Cases That Test Your Skills

Seeing snakes that aren’t there

Current Psychiatry. 2019 December;18(12):42,44-48

References

1. Cherland E, Fitzpatrick R. Psychotic side effects of psychostimulants: a 5-year review. Can J Psychiatry. 1999; 44(8):811-813.
2. Ross RG. Psychotic and manic-like symptoms during stimulant treatment of attention deficit hyperactivity disorder. Am. J. Psychiatry. 2006;163(7):1149-1152.
3. Rashid J, Mitelman S. Methylphenidate and somatic hallucinations. J Am Acad Child Adolesc Psychiatry. 2007;46(8):945-946.
4. Rubio JM, Sanjuán J, Flórez-Salamanca L, et al. Examining the course of hallucinatory experiences in children and adolescents: a systematic review. Schizophr Res. 2012;138(2-3):248-254.
5. Iversen L. Neurotransmitter transporters and their impact on the development of psychopharmacology. Br J Pharmacol. 2006;147(Suppl 1):S82-S88.
6. Howes OD, Kambeitz J, Kim E, et al. The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry. 2012;69(8):776-786.
7. Bloom AS, Russell LJ, Weisskopf B, et al. Methylphenidate-induced delusional disorder in a child with attention deficit disorder with hyperactivity. J Am Acad Child Adolesc Psychiatry. 1988;27(1):88-89.
8. Shibib S, Chaloub N. Stimulant induced psychosis. Child Adolesc Ment Health. 2009;14(1):1420-1423.
9. Lucas AR, Weiss M. Methylphenidate hallucinosis. JAMA. 1971;217(8):1079-1081.
10. Kraemer M, Uekermann J, Wiltfang J, et al. Methylphenidate-induced psychosis in adult attention-deficit/hyperactivity disorder: report of 3 new cases and review of the literature. Clin Neuropharmacol. 2010;33(4):204-206.
11. Mosholder AD, Gelperin K, Hammad TA, et al. Hallucinations and other psychotic symptoms associated with the use of attention-deficit/hyperactivity disorder drugs in children. Pediatrics. 2009; 123:611-616.
12. Gross-Tsur V, Joseph A, Shalev RS. Hallucinations during methylphenidate therapy. Neurology. 2004;63(4):753-754.
13. Halevy A, Shuper A. Methylphenidate induction of complex visual hallucinations. J Child Neurol. 2009;24(8):1005-1007.
14. Porfirio MC, Giana G, Giovinazzo S, et al. Methylphenidate-induced visual hallucinations. Neuropediatrics. 2011;42(1):30-31.
15. Griffith J. A study of illicit amphetamine drug traffic in Oklahoma City. Am J Psychiatry. 1966;123(5):560-569.
16. Young JG. Methylphenidate-induced hallucinosis: case histories and possible mechanisms of action. J Dev Behav Pediatr. 1981;2(2):35-38.
17. Stein MA, Sarampote CS, Waldman ID, et al. A dose-response study of OROS methylphenidate in children with attention-deficit/hyperactivity disorder. Pediatrics. 2003; 112(5):e404. PMID: 14595084.
18. Hsieh JH, Stein DJ, Howells FM. The neurobiology of methamphetamine induced psychosis. Front Hum Neurosci. 2014;8:537. doi:10.3389/fnhum.2014.00537.
19. Shyu YC, Yuan SS, Lee SY, et al. Attention-deficit/hyperactivity disorder, methylphenidate use and the risk of developing schizophrenia spectrum disorders: a nationwide population-based study in Taiwan. Schizophrenia Res. 2015;168(1-2):161-167.
20. MacKenzie LE, Abidi S, Fisher HL, et al. Stimulant medication and psychotic symptoms in offspring of parents with mental illness. Pediatrics. 2016;137(1). doi: 10.1542/peds.2015-2486.
21. Schaeffer J, Ross RG. Childhood-onset schizophrenia: premorbid and prodromal diagnosis and treatment histories. J Am Acad Child Adolesc Psychiatry. 2002;41(5):538-545.
22. Faedda GL, Baldessarini RJ, Blovinsky IP, et al. Treatment-emergent mania in pediatric bipolar disorder: a retrospective case review. J Affect Disord. 2004;82(1):149-158.
23. DelBello MP, Soutullo CA, Hendricks W, et al. Prior stimulant treatment in adolescents with bipolar disorder: association with age at onset. Bipolar Disord. 2001;3(2):53-57.
24. Soutullo CA, DelBello MP, Ochsner BS, et al. Severity of bipolarity in hospitalized manic adolescents with history of stimulant or antidepressant treatment. J Affect Disord. 2002;70(3):323-327.
25. Reichart CG, Nolen WA. Earlier onset of bipolar disorder in children by antidepressants or stimulants? An hypothesis. J Affect Disord. 2004;78(1):81-84.
26. Ikeda M, Okahisa Y, Aleksic B, et al. Evidence for shared genetic risk between methamphetamine-induced psychosis and schizophrenia. Neuropsychopharmacology. 2013;38(10):1864-1870.

