Letters to the editor

Letters to the Editor
Mania Associated With Initiation of Ziprasidone plied to our report, 6 of their 8 criteria favor our interpretationthat ziprasidone was the cause of our patient’s manic symptoms.
Two criteria are not met, yet only because olanzapine was be- Sir: The efficacy of atypical antipsychotics in the treatment
gun concurrent with ziprasidone discontinuation and because of psychotic disorders is well established. Although olanzapine there was no rechallenge with ziprasidone. Our patient’s lack of carries an additional indication for bipolar disorder, there are further manic symptoms despite no treatment with lithium or cases of mania associated with risperidone1,2 and olanzapine3,4 mood stabilizers in the 3 months following lends further cred- treatment in some patients. We present a case report of mania ibility to our interpretation that ziprasidone was the cause of his that was apparently induced in a patient shortly after beginning therapy with another atypical antipsychotic, ziprasidone.
Head-to-head trials among atypical antipsychotics with in- cidence of (hypo)mania development included as an outcome Case report. Mr. A was a 20-year old man with a history
measure would be useful. This would allow productive specula- of auditory hallucinations, paranoid delusions, flat affect, and tion on a causative mechanism, based on the known differences social withdrawal. His symptoms worsened over several weeks, in neuronal receptor affinities of agents in this class. For now, necessitating admission to our inpatient psychiatric unit. Halo- clinicians should be aware that ziprasidone, like other atypical peridol and risperidone trials had been attempted in the past, but antipsychotics, may induce mania in predisposed patients.
he had refused treatment for 8 months prior to meeting us. Re-garding this period, family members related waxing and waning Dr. Nolan reports no financial or other relationship relevant to the of symptoms throughout, and they urged him to resume treat- subject matter of this letter; Dr. Schulte is on the speaker/advisory boards ment. He had no history of drug/alcohol abuse, and his past of Pfizer, Lilly, Janssen, Abbott, and Forest. medical/neurologic history was unremarkable.
With the patient meeting DSM-IV-TR diagnostic criteria for schizophrenia, we began ziprasidone, 20 mg b.i.d., with 20-mgb.i.d. increases over 4 days to 80 mg b.i.d. Due to daytime seda- 1. Diaz SF. Mania associated with risperidone use [letter]. J Clin tion, his dose was changed to 160 mg h.s. That night, because he slept poorly but related no other symptoms, ziprasidone was 2. Koek RJ, Kessler CC. Probable induction of mania by risperidone decreased to 80 mg h.s. The following night, he displayed in- [letter]. J Clin Psychiatry 1996;57:174–175 creased energy with elated mood. He had increased religiosity 3. Reeves RR, McBride WA, Brannon GE. Olanzapine-induced mania.
and jumped over chairs, danced, and sang on a table. Loraze- pam (2 mg) was emergently administered twice over 36 hours 4. Lykouras L, Gournellis R, Angelopoulos E. Manic symptoms induced by olanzapine. Eur Neuropsychopharmacol 2001;11:97–98 for his agitation and manic behavior. The ziprasidone therapy 5. Keck PE Jr, Reeves KR, Harrigan EP. Ziprasidone in the short-term was discontinued, and olanzapine therapy was initiated as he treatment of patients with schizoaffective disorder: results from two refused lithium and valproic acid. The manic symptoms re- double-blind placebo-controlled, multicenter studies. J Clin solved over 48 hours, and his psychotic symptoms resolved over 30 days. Follow-up at 3 months, during which time he was 6. Aubry JM, Simon AE, Bertschy G. Possible induction of mania and maintained on 20 mg of olanzapine daily, revealed no further hypomania by olanzapine or risperidone: a critical review of reported symptoms of mania, although some paranoid delusions re- cases. J Clin Psychiatry 2000;61:649–655 Brock P. Nolan, M.D.
Jerome J. Schulte, Jr., M.D.
On the basis of a recent literature search, this case represents the first report of mania associated with ziprasidone. Despite reports of the induction of mania by atypical antipsychotics, many authors find these agents (including ziprasidone5) helpfulin treating manic symptoms seen in bipolar and schizoaffectivedisorders. In a review of risperidone/olanzapine-induced mania, it was speculated the cause was due to 5-HT /D receptor occu- pancy.6 However, ziprasidone differs from the older atypicalsin its profound 5-HT and 5-HT/norepinephrine (NE) reuptake inhibition effect—similar to amitriptyline and imipramine.
Sir: Maina et al.1 recently published in the Journal a very
Perhaps the tricyclic-like antidepressant effect of ziprasidone interesting randomized trial of amisulpride, paroxetine, and ser- traline for burning mouth syndrome (BMS). They cite case We acknowledge that this case could represent a manic reports indicating that antidepressants have sometimes been break in a patient who suffers from schizoaffective disorder.
helpful in treating BMS. A recent Cochrane Review summarizes However, when the criteria proposed by Aubry et al.6 are ap- previous treatment trials for BMS.2 I report a case in which the COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC.
patient’s BMS symptoms were the result of, rather than relieved 2. Zakrzewska JM, Glenny AM, Forssell H. Interventions for the treatment of burning mouth syndrome (Cochrane Review).
