SCHRES-06314; No of Pages 6 Schizophrenia Research xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Clinical and functional implications of a history of childhood ADHD in first-episode psychosis Aldanie Rho a, Alexandru Traicu a,b, Martin Lepage b, Srividya N. Iyer a,b, Ashok Malla a,b, Ridha Joober a,b,⁎ a b
Douglas Mental Health University Institute, Research Institute, Boulevard LaSalle, H4H 1R3 Montreal, QC, Canada McGill University, Faculty of Medicine, Department of Psychiatry, Ludmer Research & Training Building, 1033 Pine Avenue West, H3A 1A1 Montreal, QC, Canada
a r t i c l e
i n f o
Article history: Received 18 November 2014 Received in revised form 23 March 2015 Accepted 26 March 2015 Available online xxxx Keywords: Attention-deficit hyperactivity disorder (ADHD) First-episode psychosis (FEP) Schizophrenia spectrum disorder (SSD) Premorbid functioning Long-term outcomes
a b s t r a c t There is mounting evidence indicating that a childhood history of attention-deficit/hyperactivity disorder (ADHD) is associated with an increased risk for psychotic disorders, including schizophrenia. However, the implications of such a history on the symptomatic and functional outcomes of patients with psychotic disorders are still not well documented. This study examined the prevalence of childhood ADHD in patients with first episode psychosis (FEP) consecutively admitted to a specialized early intervention clinic covering a well-defined catchment area, and compared patients with and without a history of childhood ADHD on socio-demographic, clinical, and functional outcomes over a six to twelve months period. Out of 179 patients with FEP, 27 (15%) were treated for ADHD during childhood, consistent with previous literature indicating an association between childhood ADHD and psychosis. FEP patients with childhood history of ADHD had lower academic achievement, earlier onset of psychosis, and higher rates of childhood conduct and learning disorder. While the two groups had similar scores on psychopathology and functioning at baseline, patients with childhood ADHD showed significantly less improvement in positive and negative symptoms, as well as social and occupational functioning. These results strongly indicate that a history of childhood ADHD in FEP is more frequent than that reported in the general population and predictive of poorer clinical response to treatment. This emphasizes the need for actively screening for a history of ADHD in FEP patients and for treatments that are tailored for these patients. © 2015 Elsevier B.V. All rights reserved.
1. Introduction An association between a history of childhood attention-deficit/ hyperactivity disorder (ADHD) and schizophrenia-spectrum disorders (SSD) has received increasing support in the recent literature, which has documented an increased risk of developing SSD later in life in children with ADHD (Biederman et al., 2006; Dalsgaard et al., 2014), and high rates of an antecedent history of ADHD in adults with SSD (Gomez et al., 1981; Marsh and Williams, 2006; Dalteg et al., 2014). It has proven a complex task to link a generally younger pool of individuals with ADHD, with typical onset in elementary school (Kieling et al., 2010), with an older pool of people with SSD, the peak onset of which is in the third decade of life (Gogtay et al., 2011). This task is further complicated by the partial developmental overlap between these heterogeneous disorders, as symptoms of ADHD typically persist into adulthood (Faraone et al., 2006), while the first episode of psychosis
⁎ Corresponding author at: Douglas Mental Health University Institute, 6875 Boulevard LaSalle, Montreal H4H 1R3, QC, Canada. Tel.: +1 514 761 6131; fax: +1 514 888 4458. E-mail addresses: [email protected] (A. Rho), [email protected] (A. Traicu), [email protected] (M. Lepage), [email protected] (S.N. Iyer), [email protected] (A. Malla), [email protected] (R. Joober).
(FEP) is typically preceded by a prodrome with prominent deficits in attention (Cornblatt et al., 2003). The exact nature of the association between ADHD and SSD has remained unclear thus far. They are both neurodevelopmental disorders which share some genetic (Williams et al., 2010; Hamshere et al., 2013) and environmental risk factors, in particular obstetric complications and early developmental abnormalities (Peralta et al., 2011; Dalsgaard et al., 2014). They each involve a dysregulation in the dopamine system, and are treated with medications that modify its function (Mehler-Wex et al., 2006). Their association is further driven, but also obscured, by prominent shared symptoms, such as deficits in attention (Barr, 2001; Carter et al., 2010). Additionally, substance abuse may be an important moderator of their relationship, as a history of childhood ADHD increases both the rate of substance use disorders (SUDs) (Charach et al., 2011), and the psychotogenic potential of drugs of abuse (Roncero et al., 2012; Salo et al., 2013). This increased rate of substance use disorders has also been noted in samples with first episode of SSD (Cassidy et al., 2011). Given the typical persistence of both ADHD symptoms and related impairment beyond adolescence (Faraone et al., 2006; Klein et al., 2012), it is important to understand whether patients with childhood ADHD who develop SSD represent a distinct clinical population that may require a modified approach to treatment (Bellak et al., 1987;
http://dx.doi.org/10.1016/j.schres.2015.03.031 0920-9964/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Rho, A., et al., Clinical and functional implications of a history of childhood ADHD in first-episode psychosis, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.03.031
2
A. Rho et al. / Schizophrenia Research xxx (2015) xxx–xxx
Levy et al., 2015). Two studies have compared participants with SSD with and without a history of childhood ADHD. Elman et al. (1997) investigating adolescents with early-onset schizophrenia, found that those with a history of childhood ADHD had more neurodevelopmental abnormalities and a more insidious course with poorer medication response and functional outcome. Peralta et al. (2011) on the other hand, concluded that obstetrical complications and neurodevelopmental delay explained much of the association of childhood ADHD with schizophrenia, with no further impact on psychopathology or response to treatment in schizophrenia. Additional data come from studies showing that individuals at high-risk for psychosis with ADHD fare worse compared to those without ADHD in terms of premorbid adjustment, psychotic symptoms, cognition, function, and progression into SSD (Oner and Munir, 2005; De la Serna et al., 2010; Hurtig et al., 2011; Kim et al., 2012). In the present study, we compared the characteristics of two groups of participants with FEP: one with a history of childhood ADHD (the FEP–ADHD group) and another without such a history (the FEP-alone group), on a broad range of demographical, clinical, and functional