Very low risk of Psychosis due to ADHD medication

Great news! New study published on March 21, 2019 provides yet more evidence to safety and efficacy of psychostimulants like Ritalin (Methylphenidate) and Adderall (Amphetamine). The study examined 337,919 adolescents and young adults who received a prescription for a stimulant for ADHD. The results showed that among adolescents and young adults with ADHD who were receiving prescription stimulants, new-onset psychosis occurred in approximately 1 in 660 patients.

ADDspeaker’ conclusion

According to Moran et al. (2019) […] Between 0.10% – 0.20% of all users of Methylphenidate or Amphetamine from between January 1, 2004, and September 30, 2015, have had a psychotic episode[…], and as we’ve learned from Levy et al. (2015) that the risk of having a comorbid psychotic disorder, when diagnosed with ADHD is around 10%, so having registered so few cases of psychotic episodes in connection with the use of ADHD stimulant medication, is case and point that stimulants are both safe, have a high efficacy and do not cause psychotic episodes for between 99.8% and 99.9% of alle users of ADHD medication.

Key findings from Moran et al. (2019) is […] that out of 337,919 incident users of stimulants, there were 343 episodes of psychosis (with an episode defined as a new diagnosis code for psychosis and a prescription for an antipsychotic medication) among the 221,846 patients in the matched population: 106 episodes (0.10%) among 110,923 patients in the methylphenidate group and 237 episodes (0.21%) among 110,923 patients in the amphetamine group. […]

This should settle this concern, once and for all.
/ADDspeaker

Dansk resumé: Fantastiske nyheder! Et helt nyt studie fra marts 2019, har nu påvist at ADHD medicin ikke øger risikoen for at man udvikler en psykose. Ud af 337.919 tilfælde hvor en person har fået en recept på ADHD medicin, har studiet vist at 0,10% udviklede en psykose af at tage Methylphenidat (Ritalin, Concerta, Medikinet etc.) og at 0,20% udviklede en psykose efter at have taget (Lis)dexamfetamin (Attentin, Elvanse). Altså er der tale om en risiko for at udvikle en psykose pga. ADHD medicin der er på 1 ud 660 personer, hvilket må siges at være ‘meget lav risiko’. Årsagen til at nogle personer får en psykose, efter at have taget ADHD medicin, skyldes med stor sandsynlighed, at personen lider af en komorbid psykotisk lidelse (f.eks. Skizofreni) som først opdages, i gennemsnit, 128 dage efter at personen har fået ADHD medicin. Vi ved at omkring 10% af alle med ADHD også lider af psykotiske lidelser, og det er derfor vigtigt at sikre at få en kvalificeret udredning for ADHD og potentielle somatiske (hjertekarsygdomme) og psykiske (Skizofreni, Bipolar lidelse) komorbiditeter.

Introduction

One of the biggest fears of using ADHD medication is the risk of developing Psychosis. The lastet published study is pay for by The National Institute of Mental Health (USA), which once and for all rules out any suspicious relations to ‘Big Pharma’, and other perceptions of bias or misconduct.

Let’s just agree on what a psychosis means;

OK, with that knowledge, let’s look at what we know so far;

According to a 2015 Canadian study the reason for this fear is based on undetected comorbid Psychotic Disorders (e.g. Schizophrenia). The authors write; […] Psychotic disorders (PD) and ADHD are highly prevalent neurodevelopmental disorders. While the lifetime prevalence of all PDs is above 3%, the lifetime prevalence of ADHD may exceed 10%. Given their high prevalence, they are bound to co-occur in a substantial number of cases. Each of these disorders is associated with an important negative impact on the functioning of people affected and their ability to achieve education, work, and other important life aspirations. One consistent commonality between ADHDand PD is a high association with smoking and other drugs of abuse. […] Levy et al. (2015)

The authors explains why the fear of psychosis is exaggerated; […] Clinicians may be reluctant to use psychostimulants together with APs for fear of worsening psychotic symptoms. In a widely cited study done over 25 years ago, Lieberman et al. (1987) reviewed studies on the effect of psychostimulants on patients with schizophrenia. They found that 40% of patients with schizophrenia had worsening of psychotic symptoms. Although, the remaining 60% either showed no change or improved, the authors used these finding to propose that PD was a DA-related disorder. […] Levy et al. (2015)

[…]Clinicians’ fear of using psychostimulants may be due to a simplistic conceptualization of DA regulation. Indeed, psychostimulants act mainly by enhancing the synaptic levels of DA through the blockade of DAT. In the prefrontal cortex, DA action is terminated mainly by the NET because there are few DATs. Psychostimulants block NETs and DATs thereby modulating the levels of both catecholamines (DA and NE). Conversely, APs exert their effects mainly by blocking postsynaptic DA D2 receptors. […] Levy et al. (2015)

[…] At first glance, psychostimulants may appear to antagonize the effects of APs. This perception may have led to the conventional reluctance to using psychostimulants in comorbid ADHD and PD. However, 2 well-replicated observations suggest that psychostimulants at therapeutic doses do not increase DA transmission in the mesolimbic pathway. The first observation identifies 2 interacting DA signalling mechanisms: 1 tonic and the other phasic. Phasic signalling corresponds to fast spikes of DA release that engage postsynaptic receptors and whose action is rapidly terminated through reuptake by DAT. In contrast, tonic signalling depends on the overall level of DA surrounding the synapse. It activates high-affinity presynaptic DA D2 autoreceptors and consequently tunes down phasic DA signalling. Low doses of psychostimulants have been shown to increase tonic transmission and decrease phasic DA spikes. However, high doses of psychostimulants can massively increase both types of transmission. This finding also makes it possible to conceptualize the difference between high doses of psychostimulants, which can induce psychosis, and low doses of psychostimulants, which can have calming and attention-enhancing effects. Therefore, it is possible that a combination of psychostimulants and APs do not antagonize each other, but rather act synergistically. […] Levy et al. (2015)