Cochrane Database Syst Rev 2001;3:CD002779 Case report. When first seen, Ms. A was a 56-year-old
3. Tarkkila L, Linna M, Tiitinen A, et al. Oral symptoms at menopause: the role of hormone replacement therapy. Oral Surg Oral Med Oral woman presenting with DSM-IV dysthymia of at least 10 years’ Pathol Oral Radiol Endod 2001;92:276–280 duration and superimposed major depressive disorder that had 4. Maier C. Vital disorders of the mouth (glossodynia) in depressive developed over the previous year. Her primary care physician involutional psychoses [in German]. Nervenarzt 1986;57:113–115 had intermittently prescribed phentermine/fenfluramine during 5. Ives TJ, Stewart RB. Doxepin-induced acute glossitis. Am J Hosp the preceding year, but these medications had been discontin- ued. She was experiencing menopausal symptoms. Her thyroid 6. de la Fuente JR, Berlanga C. Glossitis associated with mianserin function was normal. Her primary care physician had started her on treatment with fluoxetine, 10 mg/day; following psychiatricevaluation, this dose was increased to 20 mg/day, and 1 month James L. Levenson, M.D.
After 2 weeks of treatment with this dose, Ms. A reported painful burning sensations in her tongue, with no visible oralchanges. No evidence of a systemic medical disorder was ob- served. Fluoxetine was discontinued, and the patient’s glosso-dynia disappeared. She was started on treatment with sertraline,50 mg/day, and after the dose was gradually raised to 100 Sir: We read with great interest the letter to the editor by
mg/day, she promptly redeveloped glossodynia. Examination Levenson on burning mouth syndrome (BMS) as a side effect of by a dentist/oral pathologist found no evidence of any oral or selective serotonin reuptake inhibitors (SSRIs). To our knowl- dental disease. Ms. A’s symptoms disappeared with discontinu- edge, it is the first report in the literature of BMS associated ation of sertraline, but recurred during a trial of venlafaxine.
She was unable to tolerate bupropion, nefazodone, mirtazapine, Three aspects of the case report must be noted: (1) diagnosis: or methylphenidate because of unrelated side effects. During the BMS symptoms appeared in a patient treated for a double this period of antidepressant trials, Ms. A also received trials of depression; (2) drugs: the BMS symptoms appeared and re- hormone replacement therapy and hysterectomy for dysfunc- curred with 2 SSRIs (fluoxetine and sertraline) and with venla- tional uterine bleeding; neither appeared to have any effect on faxine, but not with citalopram; and (3) doses: BMS symptoms were experienced with fluoxetine, 30 mg/day, but not with Because the patient had experienced the most benefit from fluoxetine, 20 mg/day, and with sertraline, 100 mg/day, but not fluoxetine, she asked to retry it. As before, she was able to toler- with sertraline, 50 mg/day (the daily dose of venlafaxine was ate 20 mg/day without side effects, but the dose was ineffective.
At a dose of 40 mg/day, intolerable glossodynia recurred.
Concerning diagnosis, the occurrence of BMS in a patient Fluoxetine was again discontinued, with subsequent disappear- with double depression is an infrequent clinical condition. In ance of oral pain. Ms. A was started on treatment with citalo- our experience,1 major depressive disorder co-occurs in almost pram, and with a dose of 40 mg/day, her depression completely 20% of patients with a principal diagnosis of BMS, with a sig- remitted. She has continued taking this dose of citalopram for nificant difference in comparison to matched non-BMS con- the past 3.5 years with no recurrence of depression or oral pain.
trols, but a lifetime diagnosis of dysthymia is present in lessthan 7% of these patients, with no statistical difference from Glossodynia has been associated with menopause3 and with controls. In conclusion, the infrequent occurrence of BMS in involutional depression.4 Neither appeared to account for this patients with double depression may further suggest that this patient’s oral pain, since it began after her depression had association depends on drug treatment.
responded to trials of antidepressants. Whenever the antidepres- Conversely, the association of BMS symptoms with several sant was discontinued, her depression worsened, but the glosso- antidepressants and not with others is difficult to interpret.
dynia resolved. Hormone replacement did not affect the course Moreover, we found another case report2 describing the onset of of her symptoms. I could find no reports in the literature of glos- BMS symptomatology after 4 weeks of therapy with clonaze- sodynia caused by antidepressants. Glossitis has been reported pam in a 52-year-old woman treated for anxiety disorder; as an antidepressant side effect,5,6 but in those cases there was previous treatment with alprazolam did not improve anxiety visible evidence of inflammation, which was entirely absent symptoms, but was not associated with BMS. The association of in this case. This patient did not experience glossodynia while BMS with a wide range of drugs conflicts with the observation taking nonserotonergic antidepressants (bupropion, mirtaz- of great differences among drugs of the same class, and this apine, nefazodone), but was on treatment with each only a short leads us to believe that BMS is not related to a pharmacologic time. She experienced glossodynia with fluoxetine, sertraline, venlafaxine, and retrial of fluoxetine. For unclear reasons, she Concerning the daily dose, oral symptoms occurred with 30 has not had this problem with citalopram. Continued follow-up mg/day of fluoxetine and with 100 mg/day of sertraline, but did has revealed no evidence of any underlying medical or neuro- not occur with lower doses (from Levenson’s letter, we do not know what dose of venlafaxine was associated with BMS). Thisis another interesting finding, but we are unable to discuss it.
