Psychopharmacology (2014) 231:4255–4270 DOI 10.1007/s00213-014-3764-2

REVIEW

Antipsychotic-induced elevation of creatine kinase: a systematic review of the literature and recommendations for the clinical practice Zacharias G. Laoutidis & Kanellos T. Kioulos

Received: 19 March 2014 / Accepted: 4 October 2014 / Published online: 16 October 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Rationale The primary antipsychotic-induced creatine kinase elevation (i.e., not due to neuroleptic malignant syndrome, extrapyramidal symptoms, etc.) is a poorly studied condition. Objectives The aims of the present study were to provide an overview of published cases with antipsychotic-induced creatine kinase elevation and give recommendations for the clinical practice. Methods PubMed and EMBASE were searched for eligible trials, case series, and case reports. We set a threshold at ten times the upper normal limit of the creatine kinase value in order to define an elevation as significant. Results The prevalence of significant creatine kinase elevation ranged between 2 and 7 %. We found a total of 42 eligible cases. Men were overrepresented in our sample (81 %). Patients with myoglobinuria were more likely to be symptomatic (Fisher’s exact test, p = 0.006), whereas neither myoglobinuria (Mann-Whitney test, p>0.10) nor symptoms (Mann-Whitney test, p=0.64) were related to the magnitude of the creatine kinase (CK) elevation. In the majority of the cases, the antipsychotic medication was discontinued (86 %). Forced diuresis was given in 36 % of the patients. Eighty-three percent of the patients had no further complications. Only one case was found with a de novo acute renal failure. Conclusions The discontinuation of the antipsychotic medication was a sufficient measure for the CK elevation to Z. G. Laoutidis (*) Department of Psychiatry and Psychotherapy, Medical Faculty of the Heinrich Heine University, Bergische Landstrasse 2, 40629 Düsseldorf, Germany e-mail: [email protected] K. T. Kioulos Eginition Hospital, 1st Department of Psychiatry, Medical Faculty, University of Athens, Vasilissis Sofias Avenue 72-74, 11528 Athens, Greece e-mail: [email protected]

subside in the majority of the cases. Cases with myoglobinuria should eventually be treated more aggressively. Further recommendations for the clinical practice are presented. Keywords Antipsychotics . Neuroleptics . Creatine kinase . Rhabdomyolysis

Introduction Since the first reports of the neuroleptic malignant syndrome (NMS), creatine kinase (CK) elevations in patients receiving antipsychotics have gained much attention among psychiatrists. As Adityanjee (1991) mentioned more than 20 years ago, there was a trend at that time to treat every CK elevation as a potential NMS. Today, this trend has clearly abated, not least because of the establishment of concrete diagnostic criteria for NMS in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; APA 1994). These criteria include both clinical manifestations (e.g., muscle rigidity and hyperthermia) and laboratory findings such as leucocytosis and CK elevation. The latter is common in NMS, however neither sufficient nor necessary for setting the diagnosis. A CK elevation may be indicative of severe muscle damage and be accompanied by pain, muscle weakness, and fatigue; however, it can also be asymptomatic and only be revealed coincidentally in routine laboratory tests. A symptomatic and marked CK elevation is defined as rhabdomyolysis. In the existing literature, the terms rhabdomyolysis and marked CK elevation are often used interchangeably without regard to accompanying symptoms or other laboratory findings. For example, rhabdomyolysis was defined in a study as a CK elevation greater than 520 IU/L, while other studies identify rhabdomyolysis with crush syndrome, a syndrome following severe muscle injury (Scharman and Troutman 2013).

4256

The exact pathophysiology of the antipsychotic-induced CK elevation is not known. A central action on dopamine receptors in the striatum may play a role (Deravajan and Dursun 2000). However, this theory does not seem to be applicable in second-generation antipsychotics (SGAs), which have a much lower affinity to D2 receptors compared to first-generation antipsychotics (FGAs). Meltzer (2000) proposed a peripheral action of drugs with 5-HT2A-antagonistic properties on serotonergic receptors of the muscles. Koren et al. (1998) reported a diminished calcium-dependent potassium efflux response in a patient with a CK elevation due to clozapine. However, this deficit remained after drug cessation. Mild non-specific abnormalities in muscle biopsies (Scelsa et al. 1996) may be indicative of direct toxic effects of antipsychotics on the sarcolemma. In order to elucidate several aspects of the antipsychotic-induced CK elevation, we decided to conduct a systematic review and present an overview of the existing literature.

Methods Search strategy We searched for studies, case series, and case reports in PubMed and EMBASE. We used several combinations of search terms like “CK, rhabdomyolysis, creatine kinase, creatine phosphokinase, and CPK” and “antipsychotic, neuroleptic, psychosis, psychotic, schizophrenia, schizophrenic, clozapine, quetiapine, olanzapine, risperidone, paliperidone, ziprasidone, aripiprazole, amisulpride, zotepine, sertindole, asenapine, haloperidol, droperidol, benperidol, bromperidol, melperone, pipamperone, butyrophenone, pimozide, fluspirilene, fluphenazine, perphenazine, mesoridazine, levomepromazine, thioridazine, perazine, prochlorperazine, trifluoperazine, chlorpromazine, triflupromazine, promazine, phenothiazine, chlorprothixene, zuclopenthixol, flupenthixol, thiothixene, thioxanthene, loxapine, molindone, and sulpiride.” Time limits were from 1 January 1960 until 31 December 2013. We further searched through the reference lists of reviews and relative articles to identify any additional reports. In order to distinguish between significant and not significant CK elevations, we set a threshold at ten times the upper normal limit of the CK value as cited in each report; this is in accordance with the definition of significant CK increase for statins (Harper and Jacobson 2007). When the article did not report the normal limits of the CK concentration, we used an arbitrary threshold of 2,000 IU/L. All cases with patients under 18 years old were excluded from consideration. We further excluded cases of intentional overdosing, first because our aim was to investigate the

