Psychotic Disorders Comorbid With Attention-Deficit Hyperactivity Disorder: An Important Knowledge Gap

Abstract

Psychotic disorders (PDs) and attention-deficit hyperactivity disorder (ADHD) are frequently comorbid. Clinicians are often reticent to treat ADHD in patients with psychosis, fearing that psychostimulants will worsen psychotic symptoms. Advances in neurobiology have challenged the simplistic dichotomy where PD is considered a disorder of high dopamine (DA), treated by DA antagonists, and ADHD a disorder of low DA, treated by DA agonists. In our paper, we review the literature on comorbid ADHD and psychosis. Treating ADHD with psychostimulants may be considered in patients with PD who have been stabilized with antipsychotics (APs). Not treating ADHD may have consequences because ADHD may predispose patients to drug abuse, which further increases the risk of PD. Nevertheless, more systematic studies are needed as there remains some uncertainty on the combined use of APs and psychostimulants in comorbid PD and ADHD.

Psychotic disorders and ADHD are highly prevalent neurodevelopmental disorders. While the lifetime prevalence of all PDs is above 3%,¹ the lifetime prevalence of ADHD may exceed 10%.² 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 ADHD³ and PD^4,5 is a high association with smoking and other drugs of abuse. In our paper, we review evidence and present some data from PEPP-Montreal, our FEP clinic. We address 3 central questions. First, what are the commonalities between ADHD and PD? Second, what evidence is there for adding psycho-stimulants to APs in patients with comorbid ADHD and PD? Third, what effect does this comorbidity and its treatment have on SUD?

Commonalities Between Attention-Deficit Hyperactivity Disorder and Psychotic Disorders

Patients with PD share impairments with patients who suffer from ADHD. Inattention remains a central feature of both ADHD and PD. Further, deficits on executive functions,⁶ and a reduced capacity for emotional processing^7,8 are observed in both disorders. Like patients with ADHD, pre-psychotic patients also tend to display heightened levels of impulsivity, low frustration tolerance, and impairments in social functioning.⁸

Inattention is among the most consistent finding in the developmental trajectories of patients who are diagnosed with PD.⁹ In a sample of 100 adults with psychosis, Gomez et al¹⁰ found that 32% reported attention deficits in childhood. Likewise, research with younger populations has shown that 24% to 47% of those diagnosed with childhood-onset schizophrenia also displayed premorbid histories of attention deficits and hyperactivity.^11–14 In a large longitudinal study (n = 1037), patients with PD were 2 times more likely to have been diagnosed with ADHD as children.¹⁵

Clinical Implications

• Patients with PDs should be assessed for ADHD.

• Psychostimulants may be considered in patients with comorbid ADHD and psychosis, provided psychotic symptoms have been stabilized.

Limitations

• More evidence is needed to firmly support the safety of psychostimulants in patients with PDs.

• ADHD is often comorbid with an SUD, which may predispose to psychosis. More evidence is needed to support the administration of psychostimulants to prevent substance use in patients with PDs.

Conversely, inattention may also be an early indicator of psychosis among high-risk people. In one study, children of parents with schizophrenia were followed through mid-adulthood. Among those who exhibited attention deficits in childhood, 58% developed schizophrenia-related psychoses in adulthood. In another study, relatives at risk for PD were more likely to have ADHD features than healthy control subjects.¹⁶ In a large Swedish study (n = 61 187) of patients with ADHD, the risk of developing schizophrenia in first-degree relatives was 2 times greater than in healthy control subjects.¹⁷ Together, these studies suggest that early signs of ADHD may predict the development of PD¹⁸ and that the 2 disorders may share genetic determinants.

Neurobiology of Psychotic Disorders and Attention-Deficit Hyperactivity Disorder

Clinicians may be reluctant to use psychostimulants together with APs for fear of worsening psychotic symptoms. In a widely cited study¹⁹ done over 25 years ago, Lieberman et al 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.

During the past decade, new knowledge has largely dispelled the simplistic dichotomy where PD is considered a disorder of high DA, treated by DA antagonists, and ADHD is considered a disorder of low DA, treated by DA agonists. In PD, it is now well accepted that lower levels of DA in the mesocortical pathway are associated with overactive phasic DA signalling in the mesolimbic pathway. This is believed to play a role in the development of positive symptoms, such as delusions and hallucinations.^20,21 Similarly, in ADHD, it has been proposed that low levels of tonic DA result in abnormally elevated stimulus-dependent phasic transmission. This results in hypersensitivity to environmental stimuli, which leads to inattention, hyperactivity, and impulsivity.²²

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.

