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David L. Ginsberg, MD

  Primary Psychiatry. 2007;14(6):19-22

Dr. Ginsberg is vice-chair of clinical initiatives in the Department of Psychiatry at New York University Medical Center in New York City.

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


 

Aripiprazole-Induced Hyponatremia

Previous Psychopharmacology Reviews have discussed the association between serotonin reuptake inhibitors (SRIs)1-6 and the syndrome of inappropriate antidiuretic hormone secretion (SIADH), which is characterized by the sustained release of antidiuretic hormone (ADH) from the posterior pituitary gland. The norepinephrine reuptake inhibitor reboxetine, approved in Europe for the treatment of depression, has also been associated with SIADH.7 Other medications associated with SIADH include tricyclic antidepressants (TCAs),8 bupropion,9 neuroleptics, carbamazepine, sodium divalproex,10 vincristine, and cyclophosphamide.11

Non-medication causes of SIADH include central nervous system disorders, pulmonary disease, cardiac failure, renal disease, and neoplasia. Affected patients have a reduced ability to excrete dilute urine and as a consequence, they retain ingested fluid, which results in expansion of the extracellular fluid. Clinical symptoms are often nonspecific and may include weakness, lethargy, headache, anorexia, nausea, and weight gain. Associated laboratory signs are hyponatremia, serum hypoosmolality, and a less than maximally diluted urine. Treatment involves fluid restriction and intravenous hypertonic saline. If untreated, the syndrome may progress to confusion, convulsions, coma, and death.

Aripiprazole is an atypical neuroleptic indicated for the treatment of schizophrenia and for acute and maintenance phase treatment of manic and mixed episodes associated with bipolar I disorder. A potent dopamine partial agonist, aripiprazole acts as an antagonist at dopamine (D)2 receptors under hyperdopaminergic conditions and as a D2 agonist under hypodopaminergic conditions. It has been theorized that dopamine partial agonists may be able to stabilize the dopaminergic system without inducing a hypodopaminergic state, thereby reducing risk of side effects associated with pure blockade of dopamine receptors. In addition to these effects, aripiprazole also acts as a partial agonist at serotonin (5-HT)1A and as an antagonist at 5-HT2A receptors. The most commonly reported side effects in association with aripiprazole use include insomnia, anxiety, headaches, nausea, vomiting, and somnolence.12 There is now a report of aripiprazole-induced hyponatremia.13

A 69-year-old man with diabetes mellitus and bipolar disorder had a history of two prior manic episodes in 2001 and 2003. Treated with sodium valproate 1,000 mg/day for his bipolar disorder, he was also taking metformin 1,000 mg/day, glibenclamide 5 mg/day, and thyroxine supplements 100 µg/day for hypothyroidism. In August 2005, the man presented with relapse of manic symptoms for 1 week. Aripiprazole 10 mg/day was added. Two days later, he developed persistent hiccups. A comprehensive clinical examination revealed no neurologic deficits. Laboratory testing revealed glucose levels of 97 mg/dL, serum sodium levels of 122 mEq/L, and serum potassium levels of 4.5 mEq/L. Thyroid and renal function tests and lipid profiles were normal. Urine specific gravity was 1.010 (ie, no ketonuria).

It was discovered that the patient had been drinking 3–4 liters of water per day for the past 3 weeks. Immediate water restriction to 1.5 L/day was initiated. Because of its temporal association with hiccoughs, aripiprazole was withheld. Sodium levels stabilized to 133 mEq/L (all sampling done at 6AM). Two days later, aripiprazole 10 mg/day was restarted. The next day, sodium levels again dropped to 120 mEq/L and aripiprazole was discontinued. Quetiapine was started and increased to 400 mg/day over 2 weeks. Subsequently, 1 week later, sodium levels gradually increased and reached normal levels of 135 mEq/L. The hiccoughs spontaneously subsided with correction of sodium levels. At this time, fluid restriction was discontinued. Over the next 8 months of follow-up, the patient maintained euthymia with normal sodium levels.

The temporal sequence of described events supports an association in this patient between use of aripiprazole with the development of hyponatremia. Persistent hiccoughs are a frequent manifestation of hyponatremia. A decrease in sodium levels of 10 mEq/L can increase the incidence of hiccough 17 times.14 Excessive water intake is not the likely etiology. For water intake to be the sole basis for hyponatremia, typically a person has to drink >10 liters/day.15 In addition, water intake could not be the basis for hyponatremia as the fall in sodium levels persisted despite fluid restriction and the patient did not develop hyponatremia in the prior episodes, despite increased fluid intake of similar quantity.