Psychopharmacology (2014) 231:4255–4270

occurrence of CK elevations in everyday clinical practice and not under exceptional circumstances, and second because an overdose can lead to seizures and prolonged immobility, when the patient is unconscious; both situations can cause a CK elevation or rhabdomyolysis. Further, we rejected cases when an alternative cause for the CK elevation could clearly be identified that could better explain the CK elevation, for example patients with infections, compulsive drinking, and subsequent hyponatremia, hypothyroidism, muscle diseases, etc. We also excluded case reports if the effect of the drug was indirect, i.e., the CK elevation was mediated through another known adverse effect (seizures, hormonal disturbances, catatonia, extrapyramidal symptoms, etc). On the other hand, we included case reports in which the trigger was defined either as exercise or as a mechanical cause, such as injury. There are studies that show that the use of statins can facilitate an exercise-induced CK elevation (Thompson et al. 1997), which may also hold true for antipsychotics. Although the design of our study does not allow us to verify this assumption because of a missing comparison group, we wanted to see to what extent mechanical causes play a role in the elevation of CK. Similarly, we included cases in which antipsychotics were involved in pharmacokinetic interactions which were held responsible for the CK elevation. Article selection and review strategy The selection of the articles involved an initial screening of title and abstract in order to find reports which were appropriate according to the criteria stated above. If it was not clear from the title or the abstract that the study should be rejected, the full text was obtained. The process was conducted independently by two authors in order to reduce the possibility of rejecting relevant articles. The data were extracted independently by both authors. In case of disagreement, a clinician experienced in schizophrenia and psychopharmacology could be involved to mediate consensual decisions. A structured format was used for the data extraction; an example is presented in Appendix Table 6. This format contains three sections with several items each: demographics and general information, clinical symptoms and diagnostics, and treatment. A case qualified for the systematic review when information was available for at least one item in at least two of the three sections. Finally, the Naranjo algorithm (Naranjo et al. 1981) for the cause-effect relationship was applied for each case. Statistical analysis Categorical data were compared using the chi-square test. When indicated, Fisher’s exact test was used instead. For continuous data, non-parametric methods were used (Mann-Whitney test).

Psychopharmacology (2014) 231:4255–4270

Results Search results A total of 833 reports were identified in our search in PubMed and 1,928 in our search in EMBASE. The full text of 110 of them was retrieved for further analysis. Seventy-four of these were rejected and 36 reports with a total of 42 cases were included in the review. An overview of the cases is presented in Tables 1 and 2. Prevalence We found four studies that estimated the prevalence of the antipsychotic-induced CK elevation (Table 3). Terao et al. (1999) showed in a prospective study that 16 of 32 patients had CK values above the upper limit of the normal range (0.10). In 23 cases, at least one of the transaminases was found to be elevated. In seven cases, WBC was also high. ECG was conducted in eight cases; in one case, unspecific T-wave changes were found, and in another, bradycardia was diagnosed. The ECG was normal in the other cases. An electromyogram (EMG) was performed in four cases and a myopathic pattern was identified in one of the cases. Treatment In 36 of the 42 cases, the antipsychotic medication was discontinued. Nine cases were then rechallenged with the same medication; in three of these, a significant CK increase

M

M

100

1994 300

M

1995 600

Kirson et al.

Keshevan et al.

M

Meltzer et al. 1996 NR

F

100

M

M

M

2009 500

2000 550

M

2010 50

1998 NR

Koren et al.

Reznik et al.

SchennachWolff et al. Tseng and Hwang

Clozapine

M

Wu and Chang

2011 15

F

M

22

21

42

36

21

42

47

29

27

31

87

25

Dose Sex Age (mg/day) (years)

2010 200

Year

Marzetti et al. 2012 15 mg qd

Aripiprazole

Ursini et al.

Amisulpride

Author

Schizophrenia

Schizophrenia

Schizophrenia

NR

Schizophrenia

Schizophrenia

Schizophrenia

Schizoaffective disorder

Schizophrenia

Schizophrenia

Bipolar disorder

GAD Dysthymia

Diagnosis

7 days

14 months

8.5 months

4 weeks

4 weeks

32 weeks

17 days (after the last dose increase) 17 weeks

5 days

1 month

Few months

2 weeks

Onset

Table 1 Clinical symptoms, comorbidity, and comedication

NR

6,776

6,520

47,195

34,360

11,004

NR (10×)

2,120

No

No

No

No

NR

NR

NR

No

2,640

Muscular weakness

Related symptoms

Tachycardia, hypertension, afebrile

None

None

Myalgia, mild tachypnea, mild tachycardia, temperature 37.2 °C NR

Myalgia, weakness, fatigue Weakness, fatigue

Myalgia

NR

Myalgia, functional Yes (hip impairment of prosthesis the prosthesis luxation) NR Fluctuating consciousness, disorientation, muscular weakness, tachycardia, mild tachypnea, afebrile

No

Possible trigger

3,644

19,660

27,621

7,241

CK max (IU/L)

NR

None

NR

NR

No

No

One major motor seizure

NR

NR

NR

NR

NR

NR

NR

Trauma and prosthesis luxation, hypertension CRF NR

Obesity, hyperinsulinemia

Medical conditions

NR

NR

NR

Yes

NR

NR

NR

Psychotic symptoms

Myotoxicity due to phenytoin. NMS, MI, trauma, exercise, im injections, infections were ruled out NMS, drugs and alcohol use, seizures, thyroid and rheumatologic disorders, injections, exercise, trauma were ruled out NMS and thyroid and rheumatologic diseases were ruled out. No drug use No agitation or restraints or im injections

NR

NR

NR

NMS and infections were ruled out

NR

NR

Trauma

Myotoxicity due to metformin

6

6

8

NR

Fluphenazine, biperiden, lorazepam

3

Phenytoin

NR

8

6

6

4

6

2

2

2

N. score

NR

None

None

Valproate, lithium

None

NR

Clozapine, valproate

Metformin

Other possible causes Comedication for CK elevation

4258 Psychopharmacology (2014) 231:4255–4270

2012 200

2006 50

2006 25

VelascoMontes et al.

Apikoglou et al.

Himmerich et al.

