Massive Asymptomatic Creatine Kinase Elevation in Youth During Antipsychotic Drug Treatment: Case Reports and Critical Review of the Literature

Abstract

A massive asymptomatic creatine kinase elevation (MACKE) has been described during antipsychotic exposure in adult psychotic patients without signs of neuroleptic malignant syndrome (NMS), or other most frequent reasons for high creatine kinase (CK) serum level (intramuscular injections, restraints, intense physical activity, dystonic reactions). In this article, we review this clinical condition, and report three cases of MACKE in nonpsychotic, drug-naïve youth during treatment with second generation antipsychotics. The diagnosis of MACKE should be considered after ruling out other possible common reasons of CK increase. The finding of MACKE should indicate a need for weekly monitoring of the CK level only when there are reasons to believe elevated CK is toxic or harmful. Further investigations are recommended when signs and symptoms raise a suspicion of NMS or rhabdomyolysis, including flu-like syndrome, fever, weakness, alteration of consciousness, muscle rigidity, tachycardia, hyper-/hypotension, and dark urine. A drug discontinuation should be considered when possible signs of NMS or rhabdomyolysis are suspected, or in cases of very high and persisting CK levels. Empirical evidence indicates that there is not a “safe” antipsychotic medication; therefore, a switch to another antipsychotic with a different profile is not necessarily a safe option. The spontaneously remitting or intermittent course suggests that the “true” MACKE should be kept distinct from both rhabdomyolysis and NMS. Raising awareness with MACKE may reduce the need for unnecessary diagnosis of NMS or rhabdomyolysis, which may otherwise lead to an unnecessary discontinuation of an effective therapeutic agent.

Introduction

Asymptomatic and spontaneous elevation of serum creatine kinase (CK), not related to neuroleptic malignant syndrome (NMS), has been described in drug-free adult psychotic patients, mainly during acute episodes (Meltzer et al. 1980; Manor et al. 1998). Other most frequent reasons for high CK serum level in psychiatric settings are intramuscular injections, restraints, intense physical activity, dystonic reactions, or other intense isometric activity (Pearlman et al. 1988). High serum CK levels have been also related to overdosage of several substances of abuse, such as cocaine and amphetamines, including “ecstasy” (Meltzer et al. 1996). Among medical conditions resulting in CK elevations, myocardial infarction, thyroid dysfunctions, and muscle injuries or syndromes are all possible causes of CK elevation. Meltzer et al. (1996) described massive asymptomatic CK elevation (MACKE) without signs of NMS during antipsychotic exposure in 11 adult psychotic patients. Since then, several case reports have been published in past decades, all including adult patients with schizophrenic spectrum disorders treated with antipsychotic agents, prevalently second generation antipsychotics (SGAs) (olanzapine, clozapine, risperidone, quetiapine, aripiprazole), or, more rarely, first generation antipsychotics (FGAs) (haloperidol, loxapine, molindone thioridazine, perphenazine) (Pearlman et al. 1988; Keshavan et al. 1994; Meltzer et al. 1996; Marcus et al. 1999; Boot and de Haan 2000; Devarajan and Dursun 2000; Holtmann et al. 2003; Marti-Bonmati et al. 2003; Perlov et al. 2005; Klein et al. 2006; Apikoglu Rabus et al. 2006; Bachman et al. 2007; Oulis et al. 2007; Punukollu and Rutherford 2008; Schennach-Wolff et al. 2010). Much less evidence is available on young patients, as only few schizophrenic adolescents has been reported to present high CK levels during treatment with SGA (Holtmann et al. 2003; Bachman et al. 2007).

The aim of this study is to critically review the available literature on this rare finding, and to describe its occurrence in young, nonpsychotic adolescents receiving SGA (risperidone and olanzapine) for nonpsychotic disorders, such as conduct disorder, bipolar disorder, and Tourette syndrome.

