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Clozapine Re-challenge after Initial Failure due to Hyperthermia in a Patient with Gilbert's Syndrome, Empty Sella Syndrome, and Chronic Liver Function Elevations.

Steven W. Powell, M.D.

Donald West, M.D.
Idiopathic unconjugated hyper-bilirubinemia, Gilbert's Syndrome, is known to be associated with schizophrenia. In 1999, Miyaoka and colleagues (1) described three case reports of schizophrenia-associated Gilbert's syndrome. Gilbert's syndrome is a benign hyperbilirubinemia that is found in the general population. In 2000, Miyaoka and colleagues were able to demonstrate the frequency of Gilbert's syndrome in schizophrenic patients relative to patients with other psychiatric disorders. Plasma bilirubin concen-trations, ICD-10 criteria, and the Positive and Negative Syndrome Scale (PANSS) showed a significantly higher incidence of hyperbilirubinemia (p<0.5) in schizophrenic patients. Additionally, schizophrenia patients with hyper-bilirubinemia demonstrated significantly higher positive and negative subscales on the PANSS (p<.0001), reflecting a possible association of hyper-bilirubinemia and psychosis. Molina, Villanueva, and Molina (3) additionally described a case report associating hyperbilirubinemia and psychosis.
Miyaoka and colleagues (4) using proton magnetic resonance spectroscopy (1H-MRS) demonstrated a decrease in the hippocampus of N-acetyl aspartate/creatine - phosphocreatinine (Naa/Cr) and myoinositol/creatine-phosphocreatinine (ml/Cr) ratios. In the basal ganglia, ml/Cr and NAA/Cr ratios were additionally decreased when compared with non-Gilbert's syndrome schizophrenic patients and healthy individuals respectively. The vermis also demonstrated a significant decrease in the ml/Cr ratio compared to healthy individuals. A conclusion was reached suggesting schizophrenia with Gilbert's syndrome is a more severe sub-type of schizophrenia in regard to brain metabolism. Miyaoka (5) additionally noted changes in signal intensities on FLAIR Magnetic resonance imaging suggesting fronto-temporal cortex, limbic system, and basal ganglia changes in schizophrenic patients with Gilbert's syndrome.
Empty Sella Syndrome or Partial Empty Sella Syndrome has been discussed only a few times in the literature in association with schizophrenia. Galderisi et al (6) and Mueler et al (7) used this as a determinate in studying MRI findings in schizophrenic patients in separate studies. Empty sella is described as a decreased volume of the hypophysis and relative increase of subarachnoid space of the sella turcica. Pituitary function is usually normal with the hormone prolactin mildly elevated in 10-15 % of patients. Temperature variations and dysregulation have been reported for those with empty sella syndrome with chronobiological studies (8) having noted aberrations in circadian rhythm patterns and temperature variations. Additionally, growth hormone, thyroid, gonadotropin, and corticotropin levels can be affected.
Fever associated with clozapine administration is reported as a relatively common phenomenon occurring in 5-55% (9) of patients, usually occurring in the initial phase of treatment. Rates are thought to vary so widely due to what is chosen as the definition of fever. Multiple etiologies have been suggested including NMS without extrapyramidal symptoms, allergic reaction, poly-serositis possibly due to tumor necrosis factor or soluble interleukin -2 receptors (10), a respiratory/gastrointestinal infection (11,12), or a benign condition (13). In the majority of patients without neutropenia, the fever resolved and patients were able to resume treatment with clozapine without further febrile episodes attributed to the medication (10-14). The occurrence of fever alone without associated extrapyramidal symptoms suggesting NMS or without neutropenia is not considered an indication for stopping clozapine. Even with leucopenia or neutropenia, re-challenge may be justified if the benefit warrants the risk, though the possibility of further blood dyscrasia is significant. (15)