measures. We tested the hypothesis that the FEP–ADHD group would have worse clinical and functional status both at baseline and at follow-up. These hypotheses were based on previously cited studies associating higher levels of illness severity in SSD with co-morbid ADHD. Our study builds on this previous work by investigating a relatively large well-characterized FEP sample of 179 participants using rigorously-standardized methodology over a longer duration of follow-up. 2. Methods 2.1. Participants The study was conducted on FEP patients treated at the Prevention and Early intervention Program for Psychoses — Montreal (PEPP), a specialized early intervention clinical research program at the Douglas Mental Health University Institute. PEPP is the sole service for FEP patients living in a catchment area of 400,000 in south-west Montreal. This helps minimize referral bias and increases the generalizability of the study's findings. Following international guidelines for specialized early intervention services for psychosis, all PEPP patients are provided with second-generation antipsychotic treatment and psychosocial interventions for a period of two years. Full details of the program are provided elsewhere (Malla et al., 2003) and on the website (douglas.mcgill.ca/pepp). 213 patients who entered PEPP consecutively between 2007 and 2013 were considered for inclusion in this study. PEPP admits patients with a first-episode psychotic disorder as defined by the Diagnostic and Statistical Manual of Mental Disease (4th edition; DSM-IV), either non-affective or affective, aged between 14 and 35 years old, with IQ higher than 70, and less than one month of previous exposure to antipsychotics. Additionally, for the present study, we excluded patients with either suspected history of childhood ADHD (32 individuals; 15%) or history of diagnosed but not treated childhood ADHD then (2 individuals; 1%), so as to maximize the reliability of the diagnosis of the ADHD. After their exclusion, the study sample comprised 179 participants. Data collection for the study was approved by the Institute's Ethics Research Board and all patients or their legal representatives have provided written informed consent. 2.2. Study design and outcome measures This was a prospective observational study, with data collected for all cases by trained evaluators using a specific protocol (Malla et al., 2003). At baseline, a Structured Clinical Interview for DSM-IV (First et al., 1995) was conducted by staff and confirmed with a senior
psychiatrist (AM or RJ) to establish primary, secondary, and substance use disorder (SUD) diagnoses. The age of first psychosis onset, the length of the psychotic prodrome, as well as the duration of untreated psychosis (DUP) were determined retrospectively using the semistructured Circumstances of Onset and Relapse Schedule (CORS) interview (Norman et al., 2004) conducted by trained evaluators. The diagnoses of childhood ADHD, conduct disorder (CD) and learning disorder (LD) were also established through the CORS. Education at baseline was coded at six levels: 1 (high School non-completers), 2 (high School completers), 3 (college non-completers), 4 (college completers), 5 (university non-completers), 6 (university completers). Socioeconomic status (SES) was measured using the Hollingshead index (Hollingshead, 1975). Medication non-adherence was assessed based on information from clients and case managers. Participants who did not conform to the medication prescriptions at least 75% of the time were considered non-adherent, based on level considered to be effective in preventing re-hospitalization (Valenstein et al., 2002; Karve et al., 2009). The Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS) (Andreasen, 1983a,b) were administered at baseline and six months of follow up. In our analysis, we used a modified SANS score without the Attention Subscale items, given their overlap with ADHD symptoms (Malla et al., 2002). Premorbid functioning was measured using the Premorbid Adjustment Scale (PAS) (Cannon-Spoor et al., 1982) total score for social and educational functioning from childhood to early adolescence. Psychosocial functioning was assessed at baseline and twelve months of follow-up using the Social and Occupational Functioning Assessment Scale (SOFAS) (Spitzer et al., 2000) and the Life Skills Profile (LSP), assessing self-care, non-turbulence, social contact, communication and responsibility (Rosen et al., 1989). These scales were administered at baseline and at twelve months after follow-up. 2.3. Statistical analysis The data were analyzed using SPSS (Statistical Package for the Social Sciences, version 20.0 for Windows). Categorical variables were compared by Pearson's Χ2 for proportions analysis, using the Fisher exact test when the Χ2 test assumptions were not met. For greater statistical power, demographic variables like marital status, SES, and non-adherence were collapsed into binary variables. Continuous variables were inspected for normality both visually through histogram and quantile–quantile plots, and by using the Kolmogorov test. Most variables were skewed, even after logarithmic transformations. For normally distributed continuous variables, we used Student's t-tests for cross-sectional data, and repeated-measures ANOVA for longitudinal data. For skewed variables, group medians were compared using the non-parametric Mann–Whitney U-test, after inspection of histogram plots confirmed the two comparison groups had similarly-shaped distributions. Statistical significance was set at 5%, using a one-tailed statistic to test the hypotheses that the comorbid FEP–ADHD group had worse clinical characteristics. 2.4. Missing data Preliminary analysis showed that the fraction of missing values increased rapidly with longer duration of follow up due to missed appointments or non-completion of scales. To strike a balance between presenting a longer longitudinal span and limiting bias from missing data, we choose to analyze follow up-data for the 6 months and the 12 months visits. This approach limited missing values to less than 20% for all variables, with the exception of the PAS total score, and the SOFAS and LSP scores at 12 months. Data appeared to be missing completely at random [Little's Missing Completely At Random test: Χ2(1522) = 766.446, p = 1.000], which indicates a low risk of bias from missing values. To confirm this, we
Please cite this article as: Rho, A., et al., Clinical and functional implications of a history of childhood ADHD in first-episode psychosis, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.03.031
A. Rho et al. / Schizophrenia Research xxx (2015) xxx–xxx
3
performed a sensitivity analysis by conducting multiple imputations (SPSS Markov Chain Monte Carlo algorithm, 10 iterations with 50 case draws and 2 parameter draws resulting in 10 imputed datasets) and reanalyzing several variables; we obtained similar results as the raw data analysis presented here.