Search Strategy

Because MACKE is still not clearly defined, and considering the overlap with rhabdomyolysis and neuroleptic malignant syndrome, we retrieved from MEDLINE^® all articles written in English between 1996 (year of publication of Meltzer's article, which provided an in-depth description) and January 2014, reporting on CK elevation during antipsychotic exposure. The relevant articles were further analyzed in order to check further articles. Two authors (S.P. and Al.M.) performed the research independently, and disagreement was resolved through discussion. Given that a review of case reports describing rhabdomyolysis and antipsychotic use has been recently published (Packard et al. 2014), we included in the present article only articles that clearly distinguished MACKE from other conditions (mainly rhabdomyolysis, serotonin syndrome, and NMS). Original research or case reports describing MACKE are summarized in Table 1.

Table 1.

Review of the Studies Reporting MACKE

First author and year of publication	No. of patients	Age range	Drug(s)/ dose when known	CK level (means or medians)/other laboratory and clinical findings	Time of onset	Management	Outcome
Pearlman et al. 1988	2	28–30	Haloperidol (15 mg)+thioridazine (300 mg), perphenazine (12 mg)	Mean: 4070 mUI/mL	2 or 3 days	Switching to thioridazine; discontinuing antipsychotics	Normalization of CK levels
Keshavan et al. 1994	1	22	Clozapine (100 mg)	6520 U/L+liver enzymes and aldolase (no values reported)	19 days	Discontinuing/reintroducing/switching to thioridazine	Normalization of CK levels/ new peak after reintroduction/ new reduction after switch
Meltzer et al. 1996	11	21–42	Melperone (1), clozapine (2),olanzapine (3), haloperidol (1), risperidone (1), loxapine (3)	Median: 9610 U/L	Between 5 days and 3 months	Monitoring or stopping-reintroducing or switching	Mainly self-limiting
Marcus et al. 1999	1	39	Olanzapine (10 mg)	4000 U/L+aspartate aminotransferase (65 UI/L)	3 days	Discontinuing drug/forced diuresis/switch to fluphenazine	Normalization of CK levels within 8 days
Devarajan and Dursun 2000	2	21–34	Risperidone (2mg)/olanzapine (10 mg), risperdone (5 mg)/olanzapine (20 mg)	Mean: 1110 U/L	8 days, it seems to be dose dependant	Switching to quetiapine/ clozapine	Normalization of CK levels
Boot and de Haan 2000	1	19	Olanzapine (20 mg)/quetiapine (dose not reported)	2 peaks: 6840 U/L+AST, ALT and LDH (slightly increased); 3942 U/L	More than 6 weeks (first peak), second peak not known	Monitoring	Normalization of CK levels within 4 days
Holtmann et al. 2003	1	17	Risperidone (3.5 mg)	9743 U/L+myalgia	Approximately 4 weeks	Discontinuing drug	Normalization of CK levels within 1 week
Marti-Bonmati et al 2003	1	54	Olanzapine (10mg)	5851 U/L	Not reported	Discontinuing drug	Reduction (4330) of CK levels after 12 h/no further follow-up
Perlov et al. 2005	1	33	Olanzapine (dose not reported)	22800 U/L+serum myoglobin (2,500 ng/ml)+AST and ALT (no values reported)	Within 7 weeks	Discontinuing drug/forced diuresis	Normalization of CK levels
Klein et al. 2006	2	30–68	Quetiapine (400 mg)/quetiapine (150 mg)	Mean: 6211 U/L+myalgia	Two weeks/3 days	Discontinuing drug/switching to olanzapine (1) and clozapine (1)	Normalization of CK levels /no further elevation
Apikoglu Rabus et al. 2006	1	33	Quetiapine (50 mg)+mirtazapine (30 mg)	9135 U/L+AST and ALT (respectively 146 U/L and 136 U/L)+LDH (929 U/L)+myalgia	Four weeks	Discontinuing drug	Normalization of CK levels within ∼14 days
Bachmann et al. 2007	1	11	Quetiapine (1200 mg)/clozapine(250mg)+aripiprazole (10 mg)	2 peaks: 1088 U/L; 4572 U/L	First peak not known, second peak ∼1 month	Monitoring	Self–limiting/normalization of CK levels within ∼7/8 days
Oulis et al. 2007	1	23	Sertindole (4mg)	3500 U/L	1 week	Discontinuing drug	CK normalization within 3 days
Punukollu and Rutherford 2008	1	25	Olanzapine (15 mg)/amisulpiride (200 mg)	3646 U/L+AST (91 U/L)+GGT (46 U/L)	Not reported	Switching to amisulpiride/discontinuing drug	CK rose again / no further follow-up
Schennach-Wolff et al. 2010	1	27	Clozapine (50 mg)	3633 U/L	5 days	Sodium-chloride infusions 4 L/day/switching to clozapine	Normalization of CK levels within 6 days/ no further increase