Quetiapine

F

M

M

M

M

Marcus et al. 1999 10

M

2000 10

Meltzer et al. 1996 20

M

2003 10

M

M

2005 10

23

33

26

42

39

19

39

54

29

33

M

2000 20

Boot and de Haan

Baumgart et al. MartiBonmati et al. Shuster

25

73

M

F

Dose Sex Age (mg/day) (years)

2010 5

Year

Punukollu and 2008 15 Rutherford Perlov et al. 2005 NR

Robert et al.

Olanzapine

Author

Table 1 (continued)

MDD

Schizoaffective disorder

Mental retardation

Schizoaffective disorder

Schizophrenia

Schizophrenia

Schizophrenia

NR

Schizophrenia

Schizoaffective disorder

NR

Delusional disorder

Diagnosis

2 weeks

4 weeks

2 weeks

11 weeks

3 days

>6 weeks

3 days

NR

2 days

7 weeks

4 months

8 days

Onset

40,100

9,135

4,267

15,100

4,000

6,840

4,000

5,851

34,503

28,000

3,646

2,986

CK max (IU/L)

Light exercise

Exercise

Self-injury

No

No

No

NR

NR

No

Mild exercise No

No

Possible trigger

Myalgia

Chest pain, myalgia, muscle tenderness

Abdominal pain

NR

None

None

Dyspnea, mild physical walking effort None

Mild muscle jerks

None

Chest pain

Camptocormia back pain

Related symptoms

NR

NR

NR

No

Yes

Yes

NR

NR

NR

NR

None

NR

NR

Pulmonary fibrosis

NR

NR

Obesity

NR

NR

NR

Medical conditions

Yes

NR

NR

NR

Psychotic symptoms

NR

Alprazolam

NR

Risperidone, topiramate, Self-injury. clonazepam, Myotoxicity due flurazepam, to comedication. biperidene Electrolyte disorders were ruled out. No drug or alcohol use or seizures. Exercise. Myotoxicity Mirtazapine, multivitamin due to mirtazapine. Hypothyroidism was ruled out. No trauma, restraints, im injections. Exercise. Myotoxicity Fluoxetine due to fluoxetine. Viral infections, electrolyte disturbances, alcohol use were excluded. No Seizures, no injury.

NMS, MI, trauma, exercise, im injections, infections were ruled out

4

4

3

5

6

9

5

6

6

Amitriptylinoxid

NR

5

5

N. score

None

NR

NMS, im injections, NR restraints, trauma, excessive physical activity were ruled out NMS was ruled out None

NMS was ruled out

NMS was ruled out

Cotoxicity with haloperidol decanoate, NMS was ruled out Exercise. NMS was ruled out NMS, infection, injury, exercise were ruled out NMS was ruled out

Other possible causes Comedication for CK elevation

Psychopharmacology (2014) 231:4255–4270 4259

2009 NR

1999 7.5

1997 1.5 mg

Hoshi et al.

Marinella

2011 240

2007 4

Karre et al.

Haloperidol

Agarkar

Ziprasidone

Oulis et al.

Sertindole

M

M

F

M

F

F

Giner et al.

2002 6

M

Webber et al. 2004 4

M

150

M

M

62

38

56

33

23

69

22

40

68

30

Dose Sex Age (mg/day) (years)

2006 400

Year

2006 3

Zink et al.

Risperidone

Klein et al.

Author

Table 1 (continued)

Schizophrenia

delirium

Schizophrenia

Schizoaffective disorder

Schizophrenia

Dysthymia

Schizophrenia

Schizophrenia, depression

Schizoaffective disorder

Psychotic depression

Diagnosis

1 day

2 days

1 week (after injection)

10 months

1 week

2 years

4 weeks

6 weeks

2 days

2 weeks

Onset

4,800

6,150

5,172

26,152

3,500

291.05 μkat/L

25,498

4,795

8,918

1,752

CK max (IU/L)

No

NR

Im Injection

Epidural injection

NR

NR

No

NR

No

NR

Possible trigger

Epigastric pain

NR

Myalgia, fatigue

NR

NR

Myalgia, muscle weakness

Fever, pain in right ankle/heel, swelling, macular rash

Aches in the left leg, respiratory problems

Myalgia, diaphoresis, tachycardia, incontinence, weakness

Myalgia

Related symptoms

No

NR

NR

NR

NR

Myotoxicity due to other drugs. NMS was ruled out.

Epidural injection. Clozapine. NMS was ruled out.

NR

Acetosalicylic acid, hydrochrorothiazide, quetiapine, omeprazole, benztropine, bisacodyl, metoprolol Flunitrazepam

Clozapine, epidural depomedrol 5 weeks prior to rhabdomyolysis

NR

Mirtazapine Myotoxicity due to mirtazapine. NMS and serotonergic syndrome were ruled out. myotoxicity due to clonazepam, simvastatine simvastatin (5 days prior to admission) biperiden, myotoxicity lormetazepam, due to nifedipine, cerivastatine cerivastatine (one month prior to admission)

7

NR NMS, MI, PM, hypothyroidism were ruled out. No agitation or im injection. Mirtazapine, lithium, Possible drug lamotrigine interactions. NMS, PM, MI, hypothyroidism were ruled out.