revealed a significant main effect of ADHD status [F(1,108) = 8.202, p = 0.005]. While graphically (see Fig. 1) the differences in LSP scores appear to increase with time, the interaction between group and time was not significant [F(1,108) = 2.714, p = 1.02].
3. Results
4. Discussion
3.1. Prevalence of childhood ADHD
4.1. Summary of findings
There were 213 patients in our initial PEPP sample. Out of these, 34 (15.8%) had a history of suspected childhood ADHD or a history of diagnosed but untreated childhood ADHD. This FEP–ADHD group (N = 27) was compared with the FEP-alone group (N = 152).
We found a higher prevalence of childhood ADHD in our FEP sample than rates in the general population (Faraone et al., 2003), consistent with previous studies of ADHD prevalence in FEP samples (Gomez et al., 1981; Dalteg et al., 2014). Our comparative analysis generally confirmed the hypothesis that FEP–ADHD individuals have worse outcomes. We found that participants with and without a history of ADHD did not differ at baseline on symptoms. However, the FEP–ADHD group had an earlier onset of psychosis, as well as lower life skills at baseline. Further, FEP–ADHD participants also had a more severe illness trajectory. During the premorbid period, they had poorer functioning, lower educational achievement, more comorbid childhood conduct and learning disorders, and a trend toward higher rates of SUD. They also had a poorer prognosis at follow-up, with more severe positive and negative symptoms, and poorer social and occupational functioning, despite starting from a similar baseline in terms of symptoms. The rates of lifetime SUD and adherence at follow-up did not differ significantly between the two groups, Therefore, the differences in symptom scores appear to indicate a poorer response to treatment in the FEP–ADHD group, which also displayed lower life skills at follow-up, as well as an opposite trend in the evolution of life-skills over the course of the follow-up. As shown in Fig. 1, a decline over the first year in the FEP–ADHD group is observed compared to a steady improvement in the FEP-alone group. The exact mechanisms through which a history of ADHD may lead to poorer treatment response in FEP remain unclear. Recent work suggests that patients with schizophrenia and limbic hyperdopaminergia have better response to antipsychotic medications than patients without elevated mesolimbic dopamine levels (Howes and Kapur, 2014). While the profile of dopamine activity in FEP–ADHD patients has not yet been characterized, we may expect generally lower dopamine activity, given the possible deficits in mesolimbic dopamine activity found in ADHD (Volkow et al., 2007). Thus, differences in dopamine activity between the FEP-alone and FEP–ADHD groups may hold the key to explaining the poorer response to antipsychotics in FEP–ADHD patients. Overall, the FEP–ADHD group demonstrated poorer functioning in all phases (premorbid, at baseline and at one year follow-up) in terms of clinical characteristics, impairment and comorbidity. The lack of difference at baseline on the SOFAS between the two groups may be related to floor effects on this scale leading to loss of sensitivity in assessing participants with very poor functioning, as indicated in the heavy skewing on the low end on this scale. The earlier age of onset of psychosis in the FEP–ADHD group may be partly related to the higher
3.2. Baseline demographic characteristics As seen in Table 1, the two groups did not differ in terms of age, marital status, or SES, but there were significantly more males in the FEP–ADHD group. The FEP–ADHD participants had significantly lower academic achievement (p = 0.007). The median participant in the FEP–ADHD group had not completed high school, whereas the median participant in the FEP-alone group had completed high school. 3.3. Measures of psychopathology The differences in psychopathology are summarized in Table 2. While the average length of prodrome and DUP did not differ between the two groups, the FEP–ADHD group experienced the onset of psychosis on average two years earlier (p = 0.01). In regards to symptom severity, SAPS and SANS scores did not differ at baseline, but the FEPADHD group had significantly higher scores at six (p = 0.002 and p = 0.023, respectively). At baseline, 93% of patients in both groups were prescribed antipsychotic medication. No significant differences were observed in medication non-adherence both at baseline, six and twelve months of follow-up. Regarding comorbidity, there was a non-significant trend toward higher lifetime SUD rates among FEP–ADHD participants (75% vs 56% for FEP-alone participants, p = 0.066). The rates of affective and nonaffective psychosis did not differ between the two groups. Finally, FEP–ADHD individuals had significantly higher rates of childhood conduct disorder and learning disorder (44% and 35%, respectively, vs 11% and 11% in the FEP-alone group). 3.4. Measures of functioning As seen in Table 3, FEP–ADHD participants had poorer premorbid functioning than FEP-alone participants (p = 0.003). In terms of functioning, the SOFAS scores did not differ at baseline, but the FEP– ADHD group had significantly lower SOFAS scores at twelve months (p = 0.005). On cross-sectional analysis, the LSP scores were poorer in the FEP–ADHD group both at baseline and at twelve months (p = 0.009 and p = 0.002, respectively). Repeated-measures ANOVA
Table 1 Baseline demographic data in participants with and without a history of childhood ADHD.