MACKE, massive asymptomatic creatine kinase elevation; AST, transaminase aspartate; ALT, alanine transaminase; LDH, lactate dehydrogenase; GGT, gamma-glutamyl transpeptidase.

Clinical Description

The finding of MACKE is usually the result of routine screenings. In our study, we have considered the following CK ranges: Normal level, <500 U/L; slight increase: 500–1500 U/L; moderate increase, 1500–3000 U/L; marked increase, 3000–5000 U/L; very marked increase, >5000 U/L. According to the available literature, an increase of CK level may occur in the first days of treatment (Meltzer et al. 1996: case 4), or several months after starting medications, but it could occur even after 2 years of treatment (Meltzer et al. 1996). The CK-MM isoenzime (skeletal muscle) is involved, whereas the isoenzime CK-MB (cardiac muscle) is normal (Meltzer et al. 1996; Boot and de Haan 2000). MACKE may occur irrespective of the dose regimen (Meltzer et al. 1996), although some evidence suggests that lowering the dosage may reduce the CK plasma level (Boot and de Haan 2000). The duration of the CK increase may last from few days to 4 weeks (Meltzer et al. 1996; Devarajan and Dursun 2000), significantly longer than the increase spontaneously occurring during acute psychotic episodes. It may be self-limiting (Meltzer et al. 1996, cases 7–9; Bachman et al. 2007), or may require drug discontinuation, with subsequent normalization (Meltzer et al. 1996, cases 2 and 4; Perlov et al. 2005; Oulis et al. 2007).

In most of the case reports, patients had previously taken other antipsychotic medications before the finding of high CK levels with one specific antipsychotic. In some patients, MACKE occurred with only one specific antipsychotic, whereas in others, multiple antipsychotics may determine the same high increase of serum CK. The rechallenge with the same drug may or may not determine recurrence of CK increase (Meltzer et al. 1996, cases 1 and 4, or case 2, respectively). Similarly, the switch to another antipsychotic drug has been associated with either a recurrence of MACKE or none (Pearlman et al. 1988, case 1; Devarajan and Dursun 2000). In one patient receiving olanzapine, MACKE spontaneously decreased despite the lack of discontinuation of the antipsychotic, but had a spontaneous recurrence 4 months later (Meltzer et al. 1996, case 7). The spontaneous remission without drug discontinuation, as well as the intermittent, waxing and waning course, suggests a state-dependent vulnerability or unidentified exogenous factors in vulnerable patients (Pearlman et al. 1988; Meltzer et al. 1996). Transaminases (aspartate [AST] and alanine [ALT]) and lactate dehydrogenase (LDH) levels are usually normal, or sometimes slightly increased, as well as blood urea nitrogen, serum creatinine, uric acid and aldolase (Keshavan et al. 1994; Boot and de Haan 2000). Also these parameters normalize when the drug is discontinued. The absence of myoglobinuria in the great majority of the patients suggests that gross skeletal injury is absent (Keshavan et al. 1994).

Differential Diagnoses

When the most frequent reasons for massive increase of serum CK in patients receiving antipsychotic treatment have been excluded, including intramuscular injections, restraints, intense physical activity, dystonic reactions, substance abuse, muscle disorders, and specific medical conditions (namely hypothyroidism and myocardial infarction), the two most worrisome differential diagnoses to be ruled out are NMS and rhabdomyolysis (Table 2).

Table 2.