Case Presentation

Mr. L, a 26-year-old single, childless, unemployed male, was initially referred to our medical center after developing hyperthermia, elevated liver function tests, and leukopenia related to initiation of clozapine for treatment of refractory schizophrenia. Mr. L. had an extensive history of drug use starting at age 17 and ending at age 23. His use included cannabis, LSD and ecstasy, the latter on a weekly basis a significant portion of the time. Mr. L initially experienced seeing auras around people at age 20. Risperidone was prescribed by an outpatient psychiatrist and symptoms resolved. He had his first psychotic break at age 22, requiring a one-month hospitalization. He was experiencing increasing delusional thoughts focusing on pacts with the devil, suicidality, and death. He was initially treated with risperidone, which was changed to ziprasidone because of elevated liver function tests. During that hospitalization he was diagnosed with Gilbert's Disease and Empty Sella Syndrome. He continued to have psychotic symptoms after discharge; listening to the devil, who he felt spoke to him. This was followed by two brief admissions associated with three suicide attempts; one by hanging and two by cutting his wrists, each accompanied by suicide notes. He had also been violent with family members including throwing chairs at family members resulting in one admission. An additional admission resulted when he pulled knife on his father during an argument regarding whether he and his brother should be allowed to take drugs. During these hospitalizations he was treated with ziprasidone and quitiapine and remained on ziprasidone while being followed as an outpatient. There were no further admissions until four years later and his condition as reported by his mother was “stable, but guarded”
Approximately a year before he was seen at our facility, he had a gradual decline in mood and motivation. Psychotic thinking became more severe including thought broadcasting. He gradually became more depressed and suicidal and required admission to a psychiatric unit near his home. He was treated for several days, discharged, and subsequently returned to the emergency department with his parents two hours later. He was refusing to eat (to prepare to die); was convinced that he was influencing everyone around him and that he did not have a separate existence. He believed that the only way he could help everyone around him was by eliminating himself and felt that he was responsible for the war in Iraq. He expressed feelings of hopelessness and utter despair and demonstrated minimal insight. His affect was flat. He was, however, willing to accept medications. Initial medications included risperidone, quitiapine., and sertraline. In the past, he had been given haloperidol once during an Emergency Department visit and improved. Haloperidol decanoate was added, based on this information. However he continuing with demonic delusions and the desire to die, so risperidone, quitiapine, and haloperidol were tapered off. Sertraline was continued and clozapine was started. Clozapine was increased at a rate of 50mg every one to two days to a total dose of 300mg daily in 8 days. Fever was documented on day 8 beginning at 101.8 escalating to 104.3 He was given acetaminophen, ibuprofen, and cold packs but remained febrile and a medical consult was obtained. His only symptoms were a slight headache and refusal to eat. HIV status was evaluated and an abdominal ultrasound and chest x-ray were performed to rule out an occult abscess; all were within normal limits. Hepatic function noted an elevated total bilirubin to 1.3: direct bilirubin elevated to 0.37: AST was 92 and ALT 124. This was a significant increase over admission labs. AST rose to 218 and ALT became 133 within one day. His WBC dropped from 7.0 to 3.6 with bandemia, eosinophilia, and an elevated sedimentation rate of 45. Pt. was transferred to the ICU. All medications were held other than Motrin and IV hydration was begun. No evidence of EPS or muscle rigidity was noted. Blood cultures were negative. His delusional state and suicidal ideation remained and his fever remained without nocturnal or diurnal variations. After 48 hours, fevers remained spiking to 103.2, and LFT elevation continued.
At this point, on the fifth day of fever, pt was transferred to our tertiary center at parental request. He was admitted to the ICU where his fever subsequently resolved and his transaminitis remained mild. Pt. was transferred to the psychiatry service with auditory hallucinations, suicidality, and feeling as though he could predict the future.
During this hospitalization, it was felt that depressive symptoms were primary and venlafaxine was begun. Additionally, aripiprazole was started to target his psychotic symptoms and to stabilize his mood. ECT was eventually begun, with improvement noted after the 3rd treatment. After a 6-week stay, the patient was discharged improved with suicidal ideation resolved. At the time of discharge, venlafaxine was at 112.5 mg daily, aripiprazole 15mg daily and trazodone 200mg each night.
Outpatient ECT treatments were scheduled for a total of 9 treatments. Pt. received three outpatient ECT treatments, but was noted at his third ECT to be swearing at fellow patients. He was paranoid, experiencing auditory hallucinations, and repeating the word "power” and was readmitted. During this admission, ECT continued for four treatments with discharge after eleven days. He remained on venlafaxine, trazodone, and with an increase in ziprazidone.