Dr. Levenson has been a consultant for Lilly. The patients with BMS whom we treated with amisulpride and with SSRIs (paroxetine and sertraline) were different from the patient described in Levenson’s case report, because weexcluded patients with comorbid major depressive disorder.3 1. Maina G, Vitalucci A, Gandolfo S, et al. Comparative efficacy of Furthermore, our sample was treated with a low dose of drug SSRIs and amisulpride in burning mouth syndrome: a single-blind (sertraline was given at 50 mg/day). No worsening of BMS was observed in any patients at any time.
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We are now studying the clinical and therapeutic features One patient developed apparent moderate gastritis with stom- of BMS comorbid with major depressive disorder, because we ach ache that responded well to standard medical treatment.
hypothesize that in these cases BMS has a different course and Two patients described mild transient headaches. Two patients prognosis. Our preliminary impression is also that in these switched from depressed mood to mild hypomania.
patients the treatment of BMS is much more difficult. We did By clinical global estimate, 12 of the 19 patients showed not find a relationship between previous or ongoing treatment marked clinical improvement, 3 showed moderate improve- with antidepressants and onset of BMS, but we now believe the ment, and 1 showed mild improvement. Thirteen patients (10 issue merits investigation in light of the interesting report by marked responders, 3 moderate responders) were able to com- pletely discontinue psychiatric medications over a mean of 5.2weeks (range, 3–10 weeks) and remain stable on EMP alone.
The authors report no financial affiliation or other relationship Of the 12 showing marked improvement, 10 have remained relevant to the subject matter of this letter. on EMP (current follow-up mean length = 13 months; range,5–21). One of the 3 moderate responders has also continued on EMP, so that 11 of 19 patients have chosen to remain on EMPrather than psychiatric medications.
1. Bogetto F, Maina G, Ferro G, et al. Psychiatric comorbidity in Of the other 8 patients, 1 was lost to follow-up. Four discon- patients with burning mouth syndrome. Psychosom Med 1998; tinued EMP because of gastrointestinal problems. Three had recurrent symptoms, stopped EMP, and resumed psychiatric 2. Culhane NS, Hodle AD. Burning mouth syndrome after taking clonazepam. Ann Pharmacother 2001;35:874–876 It is clear that the effectiveness and safety of EMP remain to 3. Maina G, Vitalucci A, Gandolfo S, et al. Comparative efficacy of be established in controlled trials, but this approach does appear SSRIs and amisulpride in burning mouth syndrome: a single-blind to represent an exciting potential direction for new research in Giuseppe Maina, M.D.
Filippo Bogetto, M.D.
Dr. Simmons reports no financial or other relationships relevant to the 1. Kaplan BJ, Simpson JSA, Ferre RC, et al. Effective mood stabiliza- tion with a chelated mineral supplement: an open-label trial in bipolardisorder. J Clin Psychiatry 2001;62:936–944 2. Popper CW. Do vitamins or minerals (apart from lithium) have Sir: Kaplan and colleagues1 are to be commended for their
mood-stabilizing effects? J Clin Psychiatry 2001;62:933–935 pioneering nutritional approach to treating bipolar disorder.
3. Stringham DR. Nutritional Supplement Support Booklet. Truehope Their clinical report described the open-label trials of 14 adults Web site. Available at: http://www.truehope.com. Accessed March with bipolar disorder who were treated with E.M.Power+ (EMP), a mixture of essential minerals, vitamins, and other nu-trients, developed by David L. Hardy and Anthony F. Stephan, Miles Simmons, M.D.
which is marketed by Evince International. While perhaps star-tling initially, this novel treatment approach appears to offer substantial benefit. Popper2 has briefly described successfulclinical use in some cases, and I report here on my own experi- ence with this same nutrient supplement.
Impressed by a striking response in a patient who learned of this supplement on the Internet, I began to discuss this option Sir: Dr. Simmons’ observations confirm our report1 that a
with other patients in my private clinical practice. After dis- micronutrient treatment has therapeutic effects in bipolar effects cussing alternative available treatments, the nature of this new in bipolar patients, a finding supported also by Popper’s clinical approach, and the lack of controlled data regarding its use, I experience.2 With a third observer describing a high response gave some treatment-resistant patients the option to try EMP rate, this nutritional approach might begin to take on increasing under careful observation. I have now worked with EMP in credibility, but it is important to note that no controlled trials treating 19 adults (mean age = 38 years; range, 18–68) with DSM-IV-TR bipolar I (N = 14) or bipolar II (N = 5) disorder, The conciseness of Dr. Simmons’ report prevented his pro- who were followed for a mean of 13 months (range, 5–21). At viding details of the transition from conventional medications the time of starting EMP, 16 patients were already receiving to this micronutrient treatment, but the prior reports describe in- pharmacotherapy (mean = 2.7 psychiatric medications). After teractions between micronutrients and conventional psychiatric gaining some experience in using EMP, I elected to start 3 un- medications that are unexpectedly strong and significantly medicated (at the time; not medication-naive) patients on this complicate the clinical management of drug-treated patients.
