 43-year-old woman with a long-standing history of bipolar disorder was started on lithium at 600 mg BID. Reportedly, this was a lower dose than her chronic therapy, which she had discontinued 1 year prior. Her other medications included naproxen sodium, amitriptyline, and mirtazapine. One week later, her lithium level was 3.2 mEq/L (therapeutic 0.6–1.2 mEq/L) and her serum creatinine was 2.3 mg/dl. Sent immediately to the emergency room, she underwent repeat chemistries which revealed further rises in her creatinine and lithium levels, to 4.2 mg/dl and 3.64 mEq/L, respectively. Initially, her vital signs were unremarkable. Subsequently, however, she developed hypothermia at 34.5oC, bradycardia to 36 beats per minute (BPM), and hypotension. Other laboratory values were significant for hypokalemia with a potassium level of 2.8 mEq/L (normal 3.7–5.2 mEq/L), metabolic alkalosis with a serum bicarbonate of 33 mEq/L (normal 22–32 mEq/L), and hypochloremia of 88 mEq/L (normal 98–108).

She was started on norepinephrine and dopamine infusions, then transferred to the medical intensive care unit for hemodynamic support and urgent hemodialysis. At this time, her ECG was remarkable for sinus rhythm/sinus bradycardia consistent with sinoatrial block with an intermittent 2:1 conduction pattern, yielding a variable rate of 78 BPM and 39 BPM, respectively. Since the P-P interval is a direct multiple of the shorter P-P cycles, this is characterized as second-degree (type II) sinoatrial block. Nonspecific T wave flattening was also present with borderline low QRS voltage and a QRS axis of approximately 90o.

During dialysis, ECGs also demonstrated 4:3, 5:4, and 6:5 second-degree type I (Wenckebach) sinoatrial block. This pattern is characterized by a sinus pause, with a duration of <2 P-P cycles, after progressively decreasing P-P intervals. After completing dialysis, the patient’s lithium level decreased to 0.41 mEq/L. There was no further evidence of sinoatrial block. The patient subsequently revealed a history of bulimia nervosa.
In the patient described here, elevated serum lithium levels likely resulted from renal insufficiency caused by a combination of dehydration and nonsteroidal anti-inflammatory drug use. The presence of vomiting associated with bulimia, added to the dehydration, and resulted in further resorption of lithium in the renal tubules. The net effect was accumulation to toxic levels. With such high serum levels of lithium, sinoatrial block may be a consequence. PP

 

References

1. Brady HR, Horgan JH. Lithium and the heart: unanswered questions. Chest. 1988;93:166-169.
2. Mitchell JE, Mackenzie TB. Cardiac effects of lithium therapy in man: a review. J Clin Psychiatry. 1982;43:47-51.
3. Tilkian AG, Schroeder JS, Kao JJ, Hultgren HN. The cardiovascular effects of lithium in man: a review of the literature. Am J Med. 1976;61(5):665-670.
4. Montalescot G, Levy Y, Farge D, et al. Lithium causing a serious sinus-node dysfunction at therapeutic doses. Clin Cardiol. 1984;7:617-620.
5. Eliasen P, Andersen M. Sinoatrial block during lithium treatment. Eur J Cardiol. 1975;3:97-98.
6. Wellens HJ, Cats VM, Duren DR. Symptomatic sinus node abnormalities following lithium carbonate therapy. Am J Med. 1975;59:285-287.
7. Wilson JR, Kraus ES, Bailas MM, Rakita L. Reversible sinus-node abnormalities due to lithium carbonate therapy. N Engl J Med. 1976;294(22):1223-1224.
8. Terao T, Abe H, Abe K. Irreversible sinus node dysfunction induced by resumption of lithium therapy. Acta Psychiatr Scand. 1996;93:407-408.
9. Lai CL, Chen WJ, Huang CH, et al. Sinus node dysfunction in a patient with lithium intoxication. J Formos Med Assoc. 2000;99:66-68.
10. Goldberger ZD. Sinoatrial block in lithium toxicity. Am J Psychiatry. 2007;164(5):831-832.