In general, the risk of hyponatremia with psychotropic medications is greatest during the first 2 weeks of treatment and is unrelated to drug dose.16 Withdrawing aripiprazole in this patient led to stabilization of sodium levels within 1 week, which corresponds to the washout period of aripiprazole. Clinicians who prescribe aripiprazole should be mindful of the potential for precipitating the acute onset of SIADH. Based on reports with other psychotropic drugs, such as SRIs, women, the elderly, and those with comorbid medical conditions appear to be at highest risk. PP

 

References

1. Hwang AS, Magraw RM. Syndrome of inappropriate secretion of antidiuretic hormone due to fluoxetine. Am J Psychiatry. 1989;146(3):399.
2. Goddard C, Patton C. Hyponatremia associated with paroxetine. BMJ. 1992;305(6865):1332.
3. Crews JR, Potts NL, Schreiber J, Lipper S. Hyponatremia in a patient with sertraline. Am J Psychiatry. 1993;150(10):1564.
4. Baliga RR, McHardy KC. Syndrome of inappropriate antidiuretic hormone secretion due to fluvoxamine therapy. Br J Clin Pract. 1993;47(2):62-63.5. Gupta AK, Saravay SM. Venlafaxine-induced hyponatremia. J Clin Psychopharmacol. 1997;17(3):223-225.
6. Safdieh JE, Rudominer R. A case of hyponatremia induced by duloxetine. J Clin Psychopharmacol. 2006;26(6):675-676.
7. Ranieri P, Franzoni S, Trabucchi M. Reboxetine and hyponatremia. N Engl J Med. 2000;342(3):215-216.
8. Anfinson TJ, Kathol RG. Laboratory and neuroendocrine assessment in medical-psychiatric patients. In: Stoudemire A, Fogel BS, eds. Psychiatric Care of the Medical Patient. New York, NY: Oxford University Press; 1993:117.
9. Bagley SC, Yaeger D. Hyponatremia associated with bupropion, a case verified by rechallenge. J Clin Psychopharmacol. 2005;25(1):98-99.
10. Branten AJ, Wetzels JF, Weber AM, Koene RA. Hyponatremia due to sodium valproate. Ann Neurol. 1998;43(2):265-267.
11. Kinzie BJ. Management of the syndrome of inappropriate secretion of antidiuretic hormone. Clin Pharm. 1987;6(8):625-633.
12. Swainston Harrison T, Perry CM. Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder. Drugs. 2004;64(15):1715-1736.
13. Behere RV, Venkatasubramanian G, Naveen MN, Gangadhar BN. Aripiprazole-induced hyponatremia: a case report. J Clin Psychiatry. 2007;68(4):640-641.
14. George J, Thomas K, Jeyaseelan L, Peter JV, Cherian AM. Hyponatremia and hiccups. Natl Med J India. 1996;9(3):107-109.
15. Tierney LM Jr, McPhee SJ, Papadakis MA. Current Medical Diagnosis & Treatment 2004. 43rd ed. New York, NY: McGraw-Hill; 2003:837.
16. Madhusoodanan S, Bogunovic OJ, Moise D, Brenner R, Markowitz S, Sotelo J. Hyponatremia associated with psychotropic medications. A review of the literature and spontaneous reports. Adverse Drug React Toxicol Rev. 2002;21(1-2):17-29.

 

Disulfiram-Induced Manic Psychosis

For years, disulfiram has been used for the treatment of alcohol dependence. Its main effect is to produce an extremely unpleasant reaction in any patient who ingests even a small amount of alcohol while disulfiram is in their system. An aldehyde dehydrogenase inhibitor, disulfiram interferes with the metabolism of alcohol by producing a marked increase in blood acetaldehyde levels. This accumulation, in some cases upwards of 10 times higher than normal, produces an array of unpleasant effects sometimes referred to as the disulfiram alcohol reaction. These effects include nausea, throbbing headache, vomiting, hypertension, flushing, sweating, thirst, dyspnea, tachycardia, chest pain, vertigo, and blurred vision. Typically, reactions occur almost immediately after the ingestion of one drink and may last up to 30 minutes.