We support Popper’s advice2 to physicians against use of Following the usage described by Hardy and Stephan3 for E.M.Power+ in patients currently taking psychiatric medica- acute phase treatment of adults, the patients were started on 32 tions, unless they have solid and ongoing consultation with an EMP capsules daily (taken as 8 q.i.d.). Most patients experi- experienced advisor. Instead, physicians who are inexperienced enced mild transient gastrointestinal symptoms, including nau- in the use of micronutrient treatment would be wise to restrict sea (6 patients), loose bowels or diarrhea (7 patients), burning stomach pain (2 patients), and stomach ache (1 patient). Most While the accumulation of similar anecdotal observations patients experienced nausea if they took EMP without food.
from multiple clinicians should counter initial skepticism, con- COPYRIGHT 2003 PHYSICIANS P
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trolled studies are needed to clarify whether micronutrient treat- The literature contains reports of clozapine- and olanzapine- ment represents an important new direction for bipolar research.
induced urinary incontinence that were treated successfully byusing an α-adrenergic agonist (ephedrine).1,2 To our knowledge, The open-label trial1 was supported in part by the Alberta Children’s this case report is the first in which fecal incontinence was ob- Hospital Foundation and the Alberta Science and Research Authority, served in association with olanzapine treatment. The specific Edmonton, Alberta, Canada; and Evince International, Farmington, Utah mechanism of incontinence in this case is difficult to determine.
(who provided the E.M.Power+ supplement free of charge). The internal anal sphincter receives a stimulatory adrenergic in-nervation. A previous study3 showed that abnormalities in the adrenergic innervation of the internal anal sphincter were seenin cases of idiopathic fecal incontinence. Recent research has 1. Kaplan BJ, Simpson JSA, Ferre RC, et al. Effective mood stabiliza- successfully demonstrated the feasibility of an adrenergic ago- tion with a chelated mineral supplement: an open-label trial in bipolardisorder. J Clin Psychiatry 2001;62:936–944 nist (topical phenylephrine) in raising resting anal tone in 2. Popper CW. Do vitamins or minerals (apart from lithium) have mood- patients with fecal incontinence.4 Olanzapine also possesses stabilizing effects? [commentary] J Clin Psychiatry 2001;62:933–935 significant α-adrenergic antagonist effects,5 which may be apossible explanation for the occurrence of fecal incontinence.
J. Steven A. Simpson, Ph.D., M.D.
One can argue that the combined effect of olanzapine and Bonnie J. Kaplan, Ph.D.
other sedative drugs could have caused fecal incontinence, but complete recovery from incontinence following withdrawal of olanzapine is sufficient evidence to document that olanzapinecan cause fecal incontinence. Our case would have been moreconvincing had we reexposed the patient to experimentallyprove the point, but we believed this approach to be unethical.
The authors report no financial affiliation or other relationship relevant to the subject matter of this letter. Sir: Fecal incontinence is a socially devastating and embar-
rassing condition. We report a case of primary insomnia that didnot respond to various anxiolytics and sedative drugs. Eventu-ally, olanzapine was added to the patient’s regimen of minor 1. Fuller MA, Borovicka MC, Jaskiw GE, et al. Clozapine-induced urinary incontinence: incidence and treatment with ephedrine.
tranquilizers. Although the patient showed improvement in sleep duration, he developed fecal incontinence. Withdrawal of 2. Vernon LT, Fuller MA, Hattab H, et al. Olanzapine-induced urinary olanzapine resulted in complete recovery from the incontinence.
incontinence: treatment with ephedrine [letter]. J Clin Psychiatry2000;61:601–602 Case report. Mr. A, a 65-year-old man, presented with a his-
3. Speakman CT, Hoyle CH, Kamm MA, et al. Adrenergic control of the tory of primary insomnia (DSM-IV criteria) of 20 years’ dura- internal anal sphincter is abnormal in patients with idiopathic faecal tion. The patient claimed that he would sleep for only 1 to 2 incontinence. Br J Surg 1990;77:1342–1344 hours per night, and, in the daytime, due to lack of sleep, he 4. Cheetham MJ, Kamm MA, Phillips RK. Topical phenylephrine would feel restless, irritable, and anxious and had poor concen- increases anal canal resting pressure in patients with faecal tration and decreased memory. During a 5-year period, he was treated with various anxiolytic and sedative drugs with no im- 5. Moore NE, Calligaro DO, Wong DT, et al. The pharmacology of provement in sleep. In July 2001, he was put on treatment with olanzapine and other new antipsychotic agents. Curr Ther Invest lorazepam, 2 mg, and zolpidem, 10 mg, at night for 15 days.
Due to lack of response, olanzapine, 2.5 mg, was added at night- D. N. Mendhekar, M.D., D.P.M.
P. K. Srivastav, M.D.
With this combination, Mr. A’s total sleep time was increased S. K. Sarin, M.D., D.M.
from 2 hours to 4 hours with no daytime symptoms, but he no- R. C. Jiloha, M.D.
ticed passage of stool in his clothes without being able to control the motion before reaching the toilet. This fecal incontinence would occur mostly in the morning, even after the patient hadattended to proper toilet activities. The frequency of inconti-nence varied from 1 to 3 times per day, and it was so obviousthat others could notice the patient’s soiled clothes. The patient continued the same drug regimen for 20 days and continued to the Polydipsia, Intermittent Hyponatremia, have fecal incontinence during this period.