Signs and Symptoms Characterizing the Main Differential Diagnosis of MACKE

	Neuroleptic malignant syndrome	Rhabdomyolysis	MACKE
Hyperthermia	+	++/−	−
Muscolar rigidity	+	−	−
Autonomic instability	+	−	−
Altered consciousness	+	−	−
Increased heart rate	++/−	+/−	−
Increased blood pressure	++/−	+/−	−
CK elevation	++/−	+/−	+
Myalgias	−	+	−
Weakness	−	+	−
Dark urine	−	+	−
Myoglobinuria	+/−	+/−	−
Elevated transaminases	+/−	+/−	+/−
Elevated serum potassium	−	++/−	−
Leukocytosis	+/−	−	−
Abdominal/muscle pain	+/−	++/−	+/−

+, The sign or the symptom is present in all cases.

++/−, The sign or the symptom is present in almost all cases, depending upon degree of severity.

+/−,The sign or the symptom can be present or not.

−, The sign or the symptom is almost never present.

MACKE, massive asymptomatic creatine kinase elevation.

NMS

NMS is a potentially life-threatening side effect of uncertain origin during treatments with both FGAs and SGAs, even in children and adolescents (Neuhut et al. 2009; Masi and Liboni 2011; Su et al. 2014). Hyperthermia, muscular rigidity, tachycardia, hyper- or hypotension, autonomic instability, myonecrosis, and altered mental status are all hallmarks of NMS (Masi and Liboni 2011). Possible diagnostic errors are catatonia, extrapyramidal side effects (EPS), or infectious diseases. When unrecognized and untreated, this condition can progress to a loss of consciousness and even death. Although CK elevation has been often reported, a clear relationship between increase of CK blood level and NMS has still to be demonstrated (Adityanjee 1991; Nisijima 2012). An elevation of CK can occur, but this finding is not always present, and, therefore, its absence may be misleading and may induce a delay in the treatments (Nisijima 2012). On the contrary, NMS criteria too heavily related to high CK serum levels without signs of fever, altered consciousness, or muscular rigidity may lead to an overdiagnosis of NMS, with high false positive rates (Adityanjee 1991). In summary, the presence of the following four symptoms – fever, muscular rigidity, altered level of consciousness and autonomic dysregulation – should be considered as alarming signs; whereas CK elevation can help an early detection, but is not a diagnostic hallmark.

Rhabdomyolysis

Rhabdomyolysis is a clinical and laboratory syndrome resulting from a rapid destruction of skeletal muscle cells, with release of muscle cell content in the plasma (Gabow et al. 1982; Marcus et al. 1999) caused by diverse mechanisms, including drugs and toxins (Hohenegger 2012). Approximately half of all patients with rhabdomyolysis present with the symptomatological triad of myalgias, weakness, and dark (tea colored) urine, with a history of trauma or medication use (Elsayed and Reilly 2010). It may or may not result in notable myoglobinuria, depending upon the amount of myoglobin released in the plasma, the glomerular filtration rate, and the urine concentration (Poels and Gabreels 1993). Rhabdomyolysis has a broad range of clinical manifestations, and this accounts for the uncertainties in criteria for its definition (Gabow et al. 1982; Poels and Gabreels 1993; Marcus et al. 1999).

Mild cases of rhabdomyolysis might exist that are subclinical, but it can be associated with elevations of serum CK (i.e., at least five times the upper limit). When skeletal muscle injury exceeds 100 g, myoglobin is massively released and detectable before CK rises, and myoglobinuria plugs the kidney, in particular under acidic conditions. Elevated CK and serum potassium levels, hyperuricosuria, and acidosis occur with the progression of tissue destruction, and the improvement of these parameters indicates a trend toward recovery. Extensive hydration for forced diuresis and early fluid resuscitation are crucial to stabilize circulation, buffer acidosis, and control serum potassium (Better and Abbassi 2011). Moreover, suggested volumes of 12 L/day should flush the tubular system to keep it protected from damage by hyperuricosuria and/or myoglobin. Thus, rapid and aggressive therapeutic intervention helps to prevent fatal complications such as arrhythmias, renal failure, and disseminated vascular coagulation (Elsayed and Reilly 2010; Better and Abbassi 2011; Hohenegger 2012). Rhabdomyolysis, with and without NMS, can occur during treatment with antipsychotics. Recently, two studies have highlighted this association, both in adults and children; it can occur especially during polytherapies, more likely in connection with a dose increase, switch, or add-on of another antipsychotic (Star et al. 2012; Packard et al. 2014).

