Ugeskr Laeger. 1996 Nov 25;158(48):6931-2.

[Serious drug interaction between clozapine-Leponex and fluvoxamine-Fevarin].

[Article in Danish]

Olesen OV1, Starup G, Linnet K.

Author information

• 1Afdeling for biologisk psykiatri, Psykiatrisk Hospital i Arhus.

Abstract

A 67 year-old woman in steady-state treatment with clozapine 150 mg/24 h was co-medicated with 100 mg/24 h of fluvoxamine. During the next months the patient suffered from nausea and occasionally vomited, but these symptoms were ascribed to fluvoxamine, and as she mentally improved, both treatments were continued. Two months after the start of fluvoxamine her serum clozapine concentration was 7570 nmol/l or 7.5 fold higher than before fluvoxamine was added. The woman was admitted to hospital, suffering from abdominal pain, dehydration and fever (38.5 degrees C). Serum creatinine concentration was increased, but normalized during hydration. After 18 days care the woman felt well and was discharged from hospital. The case report shows that certain combinations of selective serotonin reuptake inhibitors and neuroleptic drugs should either be avoided or the serum concentrations of the drugs closely followed.

Prog Neuropsychopharmacol Biol Psychiatry. 2006 Sep 30;30(7):1277-82. Epub 2006 Jun 23. Serum creatine kinase levels in chronic psychosis patients--a comparison between atypical and conventional antipsychotics. Melkersson K. Author information

• Department of Molecular Medicine and Surgery, Karolinska Institute, c/o Sollentuna Psychiatric Polyclinic, Nytorpsvägen, 10 SE-191 35 Sollentuna, Sweden. [email protected]

Abstract

.. this study compared serum creatine kinase levels in chronic psychosis patients treated with either atypical or conventional antipsychotics. Forty-nine patients, receiving clozapine (n=18), or olanzapine (n=18), or conventional agents (n=13), were studied. Fasting serum samples were analyzed for creatine kinase. A significant difference in median creatine kinase level was found among the treatment groups (p=0.03), in that the creatine kinase level was higher both in the patients receiving clozapine and in the patients receiving olanzapine, compared to that in patients receiving conventional antipsychotics, p=0.001 and p

So it looks that my patient might be yet another case like from the second paper. I am considering discontinuation of clozapine, but it will be difficult due to complex psychopathology and prevoius unresponsiveness to other drugs. Thanks for help.

Okey, but it makes a good case report. Let me read it then:)

Best wishes

Béatrice

just to clarify: how long is the patient taking clozapine, is the dose stable and for how long? What about other lab workup? Have you look at the imunology? (a lot of imunological disorders can lead to elevated levels of CPK and in the early stages patients are asymptomatic). Let me know what happened.Best wishes, Olga  

Clozapine has been stable for three months although changing the dose from 100 to 150 led to a huge increase of CK and changing to 100 again to decrease. The CK is definitely associated with clozapine dose, strange thing is that the levels of CK are extremely high. Patient will have EMG Monday and then muscle biopsy, will see. 

The first thing what you need to consider is myocarditis or pericarditis. The dose is not very high, therefore a couple parameters you need to check:

eosinophilia, CRP is more sensitive than Troponin ,ECG

when it is pericarditis echocardiography needs to be arranged

CRP is low, no changes in ECG, troponin was not made but no indications. Do you think echo should still be done?

Yes, and also troponin should be assessed

Very High CPK could be found in Polymyositis. Dermatopolymyositis, Muscular Dystrophies etc. Is there  weakness and muscle wasting as well? Without high fever, rigidity, autonomic instability unlikely to be NMS. I recently had a patient with similar presentation who had weakness in lower limbs but very high CPK

EMG should be helpful

We have done EMG. Unfortunately, no explanation by this. Changes are uncharacteristic, EMG-specialist suggested biopsy which patient declined. Clinically, still no particular symptoms. After clozapine dose adjustment (now 75 mg/day) CPK levels acceptable (less than 150). 

how long was cpk raised? was there any muscle weakness? myoglobinuria? elevation of troponin

no symptoms at all. no myoglobinuria. no troponin elevation. CPK raises timely related to small dose adjustments of clozapine

 An interesting paper:

Extensive elevation of creatine kinase with generic clozapine, but not with Leponex.

Schennach-Wolff, Rebecca; Stübner, Susanne; Riedel, Michael ; Müller, Norbert. Psychiatry Research 176.1 (Mar 30, 2010): 93. .....

Conclusion: If CK elevation is observed during clinical monitoring in treatment with generic clozapine, switching to Leponex treatment might be a satisfactory choice.

Another paper:

 " It’s a typical case of clozapine toxicity" This email: [email protected] belongs to dr Sandip Anand, who wrote the paper. I guess he could give additional input in this case.

So what is your conclusion now?