Age at study entry: M (SD) Gender: Ns — % males Marital status: Ns — % singles Lower SES: % lower Education: Md
FEP-alone group (n = 152)
FEP–ADHD group (n = 27)
Analyses
23.8 (4.7) 104 — 69% 139 — 92% 0–0% 3 (HS completer)
22.3 (3.7) 25 — 93% 26 — 96% 2–7% 2 (HS non-completer)
t(177) = 1.528; p = 0.13 Χ2(1) = 6.376; p = 0.007⁎ FET, p = 0.402 FET, p = 0.391 U = 1159, p = 0.003⁎
Abbreviations: HS: high school; M (SD): mean (standard deviation); Md (R): median (range); Ns — %: number — percentage. t: Student's t-test; U: Mann–Whitney U-test; Χ2: Χ2 test for proportions; FET: Fisher's Exact test. ⁎ Result significant at 5% level.
Please cite this article as: Rho, A., et al., Clinical and functional implications of a history of childhood ADHD in first-episode psychosis, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.03.031
4
A. Rho et al. / Schizophrenia Research xxx (2015) xxx–xxx
Table 2 Psychopathology at baseline and follow-up in participants with and without a history of childhood ADHD.
Age at psychosis onset: M (SD) Prodrome: Md in weeks (R) DUP: Md in weeks (R) Medication non-adherence at baseline: % Medication non-adherence at 6 months: % Medication non-adherence at 12 months: % SAPS at baseline: Md ® SAPS at 6 months: Md ® SANS at baseline: Md ® SANS at 6 months: Md ® Non-affective psychosis: % SUD (lifetime diagnosis) at baseline: % Childhood LD: % Childhood CD: %
FEP-alone group (n = 152)
FEP–ADHD group (n = 27)
Analyses
23.2 (4,7) 26.1(0–965) 15(0.1–1049.4) 9.2% 27.4% 20.9% 36(5–90) 3(0–41) 28(0–61) 16(0–61) 64% 56% 11% 11%
21.3 (3.5) 39.1 (0–424.1) 16.1 (0.57–476.9) 19.2% 26.9% 25.0% 40 (15–79) 11 (0–51) 24 (6–67) 23,5 (4–49) 82% 75% 35% 44%
t(44.9) = 2.436; p = 0.01⁎ U = 1602, p = 0.237 U = 1568.5, p = 0.104 Χ2(1) = 2.332; p = 0.121 Χ2(1) = 0.003; p = 0.584 Χ2(1) = 0.194; p = 0.421 U = 1977, p = 0.423 U = 955.5, p = 0.002⁎ U = 1825, p = 0.479 U = 1124, p = 0.023⁎ Χ2(1) = 3.211; p = 0.081 Χ2(1) = 2.95; p = 0.066 Χ2(1) = 9.773; p = 0.005⁎ Χ2(1) = 19.989; p = b0.0005⁎
Abbreviations: DUP: duration of untreated psychosis; SAPS: Scale for Assessment of Positive Symptoms; SANS: Scale for Assessment of Negative Symptoms; SUD: substance use disorder; LD: learning disorder; CD: conduct disorder; M (SD): mean (standard deviation); Md (R): median (range); %: percentage. t: Student's t-test; U: Mann–Whitney U-test; Χ2: Χ2 test for proportions; FET: Fisher's Exact test. ⁎ Result significant at 5% level.
proportion of males in this group, who typically have an earlier onset (Eranti et al., 2013).