TREATMENT Discontinuation and re-challenge

After 3 days, we discontinue OROS methylphenidate. Five days after discontinuation, R’s visual hallucinations and aggressive behaviors completely resolve. After not receiving stimulants for 2 weeks, R is restarted on short-acting methylphenidate, 5 mg/d, because he had a relatively good clinical response to short-acting methylphenidate previously. After 14 days, the short-acting methylphenidate dosage is increased to 5 mg twice daily without the re-emergence of psychosis or aggressive behaviors.

The authors’ observations

Although stimulant-induced psychosis can be a disturbing adverse effect, severe ADHD greatly affects a person’s functioning at school and at home and can lead to several comorbidities, including depression, anxiety, and substance abuse. For these reasons, most patients with ADHD who experience psychotic symptoms are re-challenged with stimulants.¹⁰ Out of the 14 cases discussed above, 4 patients were restarted on the same stimulant or a different ADHD medication; 2 of them had the same psychotic symptoms days after the reintroduction of the drug and the other 2 had no recurrence.^10,12,13

Stimulant-induced hallucinations

The emergence of hallucinations with methylphenidate or amphetamines has been attributed to a chronic increase of dopamine levels in the synaptic cleft, while the pathophysiological mechanisms are not clearly known. In some cases, hallucinations emerged after taking the first low dose, which has been thought to be an effect of idiosyncratic mechanism. Stimulants cause an increase of the releasing of catecholamines. Porfirio et al¹⁴argue that high-dose stimulants can deteriorate the response to visual stimuli, causing a different perception of visual stimuli in susceptible children, based on the information that norepinephrine is released in the lateral geniculate nucleus, and it increases the transmission of visual information.

An idiosyncratic drug reaction

Despite the existence of many theories on the pathophysiology of stimulant-induced psychosis (Box^15-18), its actual mechanism remains unknown. In R’s case, given the speed with which his symptoms developed, the proposed mechanisms of action may not explain his psychotic symptoms. We must consider an idiosyncratic drug reaction as an explanation. This suggestion is supported by the fact that re-challenging with a stimulant did not re-induce psychosis in 2 out of the 4 cases described in the literature,^10,12,13as well as in R’s case.

Box

The pathophysiology of stimulant-induced psychosis

Although the subjective effects of methylphenidate and amphetamines are similar, neurochemical effects of the 2 stimulants are distinct, with different mechanisms of action. Methylphenidate targets the dopamine transporter (DAT) and the noradrenaline transporter (NET), inhibiting DA and NA reuptake, and therefore increasing DA and NA levels in the synaptic cleft. Amphetamine targets DAT and NET, inhibiting DA and NA reuptake, and therefore increasing DA and NA levels in the synaptic cleft. It also enters the presynaptic neuron, preventing DA/NA from storing in the vesicles. In addition, it promotes the release of catecholamines from vesicles into the cytosol and ultimately from the cytosol into the synaptic cleft.¹⁸

Generally, amphetamines are twice as potent as methylphenidate. As such, lower doses of amphetamine preparations can cause psychotic symptoms when compared with methamphetamine products.¹⁷ Griffith¹⁵ showed that paranoia manifested itself in all participants who were previously healthy as they underwent repeated administration of 5 to 15 mg of oral dextroamphetamine many times per day for up to 5 days in a row, leading to cumulative doses ranging from 200 to 800 mg.¹⁵ At such doses, the effects are similar to those obtained with illicit use of methamphetamine, a drug of abuse for which psychosis-inducing effects are well documented.

Psychosis in reaction to therapeutic doses of methylphenidate may have a mechanism of action that is shared by psychosis in response to chronic use of methamphetamine. Several hypotheses have been suggested to explain the mechanism behind stimulantinduced psychosis in cases of chronic methamphetamine use:

Young,¹⁶ who had one of the first proposed theories in 1981, hypothesized attributing symptoms to dose-related effects at pre- and post-synaptic noradrenergic and dopaminergic receptors.
Hsieh et al¹⁸ hypothesized that methamphetamine use causes an increased flow of dopamine in the striatum, which leads to excessive glutamate release into the cortex. Excess glutamate in the cortex might, over time, cause damage to cortical interneurons. This damage may dysregulate thalamocortical signals, resulting in psychotic symptoms.¹⁸

Although the mechanisms by which psychotic symptoms associated with stimulants occur remain unknown, possibilities include^10,19:

genetic predisposition
changes induced by stimulants at the level of neurotransmitters, synapses, and brain circuits
an idiosyncratic drug reaction.

Continue to: What to consider before prescribing stimulants

References

Chronic pain more common in women with ADHD or ASD

Seeing snakes that aren’t there

References

TREATMENT Discontinuation and re-challenge

The authors’ observations

Stimulant-induced hallucinations

An idiosyncratic drug reaction

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