5

1

3

1

3

3

2

4

7

N. score

Other possible causes Comedication for CK elevation

HDC (ifosfamide, Choriocarcinoma carboplatin, (testis), etoposide) retroperitoneal tumor, hydronephrosis, renal failure, lung metastasis, gynecomastia Famotidine, aspirin, Asthma NMS, seizures, MI, nitroglycerine infection, electrolyte patch, benztropine, disturbances were clorazepate ruled out

Hypertension, hyperlipidemia, obesity

Herniated disk

NR

Developed compartment syndrome; Obesity, allergies Obesity, hypertension, hypercholisterinemia

NR

NR

Venous thrombosis, pulmonary embolism

NR

NR

NR

NR

Medical conditions

NR

Psychotic symptoms

4260 Psychopharmacology (2014) 231:4255–4270

1988 300

1988 12

M

M

M

30

28

26

Schizophrenia

BPD

Schizophrenia

Schizophrenia

NR

ASPD

Schizophrenia

NR

Diagnosis

2 days

9 days

19 days

7 hours

3 weeks

>1 year

2 days

6 days

Onset

2,560

5,580

11,723

18,500

177,000

25,470

16,587

19,420

CK max (IU/L)

Substernal tenderness, tachypnea, tachycardia, afebrile

None

Lethargy, hypotension, myalgia, weakness, diaphoresis, tachycardia, tachypnea, low fever (37.6 °C), sensory deficits, decreased deep tendon reflexes, cogwheeling, erythymatous left calf

NR

Related symptoms

Yes

No

Exercise

No

NR

NR

Flu-like symptoms, low grade fever, mild muscular pain

No

Yes

NR

NR

NR

NR

Tardive dyskinesia

NR

NR

NR

Yes

NR

NR

Medical conditions

Negative symptoms

Psychotic symptoms

4 im lethargy, nausea, myalgia, Yes injections arthralgia, tachycardia, tachypnea, afebrile, urine incontinence

No

Exercise

NR

No

Possible trigger

1

Lithium, benztropine

NMS was ruled out

Exercise. NMS was ruled out. No restraints or dystonia or self-mutilation.

NR

NR

5

4

6

3

3

7

7

N. score

NR

Promethazine, profenamine, oxprenolol, coenzyme-Q

None

NR

Infection. NMS, MI, NR trauma, exercise, im injections were ruled out

NMS, MI, trauma, exercise, im injections, infections were ruled out im injections. Myotoxicity due to lithium. Rheumatologic causes and viral hepatitis were ruled out.

Excessive exercise. MI, hepatitis, hypothyroidism, alcoholism were ruled out.

NMS, MI, trauma, exercise, im injections, infections were ruled out NR

Other possible causes Comedication for CK elevation

ASPD antisocial personality disorder, BPD borderline personality disorder, CRF chronic renal failure, F female, GAD generalized anxiety disorder, im intramuscular, M male, MDD major depressive disorder, MI myocardial infarct, N. Score Naranjo Score, NMS neuroleptic malignant syndrome, NR not reported, PM polymyositis.

Pearlman et al

Thioridazine

Pearlman et al

Perphenazine

Meltzer et al. 1996 400

Melperone

31

M

Thase and Shostak

1984 50 po, 125 IM

27

55

F

1999 75

40

Meltzer et al. 1996 100

Loxapine

Terao et al.

Levomepromazine

M

M

1995 30

Marsh and Dolson

34

Dose Sex Age (mg/day) (years)

M

Year

Meltzer et al. 1996 NR

Author

Table 1 (continued)

Psychopharmacology (2014) 231:4255–4270 4261

2010 2,986

2008 3,646

2005 28,000

2005 34,503

Robert et al.

Punukollu and Rutherford

Perlov et al.

Baumgart et al.

Olanzapine

1994 6,520

NR

47,195

Keshevan et al.

No

1995 34,360

Kirson et al.

NR

NR

NR

NR

No

No

1996 11,004

Meltzer et al.

NR

2,120

1998 NR (10x) Yes

2000 2,640

Reznik et al.

Koren et al.

NR

NR

Tseng and Hwang 2009 6,776

Schennach-Wolff et al.

Yes

NR

2011 19,660

Wu and Chang

Yes

NR

2010 3,644

2012 27,621

Clozapine

Further tests

NR

No

ALT↑, AST↑, serum myoglobin↑; renal values, electrolytes,, inflammation values: normal AST↑, LDH↑ NR

No

NR

NR

MRI: necrosis paraspinal muscles ECG: normal

NR

NR

NR

No

No

EMG: brief motor units potentials of short duration, chest X-ray: normal, ECG: normal, potassium efflux: severely decreased NR

MSNCV: non-specific signs

MSNCV: mild myopathic pattern

NR

NR

NR

No

EMG: normal, muscular biopsy: normal

No

NR

NR

NR

NR

NR

Yes (CRF)

AST↑, CRP↑; ALT, No electrolytes: normal ALT↑, ALP↑, GGT↑; CBC, No Urea, electrolytes, CRP: normal

Aldolase↑, LDH↑, AST↑, ALT↑; creatinine, GGT, ALP: normal total bilirubin↑, aldolase↑, AST↑, ALT↑, LDH↑; GGT , ALP: normal aldolase↑, ALT↑, AST↑; WBC: normal

GGT↑

ALT↑, AST↑, LDH↑; CBC, electrolytes, creatinine, urea, thyroid tests: normal

NR

NR

NR

NR

AST↑, WBC↑; negative drug screening test

NR

ALT↑, AST↑, aldolase↑, myoglobin↑

NR

Yes

Yes

Yes

Yes

NR

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

No (dose reduction)

Yes

Yes

Yes

Yes

Discontinuation of AP

NR

NR

Yes

Yes

NR

NR

NR

NR

Yes

Yes

Yes

Yes

NR

Forced diuresis

Renal function deterioration

CK max (IU/L)

Urine Other test values

Treatment

Diagnostic tests

2010 7,241

Year

Marzetti et al.

Aripiprazole

Ursini et al.

Amisulpride

Author

Table 2 Laboratory tests, treatment, and outcome

14

14

59 days

10

22

9

7

6

NR

NR

NR

7

6

NR

12

21

Yes; no CK elevation (without metformin)

Rechallenge

NC

NC

Camptocormia resolved NC

NC

NC

NC

Acute psychotic exacerbation

NC

NC

NC

NC

NC

No; switch to risperidone (transient CK elevation: 3860 IU/L)

NR

No; switch to amisulpride (mild CK elevation) and discontinuation

No

Yes; CK elevation (>4,000 IU/L), discontinued

NR (hepatitis in previous trial with clozapine)

NR

Yes; no CK elevation (without phenytoin)

NR

Not discontinued

No; switch to unknown medication

Not discontinued

Yes: Leponex® instead of generic clozapine (no CK elevation)

Complications due NR to trauma NC NR

NC

Normalization Outcome of CK (days)

4262 Psychopharmacology (2014) 231:4255–4270

No

No

Bood and de Haan 2000 6,840

1996 15,100

1999 4,000

Meltzer et al.