4.2. Comparison with past research Our results generally replicate those of Elman et al. (1997) who also found that a history of childhood ADHD was associated with poorer premorbid function, earlier onset, and poorer response to treatment. However, we did not find a longer prodrome in the FEP–ADHD group. While conducted in a different clinical sample, our findings are generally concordant with the literature on individuals at high-risk for SSD, where worse outcomes have been associated with comorbid ADHD (Oner and Munir, 2005). More recently, Peralta et al. (2011) found that obstetrical complications and neurodevelopmental delay mediated most of the association between recollected childhood ADHD symptoms and SSD. These variables are not regularly assessed at PEPP, so we were not able to test their influence in our study. The finding that the FEP–ADHD group also was more likely to have been diagnosed with CD and LD in childhood is in agreement with the high rates of CD and LD comorbidity in the general ADHD population (Biederman et al., 1991). Finally, our findings, especially those related to treatment response, are compatible with the hypothesis (Elman et al., 1997; Levy et al., 2015) that FEP patients with comorbid ADHD represent a special clinical group within the larger FEP population which may not be adequately served by our current treatments. We believe this underscores the need for future research into tailored treatment approaches for patients with FEP and comorbid ADHD.
4.3. Study strengths and weaknesses Our study is the first to compare FEP individuals with and without a history of ADHD over a significant duration of follow-up (up to one year) by using a mostly prospective, systematic, and wellstandardized assessment protocol. We compared the two groups on a broad range of domains, paying attention not only to illness symptoms, but also to their level of functioning. In the FEP–ADHD group, we only included participants who had reported receiving a clear diagnosis (and treatment) of ADHD as children. By doing so, we avoided the dangers of making retrospective diagnoses, which are overestimated in this population by recall bias and by the overlap between prodromal inattention and ADHD symptoms. This approach, however, may have led to the exclusion of some participants whose ADHD went undiagnosed in childhood. A potential limitation is the reliance on recalled information for the variables pertaining to the period prior to the index episode. We attempted to mitigate against recall bias and incomplete information by gathering data from multiple informants using structured interview-based instruments, such as the CORS. While including all FEP patients with a broad list of DSM-IV diagnoses results in a more naturalistic sample and increases statistical power, it does limit the generalizability of our finding to schizophrenia alone samples. The lack of data on current ADHD status of participants has made it necessary to rely on past history of diagnosis for our analysis. While we acknowledge this as a significant limitation, we note that pediatric ADHD persists into adulthood in around two-thirds of patients according to a large number of follow up studies, with higher persistence in patients with psychiatric comorbidities (Kooij et al., 2010). Therefore,
Table 3 Functioning at baseline and follow-up in participants with and without a history of childhood ADHD.
PAS: M (SD) SOFAS at baseline: Md (R) SOFAS at 12 months: Md (R) LSP at baseline: M (SD) LSP at 12 months: M (SD)
FEP-alone group (n = 152)
FEP–ADHD group (n = 27)
Analyses
0.27 (0.013) 35 (20–70) 60 (23–91) 132.4 (15.1) 136.6 (12.5)
0.37 (0.42) 35 (15–70) 50 (31–80) 123.8 (13.5) 127.91 (11.1)
t(109) = −2.899; p = 0.003⁎ U = 1951.5, p = 0.446 U = 880.5, p = 0.005⁎ t(143) = 2.405; p = 0.009⁎ t(130) = 2.972; p = 0.002⁎
Abbreviations: PAS: Premorbid Adjustment Scale; SOFAS: Social and Functional Assessment Scale; LSP: Life Skills Profile; M (SD): mean (standard deviation); Md (R): median (range); %: percentage. t: Student's t-test; U: Mann–Whitney U-test. ⁎ Result significant at 5% level.
Please cite this article as: Rho, A., et al., Clinical and functional implications of a history of childhood ADHD in first-episode psychosis, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.03.031
A. Rho et al. / Schizophrenia Research xxx (2015) xxx–xxx
5
Fig. 1. LSP evolution from baseline to 12 months in participants with or without a history of childhood ADHD.
we estimate that the symptoms of ADHD were still present in most patients from the FEP–ADHD group. Due to lack of information, we were unable to control our analysis for some potential mediators of the relationship between ADHD and FEP, including obstetric complications and developmental deficits. Moreover, it might have been informative to conduct symptom-level analyses for the SAPS and SANS, but given our sample size, this analysis would have had limited validity. Finally, given that the territory of FEP and ADHD is relatively unchartered, we chose not to adjust our significance level for multiple comparisons. We acknowledge that this increases the risk of spurious results, but believe this risk is low given the plurality of our findings consistently showing worse outcomes for the FEP–ADHD group. 4.4. Conclusion FEP participants who were diagnosed with ADHD in childhood had poorer premorbid function, earlier onset of illness, and poorer clinical and functional outcomes up to one year after follow-up, suggesting a poorer response to treatment compared to participants without ADHD. This suggests the necessity of further studies to clarify the association between ADHD and FEP and to test the efficacy of treatments tailored for this population. Role of funding source No funding source.
Contributors Aldanie Rho, Alexandru Traicu and Ridha Joober designed the study and wrote the protocol. Aldanie Rho and Alexandru Traicu performed the literature search and statistical analyses, and wrote the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest All authors declare that they have no conflicts of interest.
Acknowledgements We would like to acknowledge Nicole Pawliuk for the assistance with data access, Serge Gallant for the assistance with the statistical analysis and reviewing the manuscript, as well as the PEPP—Montreal staff for their help with participants' recruitment and evaluation.