Toward a Putative Pathophysiology

To date, a clear explanation of MACKE is not available, and multiple, nonalternative pathways may lead to increased serum CK. It can be hypothesized that MACKE can occur only in vulnerable individuals (Meltzer et al. 1996; Bachman et al. 2007), and that this vulnerability may be state dependent, or transitorily affected by unidentified exogenous factors. It is probably related to damage that increases the permeability of membranes of muscular cells, but is not severe enough to determine rhabdomyolysis (Keshavan et al. 1994; Apikoglu Rabus et al. 2006), although it cannot be ruled out that it may be the first phase of a frank rhabdomyolysis.

Meltzer and colleagues (1996) hypothesized that the binding of some antipsychotics to the high-affinity 5-HT2 receptors in the sarcolemma may result in an accumulation of 5-HT by passive diffusion, with increased permeability, and following elevation of serum CK, whereas cell injury and necrosis is less likely, given the rarity of high serum myoglobin (Marcus et al. 1999). However, although haloperidol does not present a 5-HT2 affinity, and chlorpromazine has a D2 affinity much more potent than 5-HT2 affinity, both these FGAs have been associated with MACKE (Meltzer et al. 1996). Furthermore, medications with potent 5-HT2 antagonism, such as nefazodone and mirtazapine, usually do not increase CK levels, although there is a report of CK increase after starting polypharmacy with both quetiapine and mirtazapine (Apikoglu Rabus et al. 2006).

Another possible explanation is an inhibition caused by the effect of antipsychotics on calmodulin function, or on protein kinase C, resulting in the leakage of CK from the muscle cells (Weiss et al. 1982; Dinan 1987). A nonalternative mechanism has been proposed by Melkersson, who postulated a direct stimulatory effect of SGAs (namely clozapine and olanzapine) on CK synthesis in muscle cells (Melkersson 2006). An alternative, “central” mechanism postulated that the blockade of the dopaminergic nigrostriatal pathway results in involuntary excessive movements, such as stiffness, rigidity, Parkinsonian-like movements, and akathisia, followed by CK increases (Devarajan and Dursun 2000). However, medications with lower dopaminergic nigrostriatal blockade, and prevalent limbic action (i.e., quetiapine and clozapine), may also be associated with high CK levels (Perlov et al. 2005; Klein et al. 2006).

Koren and colleagues reported on a patient with a rabdomyolysis during treatment with clozapine, who presented a severe decrease of calcium-dependent potassium channel efflux in the red blood cells (Koren et al. 1998). These channels have been described in several tissues, including the muscle cells, where they determine a hyperpolarization of muscles cells, resulting in decreased susceptibility to triggering stimuli. The authors postulated that the clozapine-induced rhabdomyolysis may be related to a potentiation of an inborn defect of the potassium maxi channels, and that this effect may be shared by other antipsychotic drugs (Koren et al. 1998). An additional, poorly explored issue, which may potentially affect the risk, is the presence of polymorphisms of drug metabolizing enzymes. For example, the adolescent patient described by Bachman and colleagues appeared to be a poor metabolizer of CYP2D6 (Bachman et al. 2007).

Clinical Vignettes

We present three clinical vignettes describing the first nonpsychotic youth with MACKE during treatment with SGAs (respectively risperidone, olanzapine, and risperidone).

