Pseudophaeochromocytoma associated with clozapine treatment

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					  Case Report

Pseudophaeochromocytoma associated with
clozapine treatment
Sarah E Prasad, Harry G Kennedy
                                                                                           Ir J Psy ch Med 2003; 20(4): 132-1 34

Abstract                                                                 paranoid schizophrenia was admitted to a secure hospital for
We describe a 44 year old man with treatment re s i s ta n t             treatment. He presented with grandiose, persecutory and reli-
schizophrenia who developed pseudophaeochromocytoma                      gious delusions accompanied by restricted and flattened
on clozapine with high blood pressure, ta ch y ca rdia and               affect and poverty of speech. Prior to admission he was
elevated 24 hour urinary catecholamines. All resolved on                 treated with risperidone and fluoxetine. Physical examination
discontinuing clozapine. We reviewed the literature and                  on admission was normal with blood pressure 130/90mmHg
found five other cases. We suggest that this is a common                 and pulse 60/minute.
side effect, transient in some patients. Elevated plasma                    He was treated for six weeks with risperidone (4mg bd). As
noradrenaline does not appear to be relevant to the unique               there was no change in mental state, risperidone was
benefits of clozapine.                                                   stopped. The patient had an 18 week trial of treatment with
                                                                         olanzapine up to 20mg daily, and a 30 week period of treat-
Key words: Schizophrenia; Clozapine; Noradrenaline;                      ment with Clopixol depot injections up to 300mg weekly.
Hypertension; Tachycardia; Pseudophaeochromocytoma.                      Although positive symptoms improved on Clopixol, there were
                                                                         marked negative symptoms throughout, with blunting of affect,
Introduction                                                             anhedonia, isolation, poverty of speech and poor self-care.
   There have been a number of new reports of                               Fluoxetine was changed to lofepramine without improve-
pseudophaeochromocytoma in patients taking clozapine. We                 ment over 17 weeks, while on Clopixol. The patient was
report a case and review the published case reports. Cloza-              started on clozapine. Due to continued low mood, four weeks
pine is an atypical antipsychotic. Treatment with clozapine is           after starting clozapine his antidepressant medication was
indicated for patients unresponsive to, or not tolerant of               changed to venlafaxine up to 150mg/day.
conventional neuroleptics.1,2 The efficacy of clozapine is supe-            Prior to starting clozapine, an ECG was done which was
rior to conventional antipsychotic agents.3 On the other hand,           unremarkable and blood pressure was within normal limits.
side effects include potentially lethal agranulocytosis,                 During the initiation of clozapine, the blood pressure was
seizures, sedation, weight gain, tachycardia, hypotension and            checked twice daily (range 120-130 systolic, 70-80 diastolic)
paradoxical hypertension.4                                                  Five days after commencing clozapine, at a dose of
   Phaeochromocytoma is a catecholamine-producing tumour                 50mg/day the blood pressure was noted to be 150/110
of the sympathetic nervous system. Signs and symptoms are                (range 170-140 systolic, 110-115 diastolic). Pulse was 100-
related to catecholamine excess, including hypertension,                 106 bts/min. The patient was asymptomatic.
sweating, headaches, and anxiety attacks. Abdominal imag-                   A cardiology team evaluated the patient on day seven. He
ing and 24-hour urinary catecholamine output are usually                 was diagnosed with essential hypertension and commenced
sufficient for diagnosis.5 In the last six years there have been         on amlodipine 5mg daily.
several case reports which have described clozapine induced                 We decided to continue with clozapine. Clozapine was
hypertension4,6,7 and clozapine induced hypertension with                gradually increased to 300mg/day in steps of 25mg per
accompanying raised urinary catecholamines, resembling the               week over the next 10 weeks and the Clopixol depot was
presentation of a phaeochromocytoma.8,9 We describe one                  stopped six weeks after commencing clozapine.
patient who developed pseudophaeochromocytoma after                         Six weeks after commencing clozapine a 24hr urine cate-
commencing clozapine.                                                    cholamine collection was done, which yielded elevated
                                                                         urinary noradrenalin (1,533nmol/24 hours; reference range
Case report                                                              50-900nmol/24 hours), the other catecholamines were within
 A 44-year-old caucasian man with an ICD-10 diagnosis of                 normal limits, adrenaline 38nmol/24 hours (reference
                                                                         range25-230nmol/24 hours), dopamine 2129nmol/24 hours
                                                                         (reference range 250-3300nmol/24 hours).
Sarah E Prasad, MB, BCh, LRCP & SI, MRCPsychRegistrar,
Central Mental Hospital, Dundrum, Dublin 14, Ireland.                       Abdominal ultrasound was performed and no abnormality
*Harry G Kennedy, BSc, MD, FRCPI, FRCPsych, Clinical                     was detected. Venlafaxine was changed to citalopram after
Director, Central Mental Hospital, Dundrum, Dublin 14, and               four weeks (ie. eight weeks after commencing clozapine) due
Clinical Senior Lecturer, Academic Department of Psychiatry,             to continued low mood and hypertension. Diastolic blood
Trinity College Dublin, Ireland.                                         pressure continued above 95mmHg much of the time despite
*Correspondence                                                          anti-hypertensive treatment. There did not seem to be a
                                                                         significant improvement of his negative symptoms during the