References Andreasen, N.C., 1983a. Scale for the Assessment of Negative Symptoms. University of Iowa, Iowa City. Andreasen, N.C., 1983b. Scale for the Assessment of Positive Symptoms. University of Iowa, Iowa City. Barr, W.B., 2001. Schizophrenia and attention deficit disorder. Two complex disorders of attention. Ann. N. Y. Acad. Sci. 931, 239–250. Bellak, L., Kay, S.R., Opler, L.A., 1987. Attention deficit disorder psychosis as a diagnostic category. Psychiatr. Dev. 5 (3), 239–263. Biederman, J., Monuteaux, M.C., Mick, E., Spencer, T., Wilens, T.E., Silva, J.M., Snyder, L.E., Faraone, S.V., 2006. Young adult outcome of attention deficit hyperactivity disorder: a controlled 10-year follow-up study. Psychol. Med. 36 (2), 167–179. Biederman, J., Newcorn, J., Sprich, S., 1991. Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am. J. Psychiatry 148, 564–577. Cannon-Spoor, H.E., Potkin, S.G., Wyatt, R.J., 1982. Measurement of premorbid adjustment in chronic schizophrenia. Schizophr. Bull. 8 (3), 470. Carter, J.D., Bizzell, J., Kim, C., Bellion, C., Carpenter, K.L., Dichter, G., Belger, A., 2010. Attention deficits in schizophrenia—preliminary evidence of dissociable transient and sustained deficits. Schizophr. Res. 122 (1–3), 104–112. Cassidy, C.M., Joober, R., King, S., Malla, A.K., 2011. Childhood symptoms of inattention– hyperactivity predict cannabis use in first episode psychosis. Schizophr. Res. 132 (2–3), 171–176. Charach, A., Yeung, E., Climans, T., Lillie, E., 2011. Childhood attention-deficit/ hyperactivity disorder and future substance use disorders: comparative metaanalyses. J. Am. Acad. Child Adolesc. Psychiatry 50 (1), 9–21. Cornblatt, B.A., Lencz, T., Smith, C.W., Correll, C.U., Auther, A.M., Nakayama, E., 2003. The schizophrenia prodrome revisited: a neurodevelopmental perspective. Schizophr. Bull. 29 (4), 633–651. Dalsgaard, S., Mortensen, P.B., Frydenberg, M., Maibing, C.M., Nordentoft, M., Thomsen, P.H., 2014. Association between Attention-Deficit Hyperactivity Disorder in childhood and schizophrenia later in adulthood. Eur. Psychiatry 29 (4), 259–263. Dalteg, A., Zandelin, A., Tuninger, E., Levander, S., 2014. Psychosis in adulthood is associated with high rates of ADHD and CD problems during childhood. Nord. J. Psychiatry 68 (8), 560–566. De la Serna, E., Baeza, I., Toro, J., Andres, S., Puig, O., Sanchez-Guistau, V., Romero, S., Bernardo, M., Castro-Fornieles, J., 2010. Relationship between clinical and neuropsychological characteristics in child and adolescent first degree relatives of subjects with schizophrenia. Schizophr. Res. 116 (2–3), 159–167. Elman, I., Sigler, M., Kronenberg, J., Lindenmayer, J., Doron, A., Mendlovic, S., Gaoni, B., 1997. Characteristics of patients with schizophrenia successive to childhood attention deficit hyperactivity disorder (ADHD). Isr. J. Psychiatry Relat. Sci. 35 (4), 280–286. Eranti, S., Maccabe, J., Bundy, H., Murray, R., 2013. Gender difference in age at onset of schizophrenia: a meta-analysis. Psychol. Med. 43 (01), 155–167. Faraone, S.V., Biederman, J., Mick, E., 2006. The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies. Psychol. Med. 36 (2), 159–165. Faraone, S.V., Sergeant, J., Gillberg, C., Biederman, J., 2003. The worldwide prevalence of ADHD: is it an American condition? World Psychiatry 2 (2), 104. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B., 1995. Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition, January 1995 FINAL. SCID-I/P Version 2.0. Biometrics Research Department, New York State Psychiatric Institute, New York, NY.
