Primary Psychiatry. 2007;14(8):19-21

Dr. Ginsberg is vice-chair of clinical affairs 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.

Aripiprazole Augmentation of Clomipramine-Refractory Obsessive-Compulsive Disorder

While currently available treatments, such as selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy (CBT), are efficacious in obsessive-compulsive disorder (OCD), only approximately 40% to 60% of patients experience significant reduction of symptoms, with many others demonstrating either partial or no response. Little practical advice is available to clinicians on next-step treatment strategies for patients who have not responded to ≥2 trials of SSRIs. Augmentation with various agents, including dopamine antagonists, typically are recommended.¹ In severe, resistant cases, neurosurgery may even be used. The following is a report on the successful use of the atypical antipsychotic aripiprazole in combination with the serotonergic tricyclic antidepressant clomipramine in a patient with severe, refractory OCD.²

In January 2006, a 37-year-old white male with a 16-year history of OCD presented with worsening of symptoms to the University Mental and Brain Disorders Clinic in Paris, France. He had never been psychotic in the past and had always retained good insight into his psychiatric condition. He received behavior therapy and several SSRIs but with only modest results due to a lack of full compliance. In addition to his OCD, he also fulfilled Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision,³ criteria for recurrent, severe major depressive disorder (MDD) with only partial remission between episodes. He scored 32 on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and 26 on the 17-item Hamilton Rating Scale for Depression (HAM-D₁₇).

During a 2-week period, clomipramine was gradually titrated to 225 mg/day, then maintained at that dose with adequate serum levels over the next 8 weeks. In conjunction with clomipramine, clonazepam 1–3 mg/day as needed was also given over the first 3 weeks. The depression responded, with a decline in HAM-D₁₇ score to 12. However, the OCD persisted, with the Y-BOCS score remaining at 30–32. Aripiprazole 15 mg/day was added to the clomipramine then maintained over the next 16 weeks. All treatments were well tolerated.

With aripiprazole augmentation, mean Y-BOCS scores and percent reductions in score from baseline were 27 (10% decrease) at week 1; 21 (30% decrease) at week 2; 16 (46.7% decrease) at week 4; and 16 (46.7% decrease) at week 6. As this response was significant, the patient was able to leave the clinic. His Y-BOCS score remained at 16 at week 10 and decreased to 15 by week 16, qualifying him as in remission of OCD. As for the MDD, aripiprazole augmentation did not result in any significant antidepressant effect. By week 16, the patient’s HAM-D17 score was 11, only one point lower than prior to addition of aripiprazole. As a result, his depression remained in only partial remission.

Aripiprazole is an atypical neuroleptic indicated for the treatment of schizophrenia and acute manic and mixed episodes associated with bipolar 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 the 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-HT_2A receptors.⁴

While OCD may take >8 weeks to respond to serotonergic antidepressants such as clomipramine, it seems plausible that addition of aripiprazole was the main ingredient in enhancing response of OCD symptoms in the patient described here. In fact, an open-label study of aripiprazole monotherapy has suggested that it might be of value in treating OCD.⁵ Interestingly, the depression of the patient described here did not respond to the addition of aripiprazole, implying that distinct pathways mediate response to OCD and to depression. PP

References

1. Fineberg NA, Gale TM, Sivakumaran T. A review of antipsychotics in the treatment of obsessive compulsive disorder. J Psychopharmacol. 2006;20:97-103.
2. Friedman S, Abdallah TA, Oumaya M, Rouillon F, Guelfi JD. Aripiprazole augmentation of clomipramine-refractory obsessive-compulsive disorder. J Clin Psychiatry. 2007;68(6):972-973.
3. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000.
4.  Abilify [package insert]. San Francisco, CA: Bristol-Myers Squibb; 2005.
5. Connor KM, Payne VM, Gadde KM, Zhang W, Davidson JR. The use of aripiprazole in obsessive-compulsive disorder: preliminary observations in 8 patients. J Clin Psychiatry. 2005;66(1):49-51.