He returned 7 days later requiring admission for waxy catatonia in addition to severe disorganization, and delusions focusing on the Iraq war. During this hospitalization, aripiprazole was discontinued and olanzapine was begun, lorazepam was added every 4-6 hours as needed, venlafaxine was increased, and two additional ECT's were performed. Pt discharged in 9 days with plans for three additional outpatient ECT treatments.
Mr. L returned eight days later with worsening psychosis. Consideration of restarting clozapine was discussed, but patient and family choose not to do this. He was discharged five days later without changes made in his medication regimen. He was hospitalized in another state four months later for a two-day stay, having gone to two residential programs with some reduction in symptoms and increase in function. After another four months of increased functioning and reduced symptoms, he again required admission to our facility after a failed attempt to hang himself. On admission he was taking lorazepam, Depakote, ziprasidone, olanzapine, and venlafaxine. It was noted that his liver function tests were again elevated, as was his ammonia level. Depakote was stopped, bupropion was started, and ziprasidone was increased. An increased prolactin level was noted consistent with his previous diagnosis of empty sella syndrome. Mr. L was discharged nine days later to a post-hospitalization residential program.
His next hospitalization at our facility occurred 6 month later after “doing well” for several months, but requiring two brief hospitalizations at other facilities in the interim. He had experienced the acute onset of depression with refusal to get out of bed. He reported attempting to hang himself with his belt in a closet twice. He reported that “the number 29”on TV was sending a message and that he could “suck the energy out of people” on the television he was watching during a bowl game. Daily medications were: olanzapine, ziprasidone, lorazepam, venlafaxine, and Depakote at a therapeutic level. He had an increase in transaminase levels (AST-180, ALT- 459) and an ammonia level of 72. Depakote was stopped, but transaminase levels continued to rise and ammonia decreased slightly.
His delusional symptoms resolved over a nine-day stay, but his self –esteem remained low. He was discharged with his LFT’s to be followed by his primary care physician. A discussion was held with patient and his parents regarding a possible re-challenge with clozapine if his psychotic symptoms returned.
Mr. L returned for care three months later with increased paranoia and psychosis. He was experiencing demons circling him and had constrained movements attempting to avoid contact with these demons. At this time, Mr. L. was presented and discussed in a departmental forum, with the decision reached to restart clozapine due to the refractoriness to all other medications at this point. It was noted in the case discussion that pt. has Gilbert's and Empty Sella syndrome, both of which have been correlated with schizophrenia, with Gilbert's being correlated to a severe subtype of schizophrenia. The patient and his family were in agreement with the re-challenge.
Ziprasidone was discontinued and clozapine was started at 12.5 mg for three days, increased by 12.5mg for the next three days, and then every fourth dose for four weeks, and then every third dose for eleven days until 300mg daily was reached. This process occurred during a hospitalization of nearly 7 weeks. This slow titration prevented reoccurrence of persistent fever, an increase in liver function tests, or other side effects. Mr. L did experience a low-grade fever of 99-101 on days three though seven of initial clozapine re-challenge and again during the 5th week. The first fever abated without difficulty and appears to have been from the re-challenge, with the second fever quite possibly attributable to a respiratory infection that had cleared, along with the fever, upon discharge. Pt. was placed on 5-day azithromycin regimen during week one and again during week 5 both for a mild cough and possible respiratory infections, which had completely resolved prior to discharge. The hospital was in the midst of a whooping cough outbreak during the patient's fever and elevated WBC's during the fifth week. Cardiac markers including CPK and Troponin I were monitored every other day along with LFT's and CBC also every other day. LFT's were noted to be elevated as they had in the past in addition to elevated bilirubin. LFT's slowly trended down continually as olanzapine was decreased incrementally. No increase in CPK, or cardiac markers was ever noted. WBC remained stable, other than some minimal elevation noted during the 5th week during the respiratory infection.
As clozapine increased, pt became more verbal and interactive. He related that the demons continued to be present but were in the background and he did not feel the need to interact with them. Olanzapine was decreased by 5mg every other day as clozapine was increased, but had to be restarted after being discontinued after the third week secondary to increased suicidal ideation and fears of demons. Olanzapine was reduced once again but remained at 5mg each night upon discharge. Lorazepam was also reduced from 1mg three times daily eventually to 0.5mg twice daily upon discharge. Pt. stabilized, and was able to be discharged contracting for safety and has, to date, remained free from inpatient hospitalization and is reported by his parents and out patient psychiatrist to be the “best he has been in years.”