                                                                                                                                     Ir J Psy ch Med 2003; 20(4): 132-1 34

    Table 1: Published cases of pseudophaeochromocytoma associated with clozapine treatment

           Case no    Clozapine dose     Duration of    Duration of       Concurrent                Heart rate                Blood pressure                           Urinary VMA
                        before VMA        treatment      clozapine        medications                 during
                       measurement      before onset    treatment                                    elevated
                                                                                                                   Before          During          After      During                  Stopping
                                         of elevated     (months)                                    pressure     clozapine      clozapine      treatment   clozapine                treatment
                                       blood pressure                                                            treatment       treatment                  treatment

Krentz         1           400             7 days           2           Fluoxetine 20mg                110          n/a          170/120           n/a      Elevated           VMA within limits
et al       (27, M)

              2            700              n/a             12           Bendrofluazide                104          n/a          143/112          n/a       Elevated           VMA within limits
            (28, F)                                                       2.5mg daily                                                                                           after treatment

              3            900              n/a             18        Sulpiride 600mg daily            130          n/a          156/100           n/a      Elevated             Clozapine not
           (38, M)                                                     Venlafaxine 150mg                                                                                            stopped
                                                                      Metformin 500mg b.d

               4           600              n/a             3           Sulpiride 200mg                n/a        120/80         180/120           n/a      Elevated             Clozapine not
            (22, M)                                                     Paroxetine 50mg                                                                                             stopped

Lie            5           300              n/a             2         Propanolol 10mg t.d.s            n/a        110/70         146/106         110/70     Elevated           VMA within limits
et al       (27, M)                                                      Amlodipine 5mg                                                                                         after treatment

Kennedy,       6           300             5 days           3          Lofepramine 210mg               100        130/90          150/100        120/70     Elevated              6 weeks after
Prasad      (44, M)                                                    Venlafaxine 225mg                                      Systolic range                                   stopping clozapine
                                                                        Citalopram 20mg                                         (170-140)                                       VMA within limits
                                                                         Amlodipine 5mg                                       Diastolic range

         period of being treated with clozapine up to 300mg/day and                                  24 hour urinary catecholamine concentration fell to within
         the blood pressure remained elevated. As a result clozapine                                 normal limits after the clozapine was stopped and the blood
         was tapered down and stopped after 13 weeks of treatment.                                   pressure also normalised in each case Clozapine was not
           Zuclopenthixol depot was recommenced at 200mg weekly.                                     stopped for cases three and four. In case four the blood pres-
         Six weeks after stopping treatment another 24-urine cate-                                   sure settled spontaneously.
         cholamine collection was done, which yielded urinary
         noradrenaline at 388nmol/24, which was within normal limits.                                Discussion
         The patient was still on amlodipine 5mg and citalopram                                         Clozapine, a tricyclic dibenzodiazepine has often been
         20mg. A 24-Holter blood pressure monitor done eight weeks                                   described as a ‘dirty drug’ because of its extensive range of
         after stopping clozapine treatment showed blood pressure                                    receptor affinities which are alpha adrenergic, dopaminergic,
         within normal limits and the cardiology team were in favour of                              histaminergic, muscarinic and serotonergic.7
         discontinuation of antihypertensive medications. Amlodipine                                    It has been reported that 4% of patients on clozapine
         was stopped and his recorded blood pressure has been                                        develop hypertension.4 Hypertension may be due to blockade
         within limits since then (120-130 systolic, 70-80 diastolic).                               of alpha-2-adrenoceptors.8,10,11 Several studies have reported
                                                                                                     an increase in plasma noradrenaline levels on clozapine treat-
         Literature review                                                                           ment.3,4,11,12 Breir et al 11 compared clozapine to haloperidol
            We searched Medline, PsychLit and hand searched                                          and fluphenazine and found that clozapine patients had
         published references, using key words, ‘clozapine’, ‘hyper-                                 plasma noradrenaline levels almost five fold greater than
         tension’ and ‘phaeochromocytoma’ and combinations of                                        those on fluphenazine or haloperidol. However they found no
         these. We also contacted the Clozapine Patient Monitoring                                   significant changes in the blood pressure or heart rate. Elman
         Service.                                                                                    et al 12 reported that clozapine treated patients had three
            The cases found consisted of five males and one female.                                  times the level of plasma noradrenaline compared to those
         Their ages ranged from 27-44 years. The dose of clozapine                                   treated with fluphenazine or placebo. It appears that some
         treatment before urine VMA measurement ranged from                                          elevation of circulating noradrenaline levels is a normal part
         300mg-900mg/24 hours. The duration of treatment was                                         of the action of clozapine.
         between two to 18 months.                                                                      Increased plasma noradrenaline has been hypothesised as
            Four patients out of the six were treated concurrently with                              underlying clozapine’s beneficial effects.11 However in this
         anti-depressant medications. Cases one and four were both                                   particular case the increase in plasma noradrenaline did not
         treated with serotonin specific reuptake inhibitors (SSRI).                                 cause a significant improvement in negative symptoms and
         Case three was treated with venlafaxine and case six was                                    clinically there was no significant improvement in symptoms
         initially treated with lofepramine, than changed to venlafaxine                             on clozapine compared to other antipsychotics. However only
         and then to a SSRI. Cases three and four were concurrently                                  300mg of clozapine was used, and for only three months. Lii
         on sulpiride treatment. Three patients were treated with anti-                              et al,9 reported a maximum dose of 300mg of clozapine for
         hypertensive medication to control their blood pressure.                                    10 weeks and also found that there was no improvement in
            Clozapine was stopped in four out of the six patients. The                               mental state though though the pseudophaeochromocytoma