In August 2001, during follow-up, oral olanzapine treatment was stopped. The next day, Mr. A observed complete recoveryof fecal incontinence. He was seen by a gastroenterologist on Sir: Excessive fluid intake by psychotic patients can pro-
the second day after stopping olanzapine to rule out any organic duce significant morbidity and possibly death due to water cause for the fecal incontinence. The findings of a per rectal ex- intoxication and hyponatremia. In patients with chronic schizo- amination were normal. No rectal prolapse was found, and anal phrenia, the prevalence of polydipsia is estimated between 6% sphincter tone was normal. No hemorrhoids or excoriations and 20%.1 In a subset of these patients, fluid intake overwhelms were found. A sigmoidoscopic examination showed normal rec- the kidney’s normal excretory capacity and produces symptom- tal and sigmoid colon. A laboratory examination also did not atic, dilutional hyponatremia, known as the polydipsia, inter- suggest organic lesions as a cause of the incontinence. Mr. A had mittent hyponatremia, and psychosis syndrome (PIP).2 The no history of urinary incontinence and was not suffering from symptoms of PIP range from mild cognitive deficits to seizures, coma, and death. While the pathophysiology is poorly under- COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC.
Table 1. Studies and Case Reports of Clozapine, Risperidone, and Olanzapine Treatment of PIP
Abbreviations: DW = diurnal weight change, Na = sodium, Osm = osmolality, PIP = polydipsia, intermittent hyponatremia, and psychosis syndrome, USG = urine specific gravity. Symbols: + = sustained symptom improvement, – = little improvement in symptoms, +/– = some improvement, butnot sustained.
stood, some authors have attributed the hyponatremia to distur- free water restriction, intravenous infusion of normal saline at bances in antidiuretic hormone function.3 Primary management 70 cm3/h, and close monitoring of serum sodium concentration.
involves limiting water intake, often difficult in the outpatient A correction of less than 12 mmol/L/day of sodium was desired setting. There have been some published case reports and open- to prevent central pontine myelinosis. Following stabilization of label studies suggesting clozapine as an effective pharmaco- hyponatremia, the patient was started on treatment with quetia- therapy for PIP.4–9 Published case reports of resolution of PIP pine (200 mg/day) and continued on treatment with haloperidol with olanzapine and risperidone are contradictory (Table 1).10–16 There have been no published reports of treating PIP with At the time of discharge, outpatient treatment involved behavioral and pharmacologic interventions to manage boththe PIP and schizophrenia. Over the course of 2 months, quetia- Case report. Mr. A is a 42-year-old white man with a history
pine was increased to 600 mg/day and haloperidol was tapered of chronic disorganized schizophrenia (DSM-IV) since 1982.
down to 5 mg/day. With the exception of 1 acute psychotic de- He has had 8 psychiatric admissions since his diagnosis, and his terioration that occurred when haloperidol was discontinued, baseline mental state is characterized by negative symptoms, the patient’s psychiatric symptoms responded well to treatment.
thought disorganization, and limited executive functioning.
In the first 20 weeks after his discharge from the hospital, Once a successful Air Force medical specialist and college stu- Mr. A’s compulsive drinking behaviors continued, as evidenced dent studying premedicine, he is now considered totally dis- by both residential staff reports and afternoon urine specific abled and lives in a closely supervised group home. His initial gravities in the low-normal range (1.007–1.008). Despite treatment with traditional antipsychotics (haloperidol, thiorid- evidence of continued excessive water intake, the patient’s af- azine, and fluphenazine) was unsuccessful, and he is considered ternoon serum sodium concentrations improved with less vari- treatment refractory. As newer agents became available, trials of ability within a few weeks and normalized within 6 months risperidone and olanzapine were attempted with limited suc- cess. The patient refused to consider clozapine.
At routine follow-up in February 2000, Mr. A’s laboratory Chronic D blockade has been shown in animals to induce results revealed a serum sodium concentration of 125 mmol/L abnormal release of angiotensin II, a dipsogen.3 In humans, and urine specific gravity of 1.005. Three months later, the chronic D blockade is associated with increased peripheral re- patient was hospitalized for symptomatic hyponatremia with se- sponse to angiotensin II. Although the profound effects of an- rum sodium concentration of 104 mmol/L, urine specific grav- giotensin II on thirst and drinking in animals have not been ity of 1.009, serum osmolality of 233 mOsm/kg H O, and urine reproduced in healthy human subjects, angiotensin II levels are osmolality of 126 mOsm/kg H O on admission. At the time, his elevated in pathologic conditions associated with increased psychotropic regimen consisted of olanzapine (20 mg/day) and thirst such as diabetes mellitus. These findings suggest that haloperidol (30 mg/day). In July 2000, he presented to the local chronic treatment with first-generation antipsychotic agents Veterans Affairs medical center complaining of slurred speech, may actually increase the likelihood of polydipsia. Furthermore, unsteady gait, and frequent falls with injuries to his face and the corrective and stabilizing effect of the second-generation neck. His live-in caregiver provided additional history that the antipsychotic clozapine on PIP has been attributed to its relative patient had been consuming 20 to 30 liters of water per day for several months. In the emergency department, the patient’s Like clozapine, quetiapine has a higher affinity for 5-HT2 serum sodium concentration was 96 mmol/L; urine specific than dopamine D receptors,17 and research suggests that quetia- gravity, 1.002; serum osmolality, 200 mOsm/kg H O; and urine pine has significantly lower binding affinity for D than risperi- osmolality, 27 mOsm/kg H O. The patient was admitted to the done or olanzapine.18 If D receptor sparing is an important intensive care unit (ICU). Despite profound hyponatremia, no component of treating PIP, then quetiapine could be hypoth- seizures were reported, and neurologic examination revealed esized to have greater benefits in treating PIP compared with only dysarthria. Management in the ICU consisted of complete other second-generation antipsychotics.
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Figure 1. Serum Sodium Concentrations in a Schizophrenia Patient With PIPa
aReference values for serum sodium concentration: low, 133 mmol/L; high, 145 mmol/L.
