9.1. Analysis.
Comparison 9 Patient reports/series: number of participants with serious adverse events, Outcome 1 Central nervous system.
| Central nervous system | |
|---|---|
| Study | |
| Psychotic conditions | |
| Abali 2007 | A 14‐year‐old girl with diagnoses of ADHD (attention deficit hyperactivity disorder), major depression and conduct disorder. During her treatment with methylphenidate of 20 mg/day and fluoxetine of 20 mg/day, she developed visual and auditory hallucinations. It may be concluded that it is possible that methylphenidate may cause hallucinations in patients treated simultaneously with fluoxetine |
| Aguilera‐Albesa 2010 | 2 case reports of the appearance of hallucinations a few hours after methylphenidate ingestion in an 8‐year‐old boy (extended‐release methylphenidate of 18 mg/day, given once daily for 2 days) and a 6‐year‐old girl (extended‐release methylphenidate of 10 mg/day for 3 days and 20 mg/day for 1 day, given once a day). Both diagnosed with ADHD according to criteria in the DSM‐IV (Diagnostic and Statistical Manual, Fourth Edition) and with IQs (intelligence quotients) > 85. These case reports suggest an individual susceptibility to psychotic symptoms after taking methylphenidate. This adverse event is considered idiosyncratic, extraordinary and unpredictable |
| Coşkun 2008 | A paediatric patient who developed tactile and visual hallucinations with the combination of osmotic release oral system (OROS) methylphenidate and fluoxetine. Comments from the study authors: In conclusion, we think that the causative agent was the combination of both medications rather than either medication alone. However, in either situation, it is important to note that this distressing side effect may occur even in the absence of underlying psychotic or substance‐related disorders, and clinicians' awareness is important in this issue, particularly in cases where polypharmacy is considered |
| Goetz 2011 | A case report of nocturnal visual hallucinations during methylphenidate treatment. A girl with ADHD and ODD (oppositional defiant disorder) experienced a 3‐hour episode of nocturnal complex bizarre visual hallucinations when treated with 18 mg of OROS methylphenidate. Nocturnal polysomnography performed 2 weeks later revealed REM (rapid eye movement) sleep reduction (17%) and fragmentation. 2 episodes of confusional arousals were recorded. This finding is typical of parasomnia associated with NREM sleep – disorder of arousal. It is hypothesized that this pre‐existing sleep impairment represents a factor of vulnerability to methylphenidate sleep side effects |
| Gross‐Tsur 2004 | 3 children with ADHD, who were treated with low doses of methylphenidate and who developed complex visual and haptic hallucinations Comments from the study authors: The causal role of methylphenidate in the development of hallucinations was based on their appearance after ingestion of the drug, resolving after its withdrawal, and the absence of psychiatric comorbidity that could explain such phenomena. In 1 patient, the hallucinations reappeared after an inadvertent re‐challenge. Because methylphenidate is a widely used, well‐studied, and safe pharmacologic agent, physicians who prescribe methylphenidate should be aware of even rare adverse manifestations occurring at therapeutic doses |
| Halevy 2009 | Several days after initiation of treatment: visual hallucinations of rats, accompanied by some tactile hallucinations. Only present during the time the patient was under the influence of methylphenidate and disappeared thereafter; immediate complete resolution upon discontinuation of the drug. Reintroduction of metyhlphenidate treatment after 2 days resulted in same complex visual hallucinations, with immediate complete resolution upon discontinuation of the drug Key conclusions of the study authors: In our case, the occurrence of hallucinations after a very low dose of methylphenidate on 2 occasions may suggest an idiosyncratic reaction. The phenomenon might also be explained by a drug‐induced dysfunction of the monoamine transmitters. Given the wide use of methylphenidate, clinicians should be aware of this possible side effect |
| Irmak 2014 | A case report of phobias and visual hallucinations during methylphenidate treatment in a 9‐year‐old boy. OROS methylphenidate gradually titrated up to 1 mg/kg. Methylphenidate prescribed at initial ADHD diagnosis and then withdrawn following the onset of phobias and visual hallucinations, as well as lack of improvement in attention problems |