Serotonin-Norepinephrine Reuptake Inhibitor-Induced Hyperprolactinemia and Galactorrhea

Dopamine acts to inhibit the release of prolactin, a hormone that initiates and sustains lactation. Perhaps through suppression of dopamine neurotransmission releasing prolactin from tonic inhibitor control of dopamine, chronic use of serotonin-enhancing antidepressants may result in a rise in prolactin levels.¹ In women, prolactin elevation can cause galactorrhea, amenorrhea, cessation of normal cyclic ovarian function, loss of libido, hirsutism, and increased long-term risk of osteoporosis and breast cancer, while in men prolactin elevation can cause impotence, loss of libido, and hypospermatogenesis.^2,3 The following is a report of hyperprolactinemia and galactorrhea associated with sequential use of the serotnin norepinephrine reuptake inhibitors (SNRIs) venlafaxine and duloxetine.⁴

A 40-year-old Caucasian female with three children and without any history of endocrine or reproductive pathology presented with dysthymic disorder. While at the time of presentation she was taking only vitamins, in the past she had failed 1-year trials each of sertraline 50 mg/day and fluoxetine 20 mg/day without any subjective endocrine changes. It was decided to initiate venlafaxine extended release (ER), which was titrated to 225 mg/day. She experienced partial improvement in depression but developed dry mouth and constipation. Addition of bupropion ER 300 mg/day improved her mood further. At this time, she developed bilateral breast discharge and nonmenstrual spotting. Magnetic resonance imaging of the patient’s pituitary gland was normal. Gynecologic and endocrine evaluations, including physical examination and laboratory studies, revealed no abnormalities other than an elevated prolactin level of 39.7 ng/mL. Bupropion ER was increased to 450 mg/day, which relieved the depression. Next, venlafaxine was decreased over several weeks, with subsequent resolution of dry mouth, constipation, and vaginal spotting. While the patient’s prolactin level normalized at 12.5 ng/mL, her breast discharge persisted. Due to worsening of mood, venlafaxine was discontinued and replaced with duloxetine 60 mg/day. Her mood improved. However, breast discharge increased, with her prolactin level rising from 10.8 ng/mL to 28.2 ng/mL within 1 month. To address complaints of fatigue, duloxetine was replaced by modafinil. Subsequently, the depression remitted. Over the next 7 weeks, the patient’s breast discharge resolved and her prolactin level decreased to 5.1 ng/mL. At last follow-up 1 year later, the patient’s depression remained stable on a combination of bupropion ER 450 mg/day and modafanil 100 mg/day.

The patient described above appears to represent the first published case of SNRI-induced, dose-dependent, nonmenstrual vaginal spotting and galactorrhea accompanied by prolactin elevation. As pointed out by the authors of this report, since serum levels were not obtained it is not known if use of bupropion ER resulted in elevated levels of venlafaxine or duloxetine. Interestingly, the dopaminergic effects of bupropion were not enough to offset this patient’s hyperprolactinemia, although it is possible but unproved that it may have attenuated it. PP

References

1. Egberts AC, Meyboom RH, De Koning FH, Bakker A, Leufkens HG. Non-puerperal lactation associated with antidepressant drug use. Br J Clin Pharmacol. 1997;44(3):277-281.
2. Petty RG. Prolactin and antipsychotic medications: mechanism of action. Schizophr Res. 1999;35(suppl):S67-S73.
3. Wang PS, Walker AM, Tsuang MT, et al. Dopamine antagonists and the development of breast cancer. Arch Gen Psychiatry. 2002;59(12):1147-1154.
4. Ashton AK, Longdon MC. Hyperprolactinemia and galactorrhea induced by serotonin and norepinephrine reuptake inhibiting antidepressants. Am J Psychiatry. 2007;164(7):1121-1122.

Phenytoin-Temozolomide Interaction Resulting in Delirium

While use of the anticonvulsant phenytoin has been associated with delirium, a substantial majority of cases occur in the context of either hepatic compromise^1,2 or drug-drug interaction.^3-5 Cases outside of accidental overdose or significant central nervous system compromise appear to be relatively uncommon and usually respond to medication withdrawal and supportive care.⁶ The following is a report of an individual undergoing treatment for metastatic brain tumor who subsequently developed delirium likely related to an interaction between the chemotherapy agent temozolomide and phenytoin.⁷