Abbreviations: ICU = intensive care unit, PIP = polydipsia, intermittent hyponatremia, and psychosis syndrome.
One limitation to this report is that during the treatment phase with quetiapine, haloperidol was being tapered and dis- 12. Kruse D, Pantelis C, Rudd R, et al. Treatment of psychogenic polydip- continued. Chronic haloperidol treatment could have contrib- sia: comparison of risperidone and olanzapine, and the effects of the uted to the patient’s developing PIP; thus, tapering off this adjunctive angiotensin-2 receptor blocking drug (irbesartan). Aust N ZJ Psychiatry 2001;35:65–68 first-generation antipsychotic with high D affinity could have 13. Kern RS, Barringer DM, Kuehnel TG, et al. Effects of risperidone on improved his water balance. In addition, staff efforts at water polydipsia in chronic schizophrenia patients. J Clin Psychopharmacol restriction, though perceived as unsuccessful, may have played a greater role in the patient’s sodium stabilization than medica- 14. Littrell KH, Johnson CG, Littrell SH, et al. Effects of olanzapine on tion. Nonetheless, the role of D receptor binding in PIP, and polydipsia and intermittent hyponatremia [letter]. J Clin Psychiatry quetiapine’s potential in particular, warrants further study.
15. Millson RC, Emes CE, Glackman WG. Self-induced water intoxica- The authors report no financial affiliation or other relationship tion treated with risperidone. Can J Psychiatry 1996;41:648–649 relevant to the subject matter of this letter. 16. Landry P. Effect of risperidone on polydipsia and hyponatremia in schizophrenia [letter]. Can J Psychiatry 1995;40:566–567 17. Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia:a comparison with haloperidol and placebo. Biol Psychiatry 1. Fuller MA, Jurjus G, Kwon K, et al. Clozapine reduces water- drinking behavior in schizophrenic patients with polydipsia.
18. Jibson MD, Tandon R. New atypical antipsychotic medication.
2. Leadbetter RA, Shutty MS, Higgins PB, et al. Multidisciplinary approach to psychosis, intermittent hyponatremia, and polydipsia.
John H. Montgomery, D.O.
3. Verghese C, De Leon J, Simpson GM. Neuroendocrine factors influencing polydipsia in psychiatric patients: an hypothesis.
Janet L. Tekell, M.D.
4. Canuso CM, Goldman MB. Clozapine restores water balance in schizophrenic patients with polydipsia-hyponatremia syndrome.
J Neuropsychiatry Clin Neurosci 1999;11:86–90 5. Henderson DC, Goff DC. Clozapine for polydipsia and hyponatremia in chronic schizophrenics. Biol Psychiatry 1994;36:768–770 6. Lee HS, Kwon KY, Alphs LD, et al. Effect of clozapine on Treatment of Leuprolide-Induced Depression psychogenic polydipsia in chronic schizophrenia [letter]. J Clin With Intramuscular Testosterone: A Case Report 7. Lyster CL, Miller AL, Seidel D, et al. Polydipsia and clozapine [letter]. Hosp Community Psychiatry 1994;45:610–611 Sir: Hypogonadal states occur naturally or with gonadotropin-
8. Spears NM, Leadbetter RA, Shutty MS. Clozapine treatment in releasing hormone (GnRH) agonist administration. Hypo- polydipsia and intermittent hyponatremia. J Clin Psychiatry 1996; gonadism in men, defined as testosterone levels < 350 ng/dL, may cause fatigue, memory loss, and diminished libido.1 Natu- 9. Wakefield T, Colls I. Clozapine treatment of a schizophrenic patient rally occurring hypogonadism in men and women has been asso- with polydipsia and hyponatremia [letter]. Am J Psychiatry 1996; ciated with depressed mood.2,3 Cases of depression and mania 10. Kar N, Sharma P, Pai K, et al. Polydipsia and risperidone.
have been associated with GnRH agonists.4–6 GnRH agonists are often utilized for treatment of prostate 11. Kawai N, Baba A, Suzuki T. Risperidone failed to improve cancer, the most common malignancy in men. The rationale is polydipsia-hyponatremia of the schizophrenic patients. Psychiatry that some prostatic malignancies may be exacerbated by testos- COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC.
terone and that tumor size may be reduced by decreasing testos- Our patient still exhibited low levels of serum testosterone 2 terone. The following case describes the emergence of major months after receiving testosterone injections, despite cessation depressive disorder with the use of the GnRH agonist leuprolide of leuprolide therapy. Normalization of testosterone levels after in the treatment of prostate cancer.