Case 1: Conduct disorder and Tourette syndrome

A 13-year-old boy was assessed in ambulatory sessions for motor and vocal tics (Tourette syndrome) of moderate to severe intensity, associated with conduct disorder, with onset during elementary school. After an acute worsening of both tics and behavior, when he was 12 years old, risperidone was started, at increasing dosages up to 3 mg/day. The medication was markedly effective for tic symptomatology, and moderately improved his behavior as well. It was well tolerated, without any abnormality on electrocardiogram (ECG) and blood analyses. During the follow-up, the clinical picture of Tourette syndrome remained stable, and the patient's behavior further improved, both at home and at school. After the patient had been receiving ∼1 year of pharmacological treatment, a marked increase of CK (3300 U/L) was found during a periodic blood examination, without any other alteration, and without clinical signs. A careful examination of muscle function failed to reveal abnormalities. ECG with QTc, echocardiography, standard urine test were all in normal ranges. The medication was rapidly discontinued, and at the following examination, after few weeks later, CK was normalized, and the patient remained asymptomatic. Given the persisting good control of tic and behavior even after drug discontinuation, the patient was not rechallenged with risperidone.

Case 2: Conduct disorder and oppositional defiant disorder

A 16-year-old boy, adopted from Russia at 6 years of age, was admitted to our hospital in Pisa for the first time 2 years ago for severe conduct disorder. After a long history of oppositional and defiant behavior, a worsening of the clinical picture occurred when the boy was of school age, including temper tantrums, aggression against objects, and low academic achievement. Risperidone was started, with partial improvement of disruptive behavior, but with several side effects, namely EPS. Risperidone was gradually discontinued, and olanzapine was titrated up to 10 mg/day. Approximately 18 months after the introduction of olanzapine, a massive increase in serum CK was found, initially 543 U/L and, 20 days later, a peak of 10,350 U/L. AST at 115 U/L (range up to 40) and LDH 394 U/L (range 135–225) were associated findings. No signs or symptoms of NMS were found. Physical and neurological examinations were in the normal range (other than a slight difficulty in releasing fingers after contraction); ECG with QTc, echocardiography, standard urine test were all in normal ranges. A genetic evaluation for myotonic dystrophy type I was negative. Olanzapine was discontinued. After 7 days, CK serum level was markedly decreased (272 U/L), and 15 days later, the level was totally normal. Olanzapine was gradually reintroduced up to 5 mg/day, and 1 month later, serum CK started to rise again, first to 290 U/L, and, 2 weeks later, to 382 U/L, along with mild increase of aldolase 9.0 U/L (normal range up to 7.6) and creatinuria 292 mg/dL (normal range 39–259). ECG, CK-MB, myoglobin, and troponin were in the normal range. Full abdominal ultrasound, neurometabolic evaluation, and brain and muscle MRI were normal. Olanzapine was gradually restarted, up to 7.5 mg/day, with further improvement of disruptive behavior and normal laboratory findings.

Case 3: Conduct disorder, oppositional defiant disorder and mood disorder not otherwise specified (NOS)

A 14-year-old boy was admitted at our hospital in Pisa ∼2 years ago for a conduct disorder, with mood dysregulation and multiple anxiety disorder. Quetiapine was firstly introduced, rapidly replaced with risperidone (1.25 mg/day) because of lack of improvement. Two months later, during a routine blood test, the patient's serum CK rose to 7284 U/L, in the absence of clinical symptoms. Cardiac causes of CK elevation were ruled out, as was cocaine use and an endocrinological assessment was performed. An in-depth neurological evaluation, transaminases, and myoglobinuria were normal. The patient was strictly monitored for CK levels and for neurological symptoms, and 2 weeks later, CK fell to consistently below 500 U/L. Given the improvement of the psychiatric picture, it was decided, under close medical control, to maintain the medication at same dosage.

Conclusion

In this article, we extensively reviewed a rare but intriguing and clinically relevant finding during treatment with both first- and second-generation antipsychotics, until now only reported with sparse case reports. According to this review, MACKE is an autonomous clinical entity (or a possible side effect) that can occur during antipsychotic drug treatment, in the absence of any additional sign of NMS or rhabdomyolysis, without any progression toward these severe clinical conditions, being self-limiting or reversible after drug discontinuation.