 

Transdermal (but not Oral) Selegiline Effective for Treatment-Resistant Depression

Originally developed an an adjunctive antiparkinsonian agent, selegiline is an irreversible monoamine oxidase (MAO) inhibitor that is selective for MAO type B at oral doses up to 10 mg/day. Lack of action of MAO type A in the central nervous system (CNS) may preclude full antidepressant activity.1 The recently approved transdermal formulation of selegiline2 appears to avoid this problem by allowing sufficient dosing to affect MAO type A in the CNS but largely avoid gastrointestinal MAO.3 By avoiding first-pass metabolism, transdermal selegiline provides approximately 50 times more parent drug to the blood than the oral formulation. The following is a case of treatment-resistant depression (TRD) in which the transdermal—but not the oral—formulation of selegiline was effective.4

A 67-year-old man with a 30-year history of recurrent depression presented in the midst of a major depressive episode of several months duration. Symptoms, consistent with melancholic depression, included anhedonia, amotivation, feeling “ill at ease and flat,” excessive worry and ruminations, decreased libido, initial and middle insomnia despite the use of sleep medication, and poor appetite with 17-lb weight loss. The patient noted a diurnal variation to his symptoms, with depression and lack of motivation worse upon awakening. His medication regimen consisted of escitalopram 30 mg/day, lithium 600 mg/day, olanzapine 5 mg at bedtime, zolpidem 10–20 mg at bedtime, clonazepam 0.5 mg during the day for anxiety and 1 mg nightly for sleep, a multivitamin, and a concentrated omega-3 fatty acid supplement.

Until 3 years prior, the patient had experienced depressive episodes only every few years. Symptoms varied but always included anhedonia and lack of motivation. Single agents such as amitriptyline or fluoxetine, or the combination of fluoxetine with lithium, typically resulted in remission of these episodes within 2–3 weeks. Three years prior, the patient’s psychotherapist of more than 20 years had died. Subsequently, the patient began having depressive episodes every 8–12 months. These more recent episodes were less responsive to treatment, with little to no benefit from single agents such as bupropion or selective serotonin reuptake inhibitors (SSRIs) and only partial response to combinations such as fluoxetine plus lithium or escitalopram plus lithium.

Initial management consisted of discontinuation of escitalopram and olanzapine followed by initiation of oral selegiline at a dosage of 5 mg/day. Two days later, selegiline was increased to 5 mg BID, and then, after 1 week, modified to 10 mg QAM. After 4 weeks of oral selegiline, there was no appreciable improvement and the medication was consequently discontinued. Next, transdermal selegiline 6 mg/24 hours was begun. By the end of the first week of treatment, the patient reported that he felt substantially better and had received numerous comments that he looked better. At 2 weeks, he exhibited brighter affect, improved mood, and increased motivation. He expressed satisfaction with work and admitted to a sense of joy in thinking about his grandchild. His appetite improved and sexual activity resumed. While still present, anxiety decreased, and the patient was able to stop the use of clonazepam during the day. Side effects included worsening of preexisting constipation and patch site skin irritation. The former resolved with increased intake of liquids while the latter was tolerable with a three-site rotation. All improvements remained stable 4 and 6 weeks after initiation of transdermal selegiline. At 10 weeks after initiation, the patient began taking olanzapine 5 mg in response to an increase in anxiety. Improvements in other symptom domains remained constant.

In the patient presented here, according to the author of the report, low-dose oral selegiline was started based on its tolerability and a positive report in TRD.5 However, the doses used would not be expected to have robust antidepressant effects. Of more interest, perhaps, is the fact that transdermal selegiline was effective for TRD in which combinations of SSRIs with lithium had been only partially effective. If its benefits in TRD are confirmed, then transdermal selegiline may establish a niche for itself in the management of this pervasive and debilitating condition. PP

 