Marcus et al.

NR

2006 40,100

2006 1,752

8,918

Himmerich et al.

Klein et al.

Oulis et al.

2007 3,500

2002 291.05 NR μkat/L

Giner et al.

Sertindole

2004 25,498

Webber et al.

NR

No

2006 4,795

NR

NR

Zink et al.

Risperidone

NR

2006 9,135

Apikoglou et al.

NR

2012 4,267

Velasco-Montes et al.

No

No

No

2000 4,000

NR

Shuster

Quetiapine

Further tests

NR

ALT↑, AST↑

AT-III, protein C, protein S, activated protein C resistant: normal WBC↑, ALT↑, AST↑

ALT↑, AST↑; WBC, K, Na, Ca, creatinine: normal ALT↑, AST↑, LDH↑; CBC: normal ALT↑, AST↑; CBC, creatinine, urea, electrolytes: normal. Negative serological tests for several viruses. WBC↑, ALT↑, AST↑; creatinine, ESR, myoglobin, TSH: normal WBC↑, ALT↑, AST↑, Creatinine↑, CRP↑; ESR, TSH: normal

AST↑, creatinine, urea, CBC: normal

Normal

CBC, creatinine, urea: normal ALT↑, AST↑, LDH↑, NTP(%)↓

NR

NR

No

NR

Yes

No

No

NR

No

No

No

NR

No

CBC, liver and renal values, No electrolytes: normal

NR

NR

NR

NR

NR

NR

ECG: normal

ECG: bradycardia

ECG: normal

NR

NR

ECG, chest x-ray, echocardiogram, chest CT (revealed pulmonary fibrosis) NR

NR

NR

NR

NR

NR

NR

NR

NR

Yes

Yes

NR

NR

NR

NR

Forced diuresis

Renal function deterioration

CK max (IU/L)

Urine Other test values

Treatment

Diagnostic tests

2003 5,851

Year

Marti-Bonmati et al.

Author

Table 2 (continued)

NR

NR

NR

20

14

NR

8

6

NR

8

NR

Yes

Yes

3

NR

NC

Resection of the peroneus longus and the peroneus brevis. Walking impairment

NC

NC

NC

NC

NC

NC

NC

NC

NC

NC

NC

Normalization Outcome of CK (days)

No (only simvastatine NR was discontinued)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No (one dose was suspended)

Discontinuation of AP

NR

Yes: toxic hepatitis after rechallenge

Medication was not discontinued (apart from simvastatine)

No; switch to aripiprazole and reboxetine

No; switch to mirtazapine and clozapine

No; switch to mirtazapine and olanzapine

No; the patient refused to take any medication

No

NR

No; switch to fluphenazine

No; switch to haloperidol

Switch to clozapine: discontinuation due to agranulocytosis; switch to quetiapine; transient CK elevation (3,942 IU/L), but no discontinuation

NR

Not discontinued (mild CK elevation under a dose of 5 mg/day)

Rechallenge

Psychopharmacology (2014) 231:4255–4270 4263

Yes

Marsh and Dolson 1995 16,587

1988 2,560

1988 5,580

NR

No

No

Creatinine↑; AST, LDH: normal

AST, LDH: normal

ALT↑, AST↑; urea, creatinine, calcium, uric acid: normal

AST↑, LDH↑; CBC, creatinine, urea: normal WBC↑, ALT↑, AST↑, LDH↑; electrolytes, creatinine, urea, uric acid: normal

AST↑, LDH↑

WBC↑, creatinine↑, urea↑, LDH, K↑, uric acid↑, phosporous↑

NR

NR

Myoglobin↑, creatinine↑

NR

WBC↑

NR

NR

ECG: nonspecific T-waves abnormalities NR

Transient rise in NR creatinine levels

No

No

No

No

NR

Doppler evaluation: normal, renal ultrasound kidneys: normal

Yes

No

NR

NR

NR

NR

ECG, U/S abdomen: normal

No

No

Yes

No

NR

NR

NR

NR

Yes

Yes

NR

Yes

NR

NR

Hemodialysis

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

Yes

Dose reduction

Discontinuation of AP

14

13

12

14

6

7

5

7

7

NR

28

5

NC

NC

NC

NC

NC

No

Left peroneal neuropathy

NC

NC

exitus

NC

NC

Normalization Outcome of CK (days)

No; switch to clonidine and diazepam

No; switch to thiothixene (no further CK elevations)

Yes: CK: 8,713 IU/L; switch to thioridazine (normal CK levels)

Yes: 150 mg/day without CK elevation

No; switch to perphenazine (no further CK elevations)

Medication was not discontinued

NR

Yes: CK: 13,200 IU/L

No

Exitus

NR (quetiapine and hydrochlorothiazide were discontinued)

Yes: 160 mg/day, no CK elevation

Rechallenge

ALT alanine aminotransferase, AP antipsychotic, AST aspartate aminotransferase, AT-III antithrombin III, Ca calcium, CBC complete blood cell count, CRP C-reactive protein, CT computed tomography, ECG electrocardiogram, EMG electromyogram, ESR erythrocyte sedimentation rate, GGT gamma-glutamyl transferase, K potassium, LDH lactate dehydrogenase, MSNCV motor and sensory nerve conduction velocity, Na sodium, NR not reported, NC no complications, NTP neutrophils, TSH thyroid stimulating hormone, U/S ultrasound, WBC white blood cells

Pearlman et al

Thioridazine

Pearlman et al

Perphenazine

Meltzer et al.

1996 11,723

Yes

Thase and Shostak 1984 18,500

Melperone

Yes

NR

1996 177,000

Meltzer et al.

Loxapine

Terao et al.

1999 25,470

No

1996 19,420

Meltzer et al.

NR

Yes

1999 6,150

1997 4,800

Hoshi et al.