Meltzer and colleagues (1996) stated that monitoring CK during antipsychotic treatment is unnecessary, because renal damage after high CK serum levels has not been demonstrated in any of the reported cases. Our findings show that MACKE can occur even in young adolescents and even in nonpsychotic disorders. The spontaneously remitting or intermittent course suggests that the “true” MACKE is not an incipient NMS, or the first step to a mild rhabdomyolysis. However, the differential diagnosis is possible only with careful monitoring and follow-up, although the methodology of this monitoring is far from clear (Boot and de Haan 2000).

The issue is how to balance a cost/benefit evaluation. Among the negative implications of close monitoring, beyond the unpleasant experience of frequent blood draws and unnecessary worry by patients and parents, an increase of healthcare costs should be considered, related not only to CK assessment, but also to further investigations in the positive cases. Our clinical vignettes are an example of a prevalently unnecessary diagnostic test that is not useful on a large scale level. Furthermore, an unnecessary discontinuation of an effective treatment may cause a destabilization of the clinical picture, with greater burden for patients and parents. Based on available evidence, supported by our experience, this risk in asymptomatic CK elevations is not demonstrated, and we maintain that is important to clearly keep distinct MACKE, rhabdomyolysis, and NMS. We agree with Meltzer and colleagues that checking CK during antipsychotic treatment is unnecessary in an asymptomatic patient, again unless there is proven harm. The finding of MACKE should lead to closer monitoring of CK levels only when there are reasons to believe elevated CK is in and of itself toxic or harmful. Further investigations are recommended only when signs and symptoms raise a suspicion for NMS or rhabdomyolysis, including flu-like syndrome, fever, weakness, alteration of consciousness, muscle rigidity, tachycardia, hyper-/hypotension, and dark urine. When one or more of these signs are present, myoglobinuria and uricosuria, serum myoglobin, blood urea nitrogen, serum creatinine, and uric acid should also be monitored. Renal function (namely myoglobinuria and uricosuria) should also be monitored.

An unduly excessive emphasis on isolated MACKE may become a “myth” leading to a harmful overdiagnosis of “suspect” NMS or rhabdomyolysis (Addonizio et al. 1986; Adityanjee 1991), and this incorrect diagnosis may lead to an unnecessary discontinuation of an effective therapeutic agent (Adityanjee 1991). Future research should elucidate a possible pathophysiological mechanism as well as generate epidemiological data.

Clinical Significance

Clinicians should be aware that MACKE can occur during antipsychotic exposure, even in nonpsychotic youth, and that it is independent of drug type and dosage. Although monitoring of the clinical picture is mandatory (including hepatic, cardiac and renal function), a sudden switch/discontinuation of the antipsychotic is usually not necessary. A “wait and see” approach can be suggested in absence of relevant clinical impairment and if CK elevation is in the moderate range (<3000 U/L) (Meltzer et al. 1996; Boot and de Haan 2000; Bachman et al. 2007), as a rapid decrease can start as early as in the following days after detection. A close monitoring of possible signs of NMS or rhabdomyolysis, including fever, muscular rigidity, altered level of consciousness, signs of renal damage, and autonomic dysregulation (temperature, electrolytes, blood pressure, heart rate) is mandatory. Dose reduction or drug discontinuation is recommended in cases of very high (>5000 U/L) and persisting (2 weeks) CK levels. Empirical evidence indicates that there is not a “safe” antipsychotic medication; therefore, a “switching strategy” to another antipsychotic seems more likely to be a jump in the dark rather than a reliable option. Switching to a drug with a different receptor's profile is not supported by available evidence. The outcome of rechallenge with the same medication after normalization of CK levels is unpredictable, but it should be considered when the psychiatric clinical picture has worsened markedly, without full recovery after switch to other antipsychotics.

Footnotes

Disclosures

Dr. Masi was on the advisory boards for Eli Lilly and Shire, has received research grants from Eli Lilly and Shire, and has been a speaker for Eli Lilly, Lundbeck, Novartis, and Shire, and has been a consultant for Otsuka. The other authors have nothing to declare.

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