GnRH therapy requires, on average, several months.11 In thiscase, although total and free testosterone levels were decreased Case report. Mr. A is a 70-year-old white man who pre-
below normal 2 months after the testosterone injection, the de- sented with depressed mood of 7 weeks’ duration, with onset, cline may have been slower than that which occurred after the per the patient’s report, within 1 week of receiving a depot leuprolide intramuscular injection for adenocarcinoma of the The interaction between mood and testosterone may be es- prostate. He reported weakness; anhedonia; decreased energy, pecially important in a subgroup of patients. Seidman et al.12 appetite, concentration, and sleep; hot flushes; anxiety; restless- have demonstrated that some men may be genetically predis- ness; and suicidal ideation. A DSM-IV diagnosis of major posed to experience depressive symptoms when total testoster- depressive disorder was made 1 month after the leuprolide in- one levels are low. In their study of 1000 men, depression was jection. Under the care of a physician, Mr. A received sertraline, inversely related to total testosterone levels only in those men 50 mg/day, for 2 weeks, without benefit, and citalopram, 20 with a specific isotype of the androgen receptor (those with mg/day, for 5 days, with intolerable anxiety. He then used lora- shorter CAG repeat length [RL]). Pope et al.13 also demon- zepam, 0.5 mg/day, for 2 weeks with minimal benefit. Mr. A strated that the relationship between mood and testosterone may had no prior psychiatric history, and at the time of presentation vary greatly and that subgroups of men may be differently to our clinic, he was using no psychotropic medications. He re- affected by administration of exogenous testosterone. In men fused treatment with antidepressants. Electrolytes, glucose, cal- who received supraphysiologic doses of testosterone, although cium, thyroid-stimulating hormone, liver function tests, and a the majority of men (84%) exhibited a minimal psychiatric re- complete blood count were within normal limits. The patient’s sponse, 16% demonstrated significant symptoms of hypomania prostate-specific antigen (PSA) level was 1.8 ng/mL (normal range, 0–4.0 ng/mL), and his total testosterone level was 26 The benefits of treating GnRH agonist–induced depression ng/dL (normal range, 350–720 ng/dL), decreased from a PSA in men with testosterone must be balanced against the risks of level of 6.0 ng/mL and total testosterone level of 139 ng/dL 1 exacerbating prostate cancer. Prostate cancer is considered a year prior. It is undetermined why the patient’s testosterone contraindication to androgen therapy.14 However, while data level was low 1 year prior; the patient’s urologist attributed it to support a role for androgens in the development of prostate can- diurnal fluctuations in testosterone levels.
cer, data are lacking to demonstrate that testosterone admin- The patient attributed his depressive symptoms to “testoster- istration causes progression of prostate cancer.15 Androgens one deficiency” and pursued testosterone therapy after a discus- appear to promote prostatic cell division and the indirect devel- sion of the risks and benefits. The following day, Mr. A received opment of prostate cancer.16 Although androgens are a neces- 200 mg of depot testosterone intramuscularly. Within 1 day, he sary component for cell proliferation, evidence suggests that reported his depression “gone.” His appetite and libido im- they do not directly stimulate cell proliferation. Careful discus- proved. He denied anhedonia and reported improved sleep and sion and consideration of the risks and benefits must occur be- concentration and decreased anxiety. One week later, he re- fore testosterone is used for depression in men with prostate ceived another injection of 200 mg. A week after the second in- jection, his total testosterone level was 673 ng/dL and freetestosterone level was 142.1 pg/mL, both within normal limits.
The authors report no financial affiliation or other relationship Two months later, Mr. A was “back to normal” without anxiety relevant to the subject matter of this letter. or depressive symptoms. A follow-up PSA test revealed a levelof < 0.1 ng/mL; total testosterone was 45 ng/dL, and free testos- terone was 8.7 pg/mL, both below the normal range.
1. Seidman SN, Rabkin JG. Testosterone replacement therapy for Treatment with GnRH agonists may precipitate depression.
hypogonadal men with SSRI-refractory depression. J Affect Disord The package insert for leuprolide lists depression as an adverse event that occurs in approximately 23% of patients treated for 6 2. Rabkin JG, Rabkin R, Wagner G. Testosterone replacement therapy months.7 Also, the package insert for another GnRH agonist, in HIV illness. Gen Hosp Psychiatry 1995;17:37–42 goserelin acetate, lists the incidence of depression at 54%.8 3. Palinkas LA, Barrett-Conner E. Estrogen use and depressive GnRH agonists may cause depression by induction of a hypogo- symptoms in postmenopausal women. Obstet Gynecol 1992; nadal state. This has never been definitively proved, and the possibility that GnRH agonists cause depression independently 4. Rosenblatt DE, Mellow A. Depression during hormonal treatment of prostate cancer. J Am Board Fam Pract 1995;8:317–320 of the production of a hypogonadal state cannot be ruled out. A 5. Rachman M, Garfield DAS, Rachman I, et al. Lupron-induced mania.
bidirectional, saturable transport of GnRH across the blood- brain barrier has been demonstrated,9 supporting a possible cen- 6. Warnock JK, Bundren JC. Anxiety and mood disorders associated tral effect of GnRH agonists that could mediate mood.
with gonadotropin-releasing hormone agonist therapy.
This is the first case report of testosterone therapy for leuprolide-induced depression. However, a placebo-controlled 7. Lupron [package insert]. Deerfield, Ill: TAP Pharmaceuticals; 1995 study of testosterone replacement in hypogonadal men with de- 8. Zoladex [package insert]. Wilmington, Del: Zeneca Pharmaceuticals; pression failed to demonstrate a significant difference between testosterone and placebo.10 The subjects had a mean baseline 9. Barrera CM, Kastin AJ, Fasold MB, et al. Bidirectional saturable transport of LHRH across the blood-brain barrier. Am J Physiol testosterone level of 266.1 ng/dL, only slightly below the nor- mal range. Therefore, the degree of hypogonadism may be im- 10. Seidman SN, Spatz E, Rizzo C, et al. Testosterone replacement portant in the emergence of depressive symptoms and the therapy for hypogonadal men with major depressive disorder: response to treatment. It is also possible that a rapid decline in a randomized, placebo-controlled clinical trial. J Clin Psychiatry testosterone precipitates depression in a subgroup of men.