NR

NR

Marinella

2009 5,172

Levomepromazine

Further tests

Forced diuresis

Renal function deterioration

CK max (IU/L)

Urine Other test values

Treatment

Diagnostic tests

2011 26,152

Year

Karre et al.

Haloperidol

Agarkar

Ziprasidone

Author

Table 2 (continued)

4264 Psychopharmacology (2014) 231:4255–4270

Psychopharmacology (2014) 231:4255–4270

4265

Table 3 Studies estimating prevalence of CK elevation due to antipsychotics Study

N

Males

Age

Duration

AP

n (CK↑)

Males

n (CK>10×)

Males

Meltzer et al. 1996

121

70 %

NR

NR

Misc

NR

NR

9

89 %

Scelsa et al. 1996

37

NR

NR

2 weeks–14 months

Clozapine

29

NR

>3

NR

Terao et al. 1999

32

100 %

57.6 years (36–73)

2 years

Misc

16

100 %

1

100 %

Reznik et al. 2000

94

65 %

38.2 years (17–61)

NR

Clozapine

13

77 %

2

50 %

AP antipsychotics, misc miscellaneous, NR not reported

was observed, and in one case with risperidone rechallenge, a toxic hepatitis was diagnosed. Of the other 27 cases, in 12, the medication was reported to have been changed, with a renewed CK elevation being observed in 3 of them. The probability of a CK elevation was not significantly higher after rechallenge than after switching to another medication (Fisher’s exact test, p=0.43); however, in 15 cases, there was no report on the further procedure (switch or rechallenge), which might have biased the results. In the six cases in which medication was not discontinued, the dose in two was reduced, while in four cases, the medication remained unchanged. Fifteen patients were given infusions with or without bicarbonates and one was treated with hemodialysis. Treatment with forced diuresis was correlated with the CK value (higher values were more likely to be treated with forced diuresis; Mann-Whitney test, p=0.0074) and was related to the presence of myoglobinuria (Fisher’s exact test, p=0.03). The presence of symptoms did not influence the decision to give forced diuresis (chi-square, 1 degree of freedom; p=0.92). In 29 cases, the time needed for the CK activity to return to normal was reported. Forced diuresis did not lead to a significantly shorter duration of CK elevation (Mann-Whitney test, p=0.41).

Outcome In the majority of the cases (35 of 42), there were no further complications from the CK elevation. There were three cases with de novo impairment of renal function. In two of them, there was only a transient elevation of creatinine; however, none of them received forced diuresis (Klein et al. 2006; Pearlman et al. 1988). In the third case, the patient suffered acute renal failure with electrolyte derailment (Marsh and Dolson 1995). There were two more cases with a worsening of pre-existing renal failure. One of them died because of respiratory failure, probably due to lung metastases (Hoshi et al. 1999). A compartment syndrome was diagnosed in one patient receiving risperidone and simvastatin (Webber et al. 2004); the patient underwent surgery with resection of his peroneus longus and brevis. Another patient treated with risperidone and cerivastatin had a mild walking impairment at the time of release but was free of symptoms at the 1-year follow-up (Giner et al. 2002). Naranjo score Twenty-two cases had a Naranjo score greater than five, i.e., the cause-effect relationship could be described at least as

Table 4 Overview of the statistical results Null hypothesis

Test

p value

The CK values are independent from the use of first- or second-generation antipsychotics

Mann-Whitney test

0.52

The magnitude of the CK elevation is independent from the presence of symptoms

Mann-Whitney test

0.64

The presence of symptoms is independent from the presence of myoglobinuria

Fisher’s exact test

0.006a

The magnitude of the CK-elevation is independent from the presence of myoglobinuria

Mann-Whitney test

>0.10

The probability of a CK elevation does not differ between patients that are rechallenged with the same medication and patients than are switched to another medication The probability of treating with forced diuresis was independent from the CK value

Fisher’s exact test

0.43

Mann-Whitney test

0.007a

The probability of treating with forced diuresis was independent from the presence of myoglobinuria

Fisher’s exact test

0.03a

The probability of treating with forced diuresis was independent from the presence of symptoms

Chi-square

0.92

Forced diuresis does not lead to a significantly shorter duration of the antipsychotic-induced CK elevation

Mann-Whitney test

0.41

A cause-effect relationship is not easier to prove in cases with a more recent onset (1 week) of antipsychotic medication

Fisher’s exact test

0.07

CK creatine kinase a

Null hypothesis is rejected

4266

“probable.” The CK elevation could “definitely” be attributed to the antipsychotic medication in only one of these cases. In the other 20 cases, the Naranjo score was between one and four which indicates a “possible” cause-effect relationship. We identified a trigger, i.e., a mechanical cause (trauma, injections, exercise) for the CK elevation, in ten cases; we can assume here an additive effect of antipsychotics on exercise- or trauma-induced CK elevations, similar to the one described for statins. One would expect that the causeeffect relationship would be easier to prove in cases with a more recent onset of antipsychotic medication. Using an arbitrary threshold of 1 week between the onset of medication and CK elevation, we could identify such a trend, but it was not statistically significant (Fisher’s exact test, p=0.07). The data above reflect the difficulties that emerge when trying to attribute an uncommon condition to a single cause.