In this case conference, we described a schizophrenic patient refractory to multiple medication and treatment regimens. Initial Clozapine challenge was unsuccessful and resulted in white blood cell, temperature, and liver abnormalities. A re-challenge was undertaken and continued despite two fever spikes. A taper over 45 days was designed to allow for a slow taper as pt. had failed Clozapine initially on a fast taper.
Of note was the co-existence of possible confounding medical conditions that could lead to temperature dysregulation and severe psychosis along with difficulties in monitoring liver enzymes. Scant evidence was found in the literature to provide guidance for a re-challenge with these variables. Literature support, though, widespread for clozapine re-challenge (15), gave little support to guide re-challenge through recurring fevers. It is known that during Clozaril therapy, patients may experience transient temperature elevations above 100.4°F (38°C), with the peak incidence usually within the first 3 weeks of treatment. The development of NMS must be closely monitored, particularly in the light of continuing treatment despite moderate fever. It is for these reasons that LFT's, CPK, CBC, and cardiac labs were drawn every other day as well as vital sign monitoring every four hours.
Gilbert's syndrome did not appear to be detrimental during the re-challenge. His bilirubin levels remained within normal limits other than an isolated bilirubin elevation during the initial re-challenge. His liver enzymes remained elevated throughout treatment, with levels paralleling his dosage of Olanzepine. It is felt that these elevations were due solely to Olanzepine as Gilbert's syndrome is associated with unconjugated hyperbilirubinemia and not AST or ALT elevations. Additionally his Gilbert's syndrome may have predisposed him to a more severe subtype of schizophrenia thus making him less responsive to other treatments.
Empty Sella Syndrome likewise did not pose difficulties in the re-challenge. Prolactin was elevated at 28.6 ng/dl and Human Growth Hormone was quite low at <0.1ng/ml. Additionally Free T4 was 0.75ng/dl and Testosterone levels were low at 183ng/dl, but the free percentage testosterone was within normal limits at 2.44% as was the free testosterone at 44.7pg/ml. Temperature dysregulation did not present as a variable with the two elevations likely from the initial re-challenge and respiratory infections.
The degree of psychosis suffered by the patient was multifactorial with numerous co-variables that could have contributed to his degree of schizophrenia. Included in these are Gilbert's syndrome and his extensive use of illegal substances. Mr. L used large amounts of cannabis, LSD, and amphetamines all of which are known to cause a disturbance in the brain which can trigger a first psychotic episodes. Also abused was Ketamine which has been noted to cause prefrontal metabolic changes that are correlated with schizophrenia-related symptoms. Additionally Mr. L abused alcohol and tobacco in the form of cigarettes.
Close monitoring of liver enzymes, complete blood counts, and cardiac markers must be adhered to in addition to strict monitoring of vital signs, particularly temperature variations. Re-challenge guidelines and treatment parameters must also be adhered to particularly regarding white blood cell and absolute neutrophil counts. With these guidelines, successful re-challenge for refractory patients is possible with time; quality nursing; and patient, family, and physician patience.