References

1. Lipper S, Murphy DL, Slater S, Buchsbaum MS. Comparative behavioral effects of clorgyline and pargyline in man: a preliminary evaluation. Psychopharmacology (Berl). 1979;62(2):123-128.
2. Bodkin JA, Amsterdam JD. Transdermal selegiline in major depression: a double-blind, placebo-controlled, parallel-group study in outpatients. Am J Psychiatry. 2002;159(11):1869-1875.
3. Patkar AA, Pae CU, Masand PS. Transdermal selegiline: the new generation of monoamine oxidase inhibitors. CNS Spectr. 2006;11(5):363-375.
4. Morgan PT. Treatment-resistant depression: response to low-dose transdermal but not oral selegiline. J Clin Psychopharmacol. 2007;27:313-314.
5. Higuchi H, Kamata M, Sugawara Y, Yoshida K. Remarkable effect of selegiline (L-deprenyl), a selective monoamine oxidase type-B inhibitor, in a patient with severe refractory depression: a case report. Clin Neuropharmacol. 2005;28(4):191-192.

 

Abacavir Sulfate-Induced Mania

Non-nucleoside reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, and stavudine have all been associated with precipitating mania.1 The following is a case report of mania in association with another non-nucleoside reverse transcriptase inhibitor, abacavir sulfate.2

A 47-year-old man infected with human immunodeficiency virus (HIV) for 9 years had a long history of alcohol and substance abuse, but had been abstinent for the past 10 years. Hepatitis C was confirmed at the time of his HIV diagnosis. Over time, transaminases remained below two times the normal values. The patient never received treatment for hepatitis C. While no personal psychiatric history was reported, there was a family history of one sibling who suffered from schizophrenia.

Soon after the diagnosis of HIV, first-line therapy with zidovudine, lamivudine, and delavirdine was initiated. The patient remained on the same therapy for 9 years. His plasmatic viral load was at a level of detection (<50 copies/mL) and he had a CD4-cell count of approximately 200 cells/mm3. He never suffered from any opportunistic infection, an indication of good immunity. In an effort to increase his CD4-cell count, his anti-retroviral regimen was changed to abacavir, lamivudine, and lopinavir/ritonavir. During this period, his CD4-cell count dropped to 159 cells/mm3, despite a viral load that remained below the level of detection.

One week after initiating the new regimen, the patient experienced emotional lability, irritability, decreased sleep, increased goal-directed activity, increased libido, increased difficulty remaining focused, and a sense of being disorganized. No signs or symptoms of hypersensitivity reaction to abacavir were noted. His creatinine, thyroid stimulating hormone, and cortisol levels were within normal values. His symptoms persisted for 3 months, during which time clonazepam 0.5 mg at bedtime was occasionally used for insomnia. Referred for psychiatric evaluation, upon interview the patient was cooperative but euphoric. Also present were psychomotor agitation, pressured speech, and emotional lability. No evidence of HIV-associated dementia or opportunistic infection was observed; specifically, sensorium was clear, and memory and executive functions were grossly intact. Following a provisional diagnosis of abacavir-induced mania, abacavir was replaced by stavudine. No other medications were prescribed. Gradually, the patient’s symptoms remitted. After 4 weeks, he reported feeling much better. Since abacavir was still considered his best therapeutic option, the patient was offered a rechallenge but declined. At the 13-month follow-up, no recurrence of mania was observed.

The temporal sequence of events described above supports a diagnosis of abacavir-induced mania. Studies in HIV-infected patients confirm substantial penetration of abacavir into the cerebrospinal fluid (CSF), with a CSF-to-plasma ratio between 0.3 and 0.44.3 The mechanism of action to explain the association of non-nucleoside reverse transcriptase inhibitors with mania is unknown. PP

 

References

1. Hallman MH, Bialer P, Worth JL, et al. HIV disease/AIDS. In: Wise MG, Rundell JR, eds. The American Psychiatric Publishing Textbook of Consultation-Liaison Psychiatry: Psychiatry in the Medically Ill. Washington, DC: American Psychiatric Publishing; 2002:825-826.
2. Brouilette MJ, Routy JP. Abacavir sulfate and mania in HIV. Am J Psychiatry. 2007;164(6):979-980.
3. Ziagen [package insert]. Mississauga, Canada: GlaxoSmithKline, Inc.; 2005.