Via one of its metabolites, disulfiram also inhibits dopamine b-hydroxylase, which converts dopamine to norepinephrine. Therefore, it has the potential to cause psychotic or mood symptoms, including mania.1-5 Now comes a report of disulfiram-induced manic psychosis in an individual with no past personal or family history of any mood or psychotic disorder.6

A 34-year-old man was brought by his family to the psychiatric emergency room of a Turkish hospital in May 2005. For the prior 3 days, the patient had suffered from insomnia, talked too much, and exhibited increased psychomotor activity. He claimed that God talked to him and told him that he was special. Upon admission, further evaluation revealed excessive alcohol consumption for 15 years. On average, he drank 5–7 standard units of alcohol per weekend. Recently, he had been arguing more frequently with his wife over his lack of financial support for his family. In the absence of exhibiting a withdrawal syndrome, he was diagnosed with alcohol abuse. Three weeks prior to the present admission, he began taking—on his own without a prescription—500 mg/day of disulfiram in an effort to give up alcohol. In Turkey, disulfiram tablets can be obtained from pharmacies without a doctor’s prescription. One week later, after consuming three standard units of alcohol, the patient experienced a disulfiram reaction with headache, flushing, and respiratory difficulty. This reaction had resulted in an overnight admission to the emergency room. Over the next 2 weeks, as confirmed by his wife, the patient refrained from drinking alcohol and maintained disulfiram at doses between 500 and 1,500 mg/day.

Mental status examination revealed that the patient had auditory hallucinations (God talked to him). He also had mystic and megalomaniac delusions (he claimed to be on a mission by God and that he was a preeminent and special person commissioned to call people upon religion). Also evident were increased speed and pressure of speech with accelerated associations. While spontaneous attention was increased, voluntary attention was diminished. Orientation to place, time, and person was normal. There was no memory disorder. Family psychiatric history was unremarkable. Laboratory tests, including complete blood count, chemistries, and thyroid function tests, were normal. Urine test for psychoactive substances was negative. Electroencephalography (EEG) was normal.

Diagnosed with manic psychosis, the patient was started on haloperidol 20 mg/day, chlorpromazine 100 mg/day, and biperiden 10 mg/day. Within 2 days, the auditory hallucinations disappeared, mystic and megalomanic delusions improved, and insight was restored. On day 6 of hospitalization, the patient was discharged with prescriptions for chlorpromazine 100 mg/day and carbamazepine 400 mg/day. One week later, chlorpromazine was discontinued. Carbamazepine was maintained to reduce his tendency to drink alcohol. However, 1 month later, the patient stopped taking carbamazepine on his own. At a follow-up outpatient visit 9 months later, the patient did not exhibit any symptoms or signs of psychosis or mood disorder.

In typical practice, disulfiram is initiated at a dose of 500 mg/day then 1 or 2 weeks later decreased to a maintenance dose of 250 mg/day. The temporal sequence of events described above, including a 12-day alcohol-free period in the context of use of higher than normal doses of disulfiram, supports an association between disulfiram and emergence of manic psychosis. Interestingly, it appears that there are more reports of disulfiram-related psychiatric complications in eastern countries. Whether this reflects reporting bias, greater use of unpure forms of disulfiram in these regions, increased genetic susceptibility to this adverse event among certain ethnic populations, or some other combination of factors is unknown. PP

References

1. Liddon SC, Satran R. Disulfiram (Antabuse) psychosis. Am J Psychiatry. 1967;123(10):1284-1289.
2. Lacoursiere RB, Swatek R. Adverse interaction between disulfiram and marijuana: a case report. Am J Psychiatry. 1983;140(2):243-244.
3. Bakish D, Lapierre YD. Disulfiram and bipolar affective disorder: a case report. J Clin Psychopharmacol. 1986;6(3):178-180.
4. Daniel DG, Swallows A, Wolff F. Capgras delusion and seizures in association with therapeutic dosages of disulfiram. South Med J. 1987;80(12):1577-1579.
5. Larson EW, Olincy A, Rummans TA, Morse RM. Disulfiram treatment of patients with both alcohol dependence and other psychiatric disorders: a review. Alcohol Clin Exp Res. 1992;16(1):125-130.
6. Ceylan ME, Turkcan A, Mutlu E, Onal O. Manic episode with psychotic symptoms associated with high dose of disulfiram: a case report. J Clin Psychopharmacol. 2007;27(2):224-225.