Clinically exaggerated reaction to clozapine (toxicity). Blood sample is now at genetics department for possible genetic background of this feature. Biopsy not done, patient withdrew consent. 

usually CPK up to 20,000 IU/L may be tolerated, 40K is too much, may consider underlying unknown medicall illness, drugs, genetic background. However, it appears to me as possible idiosyncratic increase.

Consider atypical neuroleptic malignant syndrome

mostly related to clozapine.Unable to state when this might happen

We have finally diagnosed an atypical neuroleptic malignant syndrome. No clue, why this particular patient reacted that strangely. 

What made you conclude this? Here is a case linked to valproate:

BMJ Case Rep. 2014 Mar 6;2014. pii: bcr2013202578. An atypical case of neuroleptic malignant syndrome precipitated by valproate.

Verma R, Junewar V, Rathaur BP.

Abstract

Neuroleptic malignant syndrome (NMS) can be caused by various drugs. We report a case of a 60-year-old woman who presented with high-grade fever, muscular rigidity, tachycardia, tachypnoea and altered sensorium along with seizures. She had been taking olanzapine for the past 2 years for psychosis. For the last month valproate was added to her treatment. Her blood investigations revealed hyponatraemia and raised serum ammonia and creatinine phosphokinase (CPK) levels. In view of hyperthermia, muscular rigidity, autonomic disturbances, altered mental status and raised CPK, a diagnosis of NMS was made. Valproate could have probably precipitated NMS; although the patient was taking antipsychotics for a long time, it was only with the addition of valproate that she developed these symptoms. Raised serum ammonia levels also indicated the presence of valproate toxicity. Seizures were probably due to electrolyte disturbances. Offending drugs were withdrawn. The patient improved with treatment by dopamine agonist and other supportive treatments.

It is worth considering the possibility of exercise. There are several papers reporting extremely high CK levels after surprisingly little exercise. For example a study of 203 people who performed 25 x flexor contractions of the elbow resulted in CK levels above 10 000 in 25% and some as high as 80 000 (Clarkson et al 2006). All were assymptomatic and there were no renal or other adverse effects subsequently.

ABSTRACT

CLARKSON P. M., A. K. KEARNS, P. ROUZIER, R. RUBIN, and P. D. THOMPSON. Serum Creatine Kinase Levels and Renal

Function Measures in Exertional Muscle Damage.

Med. Sci. Sports Exerc.,Vol. 38, No. 4, pp. 623–627, 2006. Purpose: Serumcreatine kinase (CK) levels are commonly used to judge the severity of muscle damage and to determine when to hospitalize patients who

present with symptoms of exertional rhabdomyolysis in order to prevent renal failure. However, no CK standard exists because of the

limited information available regarding exercise-induced CK elevation and renal function. This study determined the magnitude of CK

elevation and the effect on renal function produced by exercise in a large subject group.

Methods: Blood samples were obtained from203 volunteers who performed 50 maximal eccentric contractions of the elbow flexor muscles. The samples, taken before and 4, 7, and 10 d

after exercise, were analyzed for markers of muscle damage (CK, myoglobin (Mb), lactate dehydrogenase, alanine aminotransferase, and

aspartate aminotransferase and for measures of renal function (creatinine, blood urea nitrogen, phosphorus, potassium, osmolality, and uric

acid).

Results: All indicators of muscle damage increased significantly after exercise (P G 0.01). CK levels were 6420, 2100, and 311%above baseline on days 4, 7, and 10 after the exercise, respectively (

P G 0.01), and Mb was 1137, 170, and 28% above baseline on days 4, 7,and 10 after exercise, respectively (

P G 0.01). Of the 203 participants, 111 had CK values at 4 d postexercise > 2,000 UILj1 and 51 hadvalues > 10,000 U

ILj1, levels used to diagnose myopathy (e.g., statin myositis) and rhabdomyolysis, respectively. There were no significantincreases in any measure of renal function. Despite marked CK and Mb elevations in some subjects, none experienced visible myoglobinuria

or required treatment for impaired renal function.

Conclusions: Exertional muscle damage produced by eccentric exercise in healthyindividuals can cause profound CK and Mb elevations without renal impairment.

Key Words: RHABDOMYOLYSIS, MYOGLOBINEMIA,KIDNEY, CREATININE, ECCENTRIC EXERCISE

Thanks for the paper abstract. That is really interesting. And quite possible with our patient :-) He is a devoted user of a stationary bike.

Catatonia is part of the differential of diagnosis of elevated cpk.

Is the patient assuming simultaneously any other therapy? e.g. cholesterol-lowering drugs?

Last week we had a case of a patient assuming 2,5 mg olanzapine to whom one of these compounds was added. After 10 days the CPK was over 16.000 and GOT >400 and GPT>300, CPK-mb was also high but the renal function, and electrolytes were good. Of course the patient complained of generalised muscle pain.

The discontinuation of the new drug and hydration have halved all the values on the second day, and pain the pain decreased from 10 to 6.5 on a VGF scale.

no statins. i am aware of this possibility, but not in this case