| Mino 1999 | A case report on methylphenidate‐induced psychosis in an adolescent with hyperkinetic disorder; use of methylphenidate for 1 month. Three weeks after starting methylphenidate (10 mg/day), the mother reported by telephone that the patient seemed depressed. Dose of methylphenidate was reduced to 5 mg/day. A week later the patient visited the clinic. The therapist diagnosed her condition as a depressive state and discontinued methylphenidate. Six weeks after discontinuation of methylphenidate she was diagnosed with a schizophrenic‐like psychotic state, due to symptoms of delusions of reference and persecution, delusional mood, silly smile and thought block. There was no evident hallucination. The patient took antipsychotic medication for 2 months and her psychotic symptoms disappeared |
| Porfirio 2011 | 3 years after start of methylphenidate treatment: An episode of complex visual hallucinations (dramatic scenes appearing before going to sleep, sometimes during the day after ingestion of methylphenidate |
| Rashid 2007 | A case report of intensified somatic hallucinations during dose increase of methylphenidate treatment in a 10‐year‐old boy with a chronic pattern of somatization, which evolved into overt somatic hallucinations with an increase in methylphenidate dosage. This pattern of somatization was retrospectively recognized as partial somatic hallucinations |
| Shibib 2009 | A report of four cases of psychosis during methylphenidate treatment Key conclusion of the study authors: Psychosis is an important, unpredictable side effect of stimulant medication. Symptoms resolve with discontinuation of treatment. Reemergence of ADHD symptoms are rapid and re‐challenge is often indicated. It would be advisable for all professionals involved in the care and treatment of patients with ADHD to receive mental health training to aid the early recognition and appropriate management of such side effects |
| Tomás Vila 2010a | After two weeks of 50% immediate‐release and 50% extended‐release methylphenidate: visual hallucinations (insects on hands, feet, abdomen and thorax), with associated itching, initiated two hours after ingestion and ceased five hours after. Discontinuation of methylphenidate and initiation of risperidone resulted in no visual hallucinations. No re‐administration of methylphenidate due to ethical reasons Key conclusions of the study authors: This is the first case report of visual hallucinations caused by 50% immediate‐release and 50% extended‐release methylphenidate, which is not surprising considering the relative recent appearance of this preparation on the market |
| Seizures | |
| Feeney 1997 | First‐reported seizure in a patient being treated with methylphenidate and sertraline combined |
| Hemmer 2001 | Reported seizures in a boy aged six, and two girls aged six and seven, receiving 0.3 to 1 mg/kg/day of methylphenidate for six weeks, 10 and three months, respectively |
| Cerebral arteritis | |
| Trugman 1988 | Key conclusions of the study authors: Cerebral arteritis and infarction were caused by chronic use of oral methylphenidate. The Cerebrospinal fluid (CSF) profile and angiogram support the diagnosis of inflammatory arteritis, yet laboratory evaluation revealed no identifiable cause. In the six years since the stroke, while not on methylphenidate, there has been no evidence of active central nervous system or systemic vasculitis |
| Self‐harm and suicidal behaviour | |
| Arun 2014 | 2 case reports with 2 children having suicidal ideation |
| Gökce 2015 | Reported a 12‐year‐old boy who made a suicide attempt after switching from 27 mg to 36 mg of OROS methylphenidate: The patient reported irritable mood when he took the first dose of 36 mg of long‐acting methylphenidate. This might be the cause of the suicide attempt. He had a full recovery after withdrawal from methylphenidate |
| Strandell 2007 | Reported concerns about suicidal behaviour, including suicide, based on information retrieved from the WHO Collaborating Centre for International Drug Monitoring (Uppsala, Sweden). A total of 116 reports of methylphenidate related to "suicide attempts", although this term was not explicitly defined. The data included reports of methylphenidate and atomoxetine |
| Death | |
| Tølløfsrud 2006 | A case report of death caused by heart failure (acute dilated cardiomyopathy) during methylphenidate treatment |
| Dyskinesia | |
| Yilmaz 2013 | Involuntary movements started about 5 hours after taking MPH. Lip‐licking, lip‐smacking and tongue‐rolling movements. Dyskinetic tongue movements inside and outside the mouth and involuntary bilateral arm swinging while sitting and standing. Opening and closing his fingers without complete extension. Occasional repetitive movements of the feet, such as beating them against each other while sitting. About 15 hours after MPH intake both hand‐mouth movements and excessive mobility had significantly resolved. Dyskinetic symptoms had completely disappeared on the second day of hospitalization, and the patient was discharged Key conclusions of the study authors: This case is reported to emphasize the potential side effects of methylphenidate, individual differences in drug sensitivities, and drug‐receptor interactions via different mechanisms |