Alopecia Associated With Quetiapine

Alopecia involves the loss of some or all of the hair from the head and sometimes from other parts of the body. Many psychotropic medications have been associated with the development of alopecia, including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), lithium, sodium valproate, and the atypical antipsychotics olanzapine and risperidone.1,2

Quetiapine is a second-generation antipsychotic indicated for the treatment of schizophrenia; as monotherapy for the acute treatment of manic episodes as well as an adjunct to treatment with lithium or divalproex for bipolar I disorder; and for bipolar depression. Pharmacologically, it is an antagonist at serotonin (5-HT)1A and 5-HT2, dopamine (D)1 and D2, histamine (H)1, and adrenergic a1 and a2 receptors.3 Derived from the New Zealand Intensive Medicines Monitoring Programme, there are now the first published reports of alopecia in association with quetiapine.4

In the first report, a 34-year-old woman with a history of psychotic depression commenced citalopram 20 mg/day and quetiapine 25 mg/day, with the latter titrated up to 100 mg/day. Approximately 6 weeks later, she noticed significant hair loss, involving whole strands. One week after onset, quetiapine was withdrawn. The hair loss resolved. At last follow-up, the patient remained on citalopram.

In the second report, another 34-year-old woman with a history of bipolar disorder was taking quetiapine 300 mg/day, zopiclone 7.5–15 mg/day, clonazepam 1 mg as needed, and salbutamol inhaler as needed. Approximately 3 weeks after beginning quetiapine at a dosage of 300 mg/day, she reported increasing hair loss. In the past, the patient had experienced a similar reaction to sodium valproate. Quetiapine was discontinued. Subsequently, her alopecia resolved.

The World Health Organization database contains 15 other reports of alopecia associated with quetiapine. Of these, seven reports contained sufficient information for an assessment of causality, with one of these also providing dechallenge information, as were present in the previous reports.

There are two main mechanisms presumed to underlie drug-induced alopecia. Normally, each hair follicle grows following a three-phase cycle: anagen (growth phase) lasting between 4–8 years in the adult scalp; catagen (transitional phase) lasting approximately 2 weeks; followed by telogen (resting phase) that lasts approximately 100 days before hair is shed.5 One mechanism, which is characteristic of antineoplastic drugs, appears to affect anagen. As a result, mitosis ceases and hair is shed within days to weeks.5 Other medications, including psychotropics, appear to act by inducing hair follicles to enter a premature telogen phase (telogen effluvium) that results in hair loss occurring 2–4 months after beginning the treatment.5-7 While the mechanism is unknown, it has been suggested that these medications may chelate zinc and selenium, which are believed to be necessary for hair growth.

Typically, medication-induced alopecia is reversible upon dosage reduction or discontinuation of the offending drug.6,7 Other options for managing this side effect include waiting for accomodation to occur or the use of zinc and selenium.8 Whether the patients described here were genetically predisposed to this effect is not known. Nevertheless, when alopecia does occur, it is important to treat as its occurrence has been associated with elevated rates of depression and anxiety,9 as well as medication noncompliance. PP

References

1. Kimyai-Asadi A, Harris JC, Nousari HC. Critical overview: adverse cutaneous reactions to psychotropic medications. J Clin Psychiatry. 1999;60(10):714-725.
2. Leung M, Wrixon K, Remick RA. Olanzapine-induced hair loss. Can J Psychiatry. 2002;47(9):891-892.
3. Seroquel [package insert]. London, England: AstraZeneca Pharmaceuticals; 2006.
4. McLean RM, Harrison-Woolrych M. Alopecia associated with quetiapine. Int Clin Psychopharmacol. 2007;22(2):117-119.
5. Tosi A, Misciali C, Piraccini BM, Peluso AM, Bardazzi F. Drug-induced hair loss and hair growth. Incidence, management and avoidance. Drug Saf. 1994;10(4):310-317.
6. Mercke Y, Sheng H, Khan T, Lippmann S. Hair loss in psychopharmacology. Ann Clin Psychiatry. 2000;12(1):35-42.
7. Gautam M. Alopecia due to psychotropic medications. Ann Pharmacother. 1999;33(5):631-637.
8. Fatemi SH, Calabrese JR. Treatment of valproate-induced alopecia. Ann Pharmacother. 1995;29(12):1302.
9. Hunt N, McHale S. The psychological impact of alopecia. BMJ. 2005;331(7522):951-953.