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J Clin Psychiatry 64:3, March 2003OSTGRADUATE PRESS, INC. COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC.
11. Nejat RJ, Rashid HH, Bagiella E, et al. A prospective analysis of time and a reduction of withdrawal symptoms in the hydroxyzine to normalization of serum testosterone after withdrawal of androgen deprivation therapy. J Urol 2000;164:1891–1894 Hydroxyzine is a great alternative for benzodiazepine in 12. Seidman SN, Araujo AB, Roose SP, et al. Testosterone level, acute and chronic anxiety reduction. Since 1993, I have pre- androgen receptor polymorphism, and depressive symptoms in scribed hydroxyzine to hundreds of patients for this purpose. In middle-aged men. Biol Psychiatry 2001;50:371–376 13. Pope HG Jr, Kouri EM, Hudson JI. Effects of supraphysiologic doses a majority of the cases, the anxiety relief has been very positive.
of testosterone on mood and aggression in normal men: a randomized Having no addictive potential, hydroxyzine is a great alternative controlled trial. Arch Gen Psychiatry 2000;57:133–140 to all the benzodiazepines, barbiturates, and other sedatives 14. Basaria S, Dobs AS. Risks versus benefits of testosterone therapy in used in treating anxiety symptoms. When switching a patient elderly men. Drugs Aging 1999;15:131–142 from a sedative to hydroxyzine, one must still take a good his- 15. Rolf C, Nieschlag E. Potential adverse effects of long-term testoster- tory and make sure to taper down the sedative (e.g., alprazolam) one therapy. Baillieres Clin Endocrinol Metab 1998;12:521–534 to reduce the likelihood of withdrawal seizures. I use a conver- 16. Cook T, Sheridan WP. Development of GnRH antagonists for sion formula of “25 mg of hydroxyzine is equal to 1 mg of lora- prostate cancer: new approaches to treatment. Oncologist 2000; zepam (or equivalent dose of a benzodiazepine).” In acute anxiety situations that require an intramuscular injection of Marlene P. Freeman, M.D.
2 mg of lorazepam, I have given the “equivalent” 50-mg intra- Scott A. Freeman, M.D.
muscular injection of hydroxyzine with success. Dosing fre-quency is between 6 and 12 hours, depending on individual response. I do not recommend exceeding a total daily dose of400 mg. In cases of alcohol intoxication or for patients whohave a known seizure disorder, pending alcohol or other seda-tive, hypnotic, or anxiolytic withdrawal, I choose the traditional Hydroxyzine for Generalized Anxiety Disorder benzodiazepine (along with thiamine injection in case of knownalcohol-induced neurotoxicity).
Hydroxyzine may also prove to be an efficacious agent for Sir: A recent comprehensive review of pharmacologic ap-
patients suffering from GAD. Most of the available literature on proaches to generalized anxiety disorder (GAD)1 referenced hydroxyzine presents it as an effective pharmacologic agent in only 2 of the 5 publications available on the use of hydroxyzine GAD. Hydroxyzine is a better option than benzodiazepines and in treatment of GAD. I present 2 other publications that report may deserve to be the secondary agent used to treat GAD if (or the effectiveness of hydroxyzine in relieving GAD and 1 that re- ports its effectiveness in relieving benzodiazepine withdrawalanxiety.1 Dr. Sagduyu reports no financial affiliation or other relationship One study enrolled 55 outpatients with comorbid anxiety relevant to the subject matter of this letter. and cardiovascular disease.2 Patients received hydroxyzine for28 days (daily dose = 50 mg). In 47 of 50 patients, Hamilton Rating Scale for Anxiety (HAM-A) scores dropped by a meanof 10 points. The reduction was most obvious in patients suffer- 1. Gorman JM. Treatment of generalized anxiety disorder. J Clin ing from somatic anxiety. Hydroxyzine was reported to be “well tolerated and safe”(p45) in this patient group.2 In another study, 2. Smulevich AB, Syrkin AL, Drobizhev MI, et al. Therapy of 29 patients with GAD were treated with hydroxyzine.3 The pa- cardio-neurotic diseases in general practice: clinical experience tients were examined both before the treatment and on days 14 with hydroxyzine [in Russian]. Klin Med (Mosk) 1999;77:43–46 and 28 of treatment. Excellent and good Clinical Global Impres- 3. Bobrov AE, Babin AG, Gladyshev OA, et al. Hydroxyzine in treat- ment of anxiety in outpatient clinic [in Russian]. Zh Nevrol Psikhiatr sions scale results were observed in 66% of the patients. Unsat- isfactory results were found in 10% of the cases. Reduction of 4. Lemoine P, Touchon J, Billardon M. Comparison of 6 different the HAM-A total score by 50% or more was observed in 48% of methods for lorazepam withdrawal: a controlled study, hydroxyzine the patients.3 A multicenter, randomized, placebo-controlled versus placebo [in French]. Encephale 1997;23:290–299 study published data on 154 outpatients with GAD, who hadbeen on treatment with 2 mg of lorazepam daily for at least 3 Kemal Sagduyu, M.D.
months.4 They were withdrawn using hydroxyzine or placebo.
University of Missouri-Kansas City School of Medicine Results proved a significant improvement of anxiety, a decrease of side effects in both of the groups treated with hydroxyzine, COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC.

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