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2. Miyaoka T, Seno H, Itoga M, Iijima M, Inagaki T, Horiguchi J: Schizophrenia-associated idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome). J Clin Psychiatry. 2000 Nov;61(11):868-71.

3. Molina Ramos R, Villanueva Curto S, Molina Ramos JM: Gilbert's syndrome and schizophrenia. Actas Esp Psiquiatr. 2006 May-Jun;34(3):206-8.

4. Yasukawa R, Miyaoka T, Mizuno S, Inagaki T, Horiguchi J, Oda K, Kitagaki H: Proton magnetic resonance spectroscopy of the anterior cingulate gyrus, insular cortex and thalamus in schizophrenia associated with idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome). J Psychiatry Neurosci. 2005 Nov;30(6):416-22.

5. Miyaoka T, Yasukawa R, Mihara T, Mizuno S, Yasuda H, Sukegawa T, Hayashida M, Inagaki T, Horiguchi J: Fluid-attenuated inversion-recovery MR imaging in schizophrenia-associated with idiopathic unconjugated hyper-bilirubinemia (Gilbert's syndrome). Eur Psychiatry. 2005 Jun;20(4):327- 31.
6. Silvana Galderisi, Antonio Vita, Alessandro Rossi, Paolo Stratta, Marco Leonardi, Mario Maj, Giordano Invernizzi: Qualitative MRI findings in patients with schizophrenia: a controlled study. Psychiatry Research. Neuro-imaging, 10 April 2000, Pages 117-126.

7. Mueller C, Rufer M, Moergeli H, Bridler R: Brain imaging in psychiatry – a study of 435 psychiatric in-patients at a university clinic. Acta Psychiatrica Scandinavica, Volume 114 Page 91 - August 2006

8. Ferrari E, Bossolo PA, Baldi F, Daguati M, Fioravanti M, Farcara S: Chronobiological study of pituitary adenomas and of the empty sella syndrome. Chronobiologia, 1982 Apr-Jun;9(2):241-8.

9. Juul Povlsen u, Noring U, Fog R, Gerlach J: tolerability and therapeutic effect of clozapine; a retrospective investigation of 216 patients treated with clozapine for up to 12 years. Acta Psychiatr. Scand. 1985; 71:176-185.

10. Jeong SH, Ahn YM, Koo YJ, Kim YS The characteristics of clozapine fever. Schizophrenia Research 2002 56(1-2): 191-193.

11. Druss BG, Mazure CM Transient fever and hematologic abnormalities during clozapine use. J. Clin. Psych-opharmacology 13:2 155-56. 1993.

12. Tremeau F, Clark CC, Printz d, Kegeles LS Malaspina D. Spiking Fevers with clozapine treatment. Clinical Neuropharmacology 1197: 20(2): 168-171.

13. Tham JC, Dickson, RA Clozapine-induced fevers and 1-year clozapine discontinuation rate. J. Clin. Psychiatry. 2002 (Oct) (10):880-84.

14. Nitenson NC, Kando JC, Frankenbeg FR, Zanarini MC. Fever associated with clozapine administration. Am. J. Psychiatry 152:7 1102. 1995.

15. Dunk LR, Annan LI, Andrews CD Re-challenge with clozapine following leucopenia or neutropenia during previous therapy. BR. J. Psychiatry 2006 Mar; 188:255-63.

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Copyright Priory Lodge Education Limited 2008

First Publishd April 2008

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