A 68-year-old man was in his usual state of good health when he developed a personality change as well as word-finding and memory difficulty. Diagnosed with a high-grade glioma, he underwent surgical left-temporal lobectomy; biopsy confirmed a Grade III oligoastrocytoma. Postoperatively he was placed on dexamethasone taper and phenytoin. At no point were there any seizures. The patient participated in rehabilitation. Subsequently, he was discharged home with a notable expressive aphasia; however, his balance, coordination, vision, and walking were maintained. Next, he underwent two cycles of therapy. The first, in mid-April 2005, consisted of external-beam radiotherapy and temozolomide. Then, 2 months later, he received a second course of treatment, this time with a substantially increased temozolomide dosage of 400 mg/day. Other medications in his regimen included phenytoin 250 mg BID, pantoprazole 40 mg/day, terazosin 10 mg HS, enoxaparin BID, ondansetron PRN, docusate sodium, and multivitamins.

On July 11, 2005, the patient’s family contacted the clinic where he was being treated to report that the patient was “constantly picking at things that are not there, is easily agitated, and gets confused at times.” Haloperidol 0.5 mg BID was begun. At the next clinic visit, the patient was observed to have increased confusion, visual hallucinations involving insects and mice, insomnia with restlessness at night, and inability to walk unaided. Serum phenytoin level had increased abruptly to 34.1. Several months earlier, between April and June 2005, at a dosage of phenytoin 250 mg BID, serum levels had ranged between 12.3 μg/mL and 22.9 μg/mL (reference range: 10–20).

Additional laboratory tests were ordered. Serum chemistries and liver enzymes were normal; serum protein was low at 5.2 g/dL (range: 6.0–8.2) while albumin was normal at 3.5 g/dL (range: 3.5–5.2). White blood cell and platelet counts were low at 2.78/μL (range: 4.3–10.0) and 126,000/μL (range: 150–400), respectively. Urinalysis was normal. Finally, a brain magnetic resonance imaging scan demonstrated a small subdural hematoma assessed as unchanged from a prior recent study.

Compared with his previous neurologic evaluation, the patient was noted to be profoundly confused, averbal, and unresponsive to most questions. No new focal neurologic findings were evident. The rapid onset and marked changes in behavior, cognition, hallucinations, and sleep-wake cycle all point to a delirium, most probably caused by an elevation in phenytoin levels; the latter possibly resulted from inhibition of phenytoin’s metabolism by the coadministered temozolomide. Subsequently, the patient was lost to follow-up.

Metabolism of phenytoin occurs in large part via the liver cytochrome P450 (CYP) 2C9 isoenzyme pathway.⁸ While not previously reported to do so, temozolomide may inhibit this isoenzyme pathway. Clinical caution is advised when coadministering temozolomide with drugs that are substrates of CYP 2C9. PP

References

1. Beier R, Zschiesche M. Changed phenytoin kinetics in chronic alcoholism [German]. Psychiatr Neurol Med Psychol (Leipz). 1982;34(10):597-601.
2. Sandford NL, Murray N, Keyser AJ, Reynolds TB. Phenytoin toxicity and hepatic encephalopathy: simulation or stimulation? J Clin Gastroenterol. 1987;9(3):337-341.
3. Destee A, Verrier A, Gelez P, Warot P. Myoclonic encephalopathy caused by isoniazid-hydantoin combination [French]. Lille Med. 1979;24(1):41-45.
4. Tollefson GD. Delirium induced by the competitive interaction between phenytoin and dipropylacetate. J Clin Psychopharmacol. 1981;1(3):154-158.
5. Brown CG, Kaminsky MJ, Feroli ER, Gurley HT. Delirium with phenytoin and disulfiram administration. Ann Emerg Med. 1983;12(5):310-313.
6.  Ambrosetto G, Tassinari CA, Baruzzi A, Lugaresi E. Phenytoin encephalopathy as probable idiosyncratic reaction: case report. Epilepsia. 1977;18(3):405-408.
7. Levy M. Delirium likely caused by interaction between phenytoin and temozolomide. Psychosomatics. 2007;48(4):359-360.
8. Kidd RS, Curry TB, Gallagher S, Edeki T, Blaisdell J, Goldstein JA. Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin. Pharmacogenetics. 2001;11(9):803-808.