Discussion To our knowledge, this is the first systematic review on primary antipsychotic-induced CK elevation, i.e., a CK increase that is not mediated through other side effects of antipsychotics, such as seizures, NMS, and EPS. The prevalence of the antipsychotic-induced CK elevation was between 2 and 7 %. Although it seems to be a relative frequent condition, we found only a few published cases. Published reviews on the adverse effects (e.g., Conley and Meltzer 2000; Correll 2007; Flanagan 2008; Wirshing 2001) and systematic reviews on the efficacy and tolerability of antipsychotics (e.g., Asenjo Lobos et al. 2010; Asmal et al. 2013; Komossa et al. 2010, 2011) do not mention the CK elevation as a possible adverse effect. However, the majority of the official prescribing information of the most common atypical antipsychotics report on CK elevation, whereas the frequency varied (the highest prevalence was reported for asenapine up to 11 % with a threshold at three times the upper normal limit). We also found several reports in FDA (https://api.fda.gov/drug/event), e.g., 434 cases for clozapine, 430 cases for olanzapine, 404 cases for risperidone, and 233 cases for haloperidol. One reason for the small number of published case reports might be that this condition is often overlooked in the clinical practice, perhaps because of its unclear clinical significance. As the prescribing information of asenapine mentions, the clinical relevance of the CK elevation is unknown. The excess of male patients in the published reports has also been observed in previous studies on rhabdomyolysis (e.g., McMahon et al 2013). The overrepresentation of the SGAs in comparison to the FGAs can probably be attributed to the different pharmacodynamic properties of these drugs, since FGAs do not have an antagonistic effect on serotonergic receptors. Another possible explanation is the fact that the

Psychopharmacology (2014) 231:4255–4270

establishment of concrete diagnostic criteria for NMS in DSM-IV coincided with increased use of atypical antipsychotics. Based on the DSM-IV criteria, a psychiatrist could make a diagnosis of asymptomatic CK elevation with greater assurance, whereas previously, similar laboratory findings may have been ascribed to an atypical form of NMS at the time when FGAs were the main drugs used. Six patients had tachypnea and tachycardia in addition to muscular symptoms. Three of them were also lethargic and a forth one had additionally diaphoresis and incontinence. These symptoms belong to the secondary diagnostic criteria of NMS; the question arises whether these cases represent an atypical manifestation of NMS. Our findings suggest that patients with myoglobinuria are more likely to be symptomatic, whereas neither myoglobinuria nor symptoms were related to the magnitude of the CK elevation. Most authors discontinued the medication. The probability of a new CK elevation after rechallenge with the same medication did not differ significantly from the probability of a renewed CK elevation after switching to another medication. Forced diuresis did not shorten the duration of the CK elevation significantly; however, patients with higher CK values were more likely to receive forced diuresis, so that the two groups are not strictly comparable and a possible benefit from forced diuresis may have remained masked by the higher CK activity. As far as the outcome is concerned, there was only one case with a de novo acute renal failure due to the CK elevation, while the two transient creatinine increases cannot be considered to be of significance. In one case with haloperidol, the patient died because of respiratory failure (Hoshi et al. 1999). He had been treated with high-dose chemotherapy because of a choriocarcinoma and developed delirium due to the neurotoxic effects of the chemotherapy. Renal function was already deteriorated when haloperidol was initiated. In our opinion, it is quite debatable to what degree haloperidol contributed to the rhabdomyolysis and the further unfavorable outcome. In the two cases with risperidone, the side effects must be attributed mainly to statins and not to risperidone. Differential diagnosis The differential diagnosis of a CK elevation should first of all consider myocardial involvement. The CK MB fraction is used to distinguish between injury of skeletal and myocardial muscle. If inconclusive, clinical symptoms, ECG, and the determination of other heart enzymes can facilitate the diagnosis. In patients receiving antipsychotics, a neuroleptic malignant syndrome needs to be excluded. Cardinal symptoms of NMS include muscle rigidity and hyperthermia; however, atypical forms of the syndrome have also been reported. Alcohol and illicit drugs, myotoxic medication (e.g., statins) seizures, and coma are the leading causes of atraumatic rhabdomyolysis (Giannoglou et al. 2007). Other common causes

Psychopharmacology (2014) 231:4255–4270

of CK elevations include trauma, strenuous exercise, rheumatic diseases, and hypothyroidism. Especially in psychiatric patients, acute dystonia (Cavanaugh and Finlayson 1984), tardive dyskinesia (Lazarus and Toglia 1985), and physical restraints (Mohr et al. 2003) have all been reported to cause elevations of creatine kinase. Finally, CK elevations have been associated with acute psychotic exacerbations (e.g., Meltzer 1968, 1969), although this relation is difficult to demonstrate because of the presence of confounding factors such as restraints, intramuscular injections, and increased muscular activity due to restlessness. Risk factors for acute renal failure in rhabdomyolysis Ten percent to 40 % of the cases with rhabdomyolysis are complicated by acute renal failure (ARF) (Chatzizisis et al. 2008). However, in the four prevalence studies mentioned above (Meltzer et al. 1996; Reznik et al. 2000; Scelsa et al. 1996; Terao et al. 1999), no ARF was observed in a total of 36 patients with antipsychotic-induced CK elevation (in a total population of 274 patients) although none of them received preventive treatment with infusions. We found three case reports in the literature with ARF due to antipsychoticinduced CK elevation. In two of them, renal failure preexisted and renal function deteriorated further after the CK elevation (Hoshi et al. 1999; Marzetti et al. 2012). In one case (Marsh and Dolson 1995), ARF appeared de novo. Advanced age, female sex, electrolyte derailment (hypocalcemia, hyperphosphatemia, low bicarbonates), and high initial creatinine levels have been associated with a less favorable outcome in patients with rhabdomyolysis in a retrospective study by McMahon et al. (2013). The cause of the CK elevation also plays a role in the outcome, with seizures, syncope, exercise, statins, and myositis having a more favorable outcome than trauma, surgery, burns, neuroleptic malignant syndrome, and compartment syndrome. There were no cases with an antipsychotic-induced CK elevation in this study.

4267

only in symptomatic patients with pathological electromyographic findings; however, none of their cases exhibited a CK value above 3,000 IU/L, so their strategy may not be effective in patients with a much higher CK activity.