Summary of Neurobiology

So what have we learned so far? We’ve learned that Psychotic disorders (PD) and ADHD are highly prevalent neurodevelopmental disorders. While the lifetime prevalence of all PDs is above 3%, the lifetime prevalence of ADHD may exceed 10%. Given their high prevalence, they are bound to co-occur in a substantial number of cases, and that Clinicians’ fear of using psychostimulants may be due to a simplistic conceptualization of DA regulation. We’ve learned that Low doses of psychostimulants have been shown to increase tonic transmission and decrease phasic DA spikes. However, high doses of psychostimulants can massively increase both types of transmission. Furthermore, it is possible that a combination of psychostimulants and APs do not antagonize each other, but rather act synergistically.

The 2019 study from NIMH

Now, let’s turn to the new 2019 study from NIMH, what are their findings?

So what does that tells us? We should notice […] that out of 337,919 incident users of stimulants, there were 343 episodes of psychosis (with an episode defined as a new diagnosis code for psychosis and a prescription for an antipsychotic medication) among the 221,846 patients in the matched population: 106 episodes (0.10%) among 110,923 patients in the methylphenidate group and 237 episodes (0.21%) among 110,923 patients in the amphetamine group. […] Moran et al. (2019)

Author’ Conclusion

[…] The absolute rate of psychosis and the difference in the rate of psychosis between the groups exposed to the two drugs was low (difference, approximately 1 per 1000 person-years), possibly because of our stringent outcome definition that led to high specificity of our relative rate estimates. However, this difference may be clinically significant in the context of an exposure with high prevalence. In the databases used for this study, 2 million patients received a prescription for amphetamine, including current users who were excluded from the population. A difference of 1 per 1000 person-years potentially confers additional risk of psychosis with amphetamine in thousands of patients. In conclusion, the risk of new-onset psychosis was approximately 1 in 660 patients who received a prescription for stimulants for ADHD, but therisk was about twice as high among patients who started amphetamine as among patients who started methylphenidate. […] Moran et al. (2019)

Additional information on this topic

In the same issue of  The New England of Medicine, Samuele Cortese, MD (an recognised authority on ADHD medication) comments on the connection between ADHD and psychotic disorders. Cortese (2019) comments that; […] Despite meta-analyses that show the efficacy of stimulants in reducing ADHD symptoms, at least in the short term, the quality of evidence and the safety of these medications continue to be debated. In particular, psychosis can occur during stimulant treatment and can be traumatic for patients and their families.[…] Cortese (2019)

What Cortese (2019) is references to, is a study by Storebø et al. (2015) where the authors concluded that; […] If methylphenidate treatment is considered, clinicians might need to use it for short periods, with careful monitoring of both benefits and harms, and cease its use if no evidence of clear improvement of symptoms is noted, or if harmful effects appear.[…] and Ramstad et al. (2018) where the authors concluded that; […] Because of sparse data and low quality of evidence, we cannot confirm or refute whether methylphenidate increases the risk of psychotic symptoms in children and adolescents with ADHD. This possible adverse event may affect 1.1% to 2.5%, and physicians, patients and caregivers should be aware of this to ensure proper treatment in case of occurrence during methylphenidate treatment. […] Ramstad et al. (2018)

Cortese (2019) concludes that; […] Therefore, whether psychosis is due to stimulant use, to inherent vulnerability to psychosis, or to the interaction of those two factors remains unclear. In this regard, an intriguing finding from post hoc analyses of the current study was that the difference in the risk of psychosis between drugs was not present when medications were prescribed by psychiatrists as compared with other physicians. A possible interpretation is that psychiatrists more readily detected prodromal psychotic features that increase the risk of treatment-related psychosis, and they avoided the prescription of amphetamine in such cases. […] Cortese (2019)

References

Cortese, S. (2019). Psychosis during Attention Deficit–Hyperactivity Disorder Treatment with Stimulants. New England Journal of Medicine, 380(12), 1178–1180.
DOI: https://dx.doi.org/10.1056/nejme1900502

Moran, L. V., Ongur, D., Hsu, J., Castro, V. M., Perlis, R. H., & Schneeweiss, S. (2019). Psychosis with Methylphenidate or Amphetamine in Patients with ADHD. New England Journal of Medicine, 380(12), 1128–1138.
DOI: https://doi.org/10.1056/NEJMoa1813751

Levy, E., Traicu, A., Iyer, S., Malla, A., & Joober, R. (2015). Psychotic Disorders Comorbid With Attention-Deficit. Can J psychiatry(Vol. 60). Retrieved from http://www.TheCJP.ca

Lieberman, J. A., Kane, J. M., & Alvir, J. (1987). Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology, 91(4), 415–433. https://www.ncbi.nlm.nih.gov/labs/pubmed/2884687-provocative-tests-with-psychostimulant-drugs-in-schizophrenia/

Ramstad, E., Storebø, O. J., Gerner, T., Krogh, H. B., Holmskov, M., Magnusson, F. L., … Simonsen, E. (2018). Hallucinations and other psychotic symptoms in response to methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder: a Cochrane systematic review with meta-analysis and trial sequential analysis. Scandinavian Journal of Child and Adolescent Psychiatry and Psychology, 5(i_current), 52–71.
DOI: https://doi.org/10.21307/sjcapp-2018-003

Storebø, O. J., Krogh, H. B., Ramstad, E., Moreira-Maia, C. R., Holmskov, M., Skoog, M., … Gluud, C. (2015). Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. BMJ (Online), 351, h5203.
DOI: https://doi.org/10.1136/bmj.h5203