Please cite this article as: Rho, A., et al., Clinical and functional implications of a history of childhood ADHD in first-episode psychosis, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.03.031
6
A. Rho et al. / Schizophrenia Research xxx (2015) xxx–xxx
Gogtay, N., Vyas, N.S., Testa, R., Wood, S.J., Pantelis, C., 2011. Age of onset of schizophrenia: perspectives from structural neuroimaging studies. Schizophr. Bull. 37 (3), 504–513. Gomez, R.L., Janowsky, D., Zetin, M., Huey, L., Clopton, P.L., 1981. Adult psychiatric diagnosis and symptoms compatible with the hyperactive child syndrome: a retrospective study. J. Clin. Psychiatry 42 (10), 389–394. Hamshere, M.L., Stergiakouli, E., Langley, K., Martin, J., Holmans, P., Kent, L., Owen, M.J., Gill, M., Thapar, A., O'Donovan, M., Craddock, N., 2013. Shared polygenic contribution between childhood attention-deficit hyperactivity disorder and adult schizophrenia. Br. J. Psychiatry 203 (2), 107–111. Hollingshead, A.B., 1975. Four Factor Index of Social Status. Howes, O.D., Kapur, S., 2014. A neurobiological hypothesis for the classification of schizophrenia: type A (hyperdopaminergic) and type B (normodopaminergic). Br. J. Psychiatry 205 (1), 1–3. Hurtig, T.M., Taanila, A., Veijola, J., Ebeling, H., Maki, P., Miettunen, J., Kaakinen, M., Joukamaa, M., Therman, S., Heinimaa, M., Jarvelin, M.R., Moilanen, I., 2011. Associations between psychotic-like symptoms and inattention/hyperactivity symptoms. Soc. Psychiatry Psychiatr. Epidemiol. 46 (1), 17–27. Karve, S., Cleves, M.A., Helm, M., Hudson, T.J., West, D.S., Martin, B.C., 2009. Good and poor adherence: optimal cut-point for adherence measures using administrative claims data. Curr. Med. Res. Opin. 25 (9), 2303–2310. Kieling, C., Kieling, R.R., Rohde, L.A., Frick, P.J., Moffitt, T., Nigg, J.T., Tannock, R., Castellanos, F.X., 2010. The age at onset of attention deficit hyperactivity disorder. Am. J. Psychiatr. 167 (1), 14–16. Kim, S.J., Lee, Y.J., Jang, J.H., Lim, W., Cho, I.H., Cho, S.J., 2012. The relationship between psychotic-like experiences and attention deficits in adolescents. J. Psychiatr. Res. 46 (10), 1354–1358. Klein, R.G., Mannuzza, S., Olazagasti, M.A., Roizen, E., Hutchison, J.A., Lashua, E.C., Castellanos, F.X., 2012. Clinical and functional outcome of childhood attentiondeficit/hyperactivity disorder 33 years later. Arch. Gen. Psychiatry 69 (12), 1295–1303. Kooij, S.J.J., Bejerot, S., Blackwell, A., Caci, H., Casas-Brugué, M., Carpentier, P.J., Edvinsson, D., Fayyad, J., Foeken, K., Fitzgerald, M., Gaillac, V., Ginsberg, Y., Henry, C., Krause, J., Lensing, M.B., Manor, I., Niederhofer, H., Nunes-Filipe, C., Ohlmeier, M.D., Oswald, P., Pallanti, S., Pehlivanidi, A., Ramos-Quiroga, J.A., Rastam, M., Ryffel-Rawak, D.R., Stes, S., Asherson, P., 2010. EUropean consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD. BMC Psychiatry 10, 67 (Sep 3). Levy, A., Traicu, A., Iyer, S., Malla, A., Joober, R., 2015. Psychotic disorders co-morbid with ADHD: an important knowledge gap. Can. J. Psychiatry 1;60 (3 Suppl 2), S48–52. Malla, A., Takhar, J.J., Norman, R., Manchanda, R., Cortese, L., et al., 2002. Negative symptoms in first-episode non-affective psychosis. Acta Psychiatr. Scand. 105 (6), 431–439. Malla, A., Norman, R., McLean, T., Scholten, D., Townsend, L., 2003. A Canadian programme for early intervention in non-affective psychotic disorders. Aust. N. Z. J. Psychiatry 37 (4), 407–413.
Marsh, P.J., Williams, L.M., 2006. ADHD and schizophrenia phenomenology: visual scanpaths to emotional faces as a potential psychophysiological marker? Neurosci. Biobehav. Rev. 30 (5), 651–665. Mehler-Wex, C., Riederer, P., Gerlach, M., 2006. Dopaminergic dysbalance in distinct basal ganglia neurocircuits: implications for the pathophysiology of Parkinson's disease, schizophrenia and attention deficit hyperactivity disorder. Neurotox. Res. 10 (3–4), 167–179. Norman, R., Malla, A., Verdi, M., Hassall, L., Fazekas, C., 2004. Understanding delay in treatment for first-episode psychosis. Psychol. Med. 34 (02), 255–266. Oner, O., Munir, K., 2005. Attentional and neurocognitive characteristics of high-risk offspring of parents with schizophrenia compared with DSM-IV attention deficit hyperactivity disorder children. Schizophr. Res. 76 (2–3), 293–299. Peralta, V., de Jalon, E.G., Campos, M.S., Zandio, M., Sanchez-Torres, A., Cuesta, M.J., 2011. The meaning of childhood attention-deficit hyperactivity symptoms in patients with a first-episode of schizophrenia-spectrum psychosis. Schizophr. Res. 126 (1–3), 28–35. Roncero, C., Ros-Cucurull, E., Daigre, C., Casas, M., 2012. Prevalence and risk factors of psychotic symptoms in cocaine-dependent patients. Actas Esp. Psiquiatr. 40 (4), 187–197. Rosen, A., HadziPavlovic, D., Parker, G., 1989. The life skills profile. Schizophr. Bull. 15 (2), 325–337. Salo, R., Fassbender, C., Iosif, A.M., Ursu, S., Leamon, M.H., Carter, C., 2013. Predictors of methamphetamine psychosis: history of ADHD-relevant childhood behaviors and drug exposure. Psychiatry Res. 210 (2), 529–535. Spitzer, R., Gibbon, M., Endicott, J., 2000. Global assessment scale (GAS), global assessment of functioning (GAF) scale, social and occupational functioning assessment scale (SOFAS). Handbook of Psychiatric Measures. American Psychiatric Association, Washington, pp. 96–100. Valenstein, M., Copeland, L.A., Blow, F.C., McCarthy, J.F., Zeber, J.E., Gillon, L., Bingham, C.R., Stavenger, T., 2002. 2002 pharmacy data identify poorly adherent patients with schizophrenia at increased risk for admission. Med. Care 40 (8), 630–639. Volkow, N.D., Wang, G.-J., Newcorn, J., Telang, F., Solanto, M.V., Fowler, J.S., Logan, J., Ma, Y., Schulz, K., Pradhan, K., 2007. Depressed dopamine activity in caudate and preliminary evidence of limbic involvement in adults with attention-deficit/ hyperactivity disorder. Arch. Gen. Psychiatry 64 (8), 932–940. Williams, N.M., Zaharieva, I., Martin, A., Langley, K., Mantripragada, K., Fossdal, R., Stefansson, H., Stefansson, K., Magnusson, P., Gudmundsson, O.O., Gustafsson, O., Holmans, P., Owen, M.J., O'Donovan, M., Thapar, A., 2010. Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genomewide analysis. Lancet 376 (9750), 1401–1408.