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.²³ However, 2 well-replicated observations suggest that psychostimulants at therapeutic doses do not increase DA transmission in the mesolimbic pathway.²⁴ 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.²¹ 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.²⁵ Therefore, it is possible that a combination of psychostimulants and APs do not antagonize each other, but rather act synergistically.^26,27

Using Psychostimulants in Patients With Psychotic Disorders and Attention-Deficit Hyperactivity Disorder

Several investigators have tried the combination of psychostimulants and APs, albeit, in a nonsystematic way. Although methodologically limited, numerous reports on individual cases and reports on limited series of patients have been published. In an early study, Weinberger et al²⁸ tested the idea that psychostimulants could be useful in alleviating negative symptoms of schizophrenia. The use of a psychostimulant was thought to enhance DA activity in the prefrontal cortex, thereby improving the cognitive functions of patients with schizophrenia. Weinberger et al administered either oral dextroamphetamine or a placebo to a sample of 21 adults with chronic schizophrenia who were stabilized on haloperidol. No information on their ADHD status was reported. They reported that none of the subjects worsened from combined treatment. Six were identified as having improved affect, cooperation, and engagement with the environment, as rated by clinicians. A recent systematic study²⁴ reviewed the effects of psychostimulants on negative symptoms. It found that, in patients who are stabilized on APs, the use of DA agonists as an adjunctive treatment results in an overall improvement in negative symptoms. They documented improvements ranging between 37.2% and 66.7%, without worsening of positive symptoms.

Pine et al⁹ reported on 2 adults who responded positively to psychostimulants for their ADHD symptoms. Despite discontinuing APs and maintaining the psychostimulants, the 2 patients remained free of psychotic symptoms during a period of 2 years. The evidence for the efficacy of psychostimulant treatment in comorbid psychosis and ADHD was recently extended to younger patients. Tossell et al²⁹ administered methylphenidate or a combination of amphetamine and dextroamphetamine to 5 children, aged 8 to 15 years, with childhood-onset schizophrenia and comorbid ADHD. Four of the 5 subjects were treated with psychostimulants once their psychotic symptoms were stabilized with clozapine. The fifth subject received psychostimulants while still actively psychotic and receiving simultaneous APs. The 4 subjects who were clinically stabilized on clozapine prior to the psychostimulant treatment showed improvements in their ADHD symptoms without any worsening of their psychosis. However, the introduction of a psychostimulant in the fifth subject caused a worsening of both psychotic and ADHD symptoms. Therefore, the authors suggest that the use of psychostimulants in childhood-onset schizophrenia should only be implemented after stabilizing psychotic symptoms.

Schaeffer and Ross¹³ have cautioned against the use of psychostimulants, especially in doses that exceed normally prescribed limits. In a retrospective study¹³ of 17 children diagnosed with childhood-onset psychosis, the authors found that 8 of the 17 children had received a formal ADHD diagnosis and 13 had been exposed to psychostimulants prior to being diagnosed with schizophrenia. The authors speculated that the widespread, and possibly excessive use, of psychostimulants might have hastened the onset of psychosis in their sample. However, the possibility that these were comorbid cases with symptoms of ADHD preceding the onset of schizophrenia cannot be excluded.

In summary, there is some evidence from case reports suggesting the benefit of combining these 2 medications. While Tossell et al’s study suggests caution in using psychostimulants when psychotic symptoms are not stabilized, other studies in adult schizophrenia suggest that psychostimulants are not associated with worsening of psychotic symptoms, particularly when patients are stabilized with APs.

Substance Use Disorder and its Link to Comorbid Attention-Deficit Hyperactivity Disorder and Psychotic Disorders

Both ADHD³ and PD^4,5 are highly associated with smoking and other drugs of abuse. A recent hypothesis suggests that, in some ADHD cases, early substance use and (or) abuse may contribute to the progression of psychosis. Compared with those without ADHD, children with ADHD have higher rates of SUDs in adolescence and adulthood. In 1 study, adolescents with ADHD were 6.2 times more likely to suffer from a SUD than were matched control subjects.^30,31 Similarly, rates of comorbid substance use in adults with ADHD (47%) were found to be significantly higher than in non-ADHD adult control subjects (38%).^31,32

Two meta-analyses have studied whether treating ADHD patients with psychostimulants affects substance use. An early meta-analysis of 6 studies grouping 1034 patients showed that children who received psychostimulants were significantly less likely to develop SUDs.³³ A recent meta-analysis of 15 studies grouping 2565 patients found that psychostimulants neither protect nor increase the risk of SUD.³⁴ However, neither of these studies addresses the case of comorbid ADHD and PD.