                                                                                                         Ir J Psy ch Med 2003; 20(4): 132-1 34

syndrome emerged with high plasma noradrenaline. These                  with treatment resistant schizophrenia are often confined to
cases suggest that the elevation of plasma noradrenaline is             secure psychiatric units. They have a severely restricted qual-
not sufficient for the therapeutic effect of clozapine                  ity of life and are at risk of suicide. Hypertension however can
   Various mechanisms for raised plasma noradrenaline levels            lead to stroke, multi-infarct dementia, cardiac failure and fail-
with clozapine treatment have been put forward such as                  ure of other organ systems. In some patients reported in the
clozapine blocking the reuptake of noradrenaline at nerve               literature the hypertension was easily controlled with appro-
terminals,11 alpha-2-adrenoceptor blockade,4,11 and also the            priate medication. We suggest that in most patients
combination of both the above which would also cause a rise             appropriately selected, the benefits of clozapine therapy
in blood pressure.11 Sulpiride is known to block alpha-2-               outweigh the high blood pressure, provided that the hyper-
adrenoceptors, and an acute hypertensive episode has been               tension is adequately controlled with anti-hypertensives. For
described with its use.10 Perhaps as stated by Krentz et al8            the future, it may be appropriate to routinely collect data on
this may have contributed to the clinical features in cases two         blood pressure and plasma noradrenaline levels to monitor
and four (see Table 1) .                                                for any other unforeseen consequences of high circulating
   Elman et al 12 found that the elevated circulating noradren-         noradrenaline levels.
aline level was entirely accounted for by spill over from the
central nervous system into the blood stream. Their findings            Declaration of interest: None.
did not support a decreased neuronal reuptake mechanism.
They proposed that clozapine’s action might result in                   1. Kane J, Honigfeld G, Singer J, Meltzer. Clozapine for the treatment-resistant schizophrenic:
increased fusion of noradrenaline storage vesicles with the             a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789-796
                                                                        2. Maudsley prescribing guidelines, 2001
axonal membrane.                                                        3. Breier A. Clozapine and Noradrengic function: Support for a novel hypothesis for superior
   We conclude that in our patient, pseudophaeochromocy-                efficacy. J Clin Psychiatry 1994; 55: 122-125
                                                                        4. Shiwach RS. Treatment of clozapine induced hypertension and possible mechanisms. Clin
toma syndrome resulted from the initiation of clozapine                 Neuropharmacology 1998; 21: 139-140
                                                                        5. Walther MM, Keiser HR, Linehan WM. Pheochromocytoma: evaluation, diagnosis and
therapy. Clozapine causes an elevation of plasma noradren-              treatment. World J Urology 1999; Feb; 17(1): 35-9
aline compared to other antipsychotics. This does not appear            6. George TP, Winter LC. Hypertension after initiation of clozapine. Am J Psychiatry 1996; 153:
to be related to its therapeutic effect.                                7. Gupta S. Paradoxical hypertension associated with clozapine. Am J Psychiatry 1994; 151:
   It appears that raised serum noradrenaline levels are                148
                                                                        8. Krentz AJ, Mikhail S, Cantrell P, Hill GM. Pseudophaeochromocytoma syndrome associated
common or normal in patients on clozapine.11,12 Hypertension            with clozapine. BMJ 2001; 322: 1213
                                                                        9. Li JKY, Yeung VTF, Leung CM et al. Clozapine a mimicry of phaeochromocytoma. Aust NZ
is also common. It is likely that pseudophaeochromocytoma               J Psychiatry 1997; 31: 889-91
with hypertension and tachycardia is a common, possibly                 10. Mayer RD, Montgomery SA. Acute hypertensive episode induced by sulpiride-a case
                                                                        report. Human Psychopharmacology 1989; 4: 149-50
transient side effect of clozapine therapy. Hypertension is             11. Breier A, Buchanan RW, Waltrip RW et al. The effect of clozapine on plasma
however a serious side effect. The clinical decision to be              norepinephrine: relationship to clinical efficacy. 1994; 10:1-7
                                                                        12. Elman I, Goldstein DS, Eisenhofer G et al. Mechanism of peripheral noradrenergic
made concerns the balancing of risks and benefits. Patients             stimulation by clozapine. Neuropsychopharmacology 1999; 20: 29-34

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