A proposed algorithm We will try here to describe an algorithm for dealing with the primary antipsychotic-induced CK elevation (Table 5). Present recommendations should be treated with the required circumspection because they are based on a small sample of published cases which might not be representative of the real population. The first question that arises is when a clinician should test for the CK value in patients who receive antipsychotics. Keeping the above limitations in mind, it seems justified to propose a control of the creatine kinase in patients with muscle symptoms. Twenty-six of the 42 cases (62 %) had symptoms, and in 25 of them, (60 %) the muscles were involved; in the rest of the cases, the pathological findings were discovered coincidentally. Although a sensitivity of 60 % cannot be regarded as satisfying, muscle symptoms are the only available indication for the presence of an increased CK value. If the findings are positive, then the cause of the CK elevation should be elucidated. As we mentioned above, the vast majority of the authors reported that the CK elevation was not of the MB subtype and that the main symptoms of NMS (fever and muscular rigidity) were not present. Thus, cardiac disease and NMS are the two diagnoses that should be ruled out at first. Further, there are a number of possible conditions that should be considered and excluded before settling on a

Table 5 A proposed algorithm Clinical recommendations 1. Test for creatine kinase when the patient has symptoms such as myalgia or weakness 2. Rule a cardiac cause out

Prevention of ARF in rhabdomyolysis No guidelines exist for the prevention of ARF in patients with CK elevation due to antipsychotics. A recent review of studies for prevention of kidney injury following rhabdomyolysis suggests that treatment with intravenous fluids should be initiated as soon as possible (Scharman and Troutman 2013); bicarbonates for urine alkalization and mannitol should be administrated only if necessary. However, it is not clear whether these recommendations for the treatment of rhabdomyolysis can be extended to the treatment of antipsychoticinduced CK elevation, which seems to be self-limiting (Meltzer et al. 1996). For example, Reznik et al. (2000) followed a more selective strategy and discontinued clozapine

3. Rule NMS out (main symptoms are hyperthermia and rigidity) 4. Rule other causes of CK elevation (hypothyroidism, infections, rheumatologic diseases, exercise, trauma, seizures, EPS, etc.) 5. Control for myoglobinuria, renal function. Individual risk assessment for acute renal failure based on clinical and laboratory parameters 6. Wait and watch, when the risk assessment is favorable 7. If the patient is receiving a statin, consider switching to rosuvastatin 8. Consider discontinuation of the antipsychotic medication, when the risk is not favorable 9. Consider giving forced diuresis, if urine is positive for myoglobin or in case of renal impairment 10. After normalization of the CK-value, consider rechallenging with the same medication or switching to another antipsychotic

CK creatine kinase, EPS extrapyramidal symptoms, NMS neuroleptic malignant syndrome

4268

diagnosis of antipsychotic-induced CK elevation, including infections, hypothyroidism, and trauma. The decision whether to stop or continue the medication should be individualized. Risk factors such as the ones described by McMahon et al. (2013) and mentioned above could be considered. Although forced diuresis is regarded as obligatory in the review by Scharman and Troutman (2013), the majority of the cases in the present review had a favorable outcome even without receiving forced diuresis. Some authors did not even intervene in the medication, so that a watch and wait strategy might not be false in cases without myoglobinuria or renal impairment and with a favorable risk profile. Otherwise, the discontinuation of the medication should be considered. In cases of myoglobinuria, electrolyte derailment, or other indicators of renal impairment, fluids should be administrated in order to achieve forced diuresis. Patients with higher CK values may be more likely to profit from forced diuresis. If the patient had been on clozapine, a rechallenge could be considered, mainly because of the lack of alternatives (clozapine is regarded as the most efficient medication in the treatment of refractory schizophrenia). If the patient had been on other antipsychotics, a switch to another antisychotic or even a rechallenge could be considered. Finally, for patients treated with statins, a switch to a statin with a more favorable pharmacokinetic interaction profile should be considered. For example, de Hert et al. (2006) found that rosuvastatin was effective and well tolerated in patients with schizophrenia who received antipsychotics. Rosuvastatin is known to be metabolized only to a limited extent and CYP2C9 appears to be the principal enzyme involved (Martin et al. 2003) whereas most of the rest statins are mainly metabolized by CYP3A4 and can interact with a large number of antipsychotics. Strengths and limitations The main strength of the present study is that, to our knowledge, this is the first review that systematically inquires into the relationship between CK elevations and the use of antipsychotics in adults. One main limitation is that this study includes only case reports and case series. Since no controlled studies considering the treatment of antipsychotic-induced CK elevation were found, all of our results should be treated with caution. Additionally, the presence of report bias cannot be ruled out; for example, cases that did not receive forced diuresis but developed acute renal failure might be less likely to be published because the psychiatrists may consider their treatment to constitute malpractice and be hence unwilling to report on them. Although the above limitations limit the robustness of our results, we have presented an extensive overview of the existing literature on this issue, which can be useful in everyday practice.

Psychopharmacology (2014) 231:4255–4270

Conclusion The primary antipsychotic-induced CK elevation seems to be a relative frequent but also overlooked condition. The fact that the outcome is more favorable in comparison to rhabdomyolysis suggests that these two conditions may represent two different clinical entities. As also mentioned in the prescribing information of asenapine, the clinical relevance of the CK elevation under antipsychotics is not known. Although the findings of a systematic review of single cases cannot be confirmatory, it seems legitimate to claim that the primary antipsychotic-induced CK elevation is a relative benign condition, especially when it is treated properly. Acknowledgments None. Conflicts of interest None.

Appendix Table 6 For the data extraction the following format was used 1st section

Demographics and general information

Author, year

Ursini, 2010

Gender

M

Age

25

Diagnosis

GAD, dysthymia

Medication

Amisulpride

Dose

200 mg/day

2nd section

Clinical symptoms and diagnostics

CKi

126

CK normal range

NR

CKmax

7,241

Onset

3 weeks (5 weeks after metformin)

Trigger

No

Symptoms

Weakness

Psychotic symptoms

NR

Comorbidity

Hyperinsulinemia

Other possible causes

NR

Comedication

Metformin

Urine

NR

Other laboratory tests

ALT↑, AST↑, myoglobin↑

Other tests

EMG (negative), biopsy (negative)

Renal function

NR

3rd section

Treatment and outcome

Forced diuresis

NR

Drug discontinuation

Yes

Normalization of CK

3 weeks

Complications

NR

Rechallenge

Yes; no CK elevation

CK creatine kinase, EMG electromyography, GAD generalized anxiety disorder, NR not reported, ALT alanine transaminase, AST aspartine transaminase

Psychopharmacology (2014) 231:4255–4270

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