It has been proposed that people with ADHD possess personality traits, such as impulsivity and novelty seeking, that are associated with the onset of substance use, which, in turn, can increase the risk of PD. Note that while most cannabis users do not develop psychopathology in adulthood, early and frequent use is linked to an increased risk of onset of psychosis and may be responsible for about 1 to 2 new cases of schizophrenia per 1000 people per year.³⁵ Indeed, a review on cannabis use and its association with psychosis suggests that smoking cannabis accounts for a 2-fold increase in the development of schizophrenia.³⁶ This suggests a possible cascade of events whereby ADHD predisposes to drug abuse, which, in turn, increases the risk of PD. For patients with ADHD and comorbid PD, little is known about the effect of using psychostimulants on substance use.

Treating Comorbid First-Episode Psychosis and Attention-Deficit Hyperactivity Disorder: Prevention and Early Intervention Program for Psychoses–Montreal Data

In FEP, estimates of the prevalence of cannabis abuse range from 13% to 75%.³⁷ Further, patients with FEP and comorbid cannabis use were found to be at a higher risk of childhood psychiatric disorders in the spectrum of ADHD.³⁸ In our PEPP-Montreal, we find that ADHD is more common in this FEP population than in the general population. We have recently begun to record the presence or absence of a formal childhood diagnosis of ADHD, as well as a childhood history of being treated with psychostimulants. Remarkably, 15% of PEPP-Montreal patients in this cohort (30 out of 202) were diagnosed by their physician as having childhood ADHD. Most of these patients (28 out of 30) had received treatment with psychostimulants for ADHD. Among those with a previous diagnosis of ADHD, 90% were boys.

While many of our FEP patients used cannabis regularly at some point during treatment (38%), the use was much higher in patients with signs of ADHD (71%). We found that childhood ADHD symptoms predicted persistent cannabis use and lifetime cannabis diagnosis after controlling for sex, education, and premorbid adjustment (P = 0.004 and P = 0.02, respectively). Symptoms of conduct disorder and oppositional defiant disorder did not predict cannabis use when controlling for hyperactivity–inattention symptoms. These results suggest a strong prevalence of comorbid ADHD in patients treated for FEP and that this comorbidity is associated with persistent cannabis use.³⁹

Since 2003, 13 patients with FEP at PEPP-Montreal received adjunctive treatment of psychostimulants, in addition to their AP treatment. We were able to determine psychotic relapse events while patients were treated with psychostimulants (using SAPS). Except for one patient who experienced a brief relapse following psychostimulants introduction, none of the other patients experienced a relapse. Further, to impute the brief relapse to the introduction of psychostimulants remains doubtful because the patient remitted quickly while still on psychostimulants. Further, positive symptoms as rated by the SAPS global score of these patients was low (mean 0.58, SD 0.78) and did not change (mean 0.058, SD 0.40) after the introduction of psychostimulants (P > 0.05). These data is highly suggestive that, when patients are stable under AP treatment, the adjunctive use of psychostimulants is safe.

Conclusion

Comorbid ADHD may occur in a sizable number of patients with PD. There is a need to better understand the etiologies of ADHD and PD because this comorbidity greatly reduces the ability to recover and maintain adequate functioning. A history of ADHD symptoms in schizophrenia is indicative of poorer psychiatric outcome. Indeed, those with both diagnoses display more disturbances in psychomotor development, show a poorer response to APs, and have significantly poorer outcomes regarding work or school performance when compared with non-ADHD control subjects with schizophrenia only.⁴⁰ Thus early recognition and adequate treatment of ADHD in patients with FEP are essential to enhance the clinical and functional outcomes of these patients. Although clinicians may be reluctant to use psychostimulants with APs, treating ADHD with psychostimulants may be considered in patients with PD who have been stabilized with APs. Nevertheless, more systematic studies are needed because there remains uncertainty within the medical community on the combined use of APs and psychostimulants in comorbid PD and ADHD.

Abbreviations

ADHD

attention-deficit hyperactivity disorder

AP

antipsychotic

DA

dopamine

DAT

dopamine transporter

FEP

first-episode psychosis

NE

norepinephrine

NET

norepinephrine transporter

PD

psychotic disorder

PEPP

Prevention and Early intervention Program for Psychoses

SAPS

scale for assessment of positive symptoms

SUD

substance use disorder