Please cite this article as: Rho, A., et al., Clinical and functional implications of a history of childhood ADHD in first-episode psychosis, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.03.031
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Clinical and functional implications of a history of childhood ADHD in first-episode psychosis Aldanie Rho a, Alexandru Traicu a,b, Martin Lepage b, Srividya N. Iyer a,b, Ashok Malla a,b, Ridha Joober a,b,⁎ a b
Douglas Mental Health University Institute, Research Institute, Boulevard LaSalle, H4H 1R3 Montreal, QC, Canada McGill University, Faculty of Medicine, Department of Psychiatry, Ludmer Research & Training Building, 1033 Pine Avenue West, H3A 1A1 Montreal, QC, Canada
a r t i c l e
i n f o
Article history: Received 18 November 2014 Received in revised form 23 March 2015 Accepted 26 March 2015 Available online xxxx Keywords: Attention-deficit hyperactivity disorder (ADHD) First-episode psychosis (FEP) Schizophrenia spectrum disorder (SSD) Premorbid functioning Long-term outcomes
a b s t r a c t There is mounting evidence indicating that a childhood history of attention-deficit/hyperactivity disorder (ADHD) is associated with an increased risk for psychotic disorders, including schizophrenia. However, the implications of such a history on the symptomatic and functional outcomes of patients with psychotic disorders are still not well documented. This study examined the prevalence of childhood ADHD in patients with first episode psychosis (FEP) consecutively admitted to a specialized early intervention clinic covering a well-defined catchment area, and compared patients with and without a history of childhood ADHD on socio-demographic, clinical, and functional outcomes over a six to twelve months period. Out of 179 patients with FEP, 27 (15%) were treated for ADHD during childhood, consistent with previous literature indicating an association between childhood ADHD and psychosis. FEP patients with childhood history of ADHD had lower academic achievement, earlier onset of psychosis, and higher rates of childhood conduct and learning disorder. While the two groups had similar scores on psychopathology and functioning at baseline, patients with childhood ADHD showed significantly less improvement in positive and negative symptoms, as well as social and occupational functioning. These results strongly indicate that a history of childhood ADHD in FEP is more frequent than that reported in the general population and predictive of poorer clinical response to treatment. This emphasizes the need for actively screening for a history of ADHD in FEP patients and for treatments that are tailored for these patients. © 2015 Elsevier B.V. All rights reserved.
1. Introduction An association between a history of childhood attention-deficit/ hyperactivity disorder (ADHD) and schizophrenia-spectrum disorders (SSD) has received increasing support in the recent literature, which has documented an increased risk of developing SSD later in life in children with ADHD (Biederman et al., 2006; Dalsgaard et al., 2014), and high rates of an antecedent history of ADHD in adults with SSD (Gomez et al., 1981; Marsh and Williams, 2006; Dalteg et al., 2014). It has proven a complex task to link a generally younger pool of individuals with ADHD, with typical onset in elementary school (Kieling et al., 2010), with an older pool of people with SSD, the peak onset of which is in the third decade of life (Gogtay et al., 2011). This task is further complicated by the partial developmental overlap between these heterogeneous disorders, as symptoms of ADHD typically persist into adulthood (Faraone et al., 2006), while the first episode of psychosis
⁎ Corresponding author at: Douglas Mental Health University Institute, 6875 Boulevard LaSalle, Montreal H4H 1R3, QC, Canada. Tel.: +1 514 761 6131; fax: +1 514 888 4458. E-mail addresses: [email protected] (A. Rho), [email protected] (A. Traicu), [email protected] (M. Lepage), [email protected] (S.N. Iyer), [email protected] (A. Malla), [email protected] (R. Joober).
(FEP) is typically preceded by a prodrome with prominent deficits in attention (Cornblatt et al., 2003). The exact nature of the association between ADHD and SSD has remained unclear thus far. They are both neurodevelopmental disorders which share some genetic (Williams et al., 2010; Hamshere et al., 2013) and environmental risk factors, in particular obstetric complications and early developmental abnormalities (Peralta et al., 2011; Dalsgaard et al., 2014). They each involve a dysregulation in the dopamine system, and are treated with medications that modify its function (Mehler-Wex et al., 2006). Their association is further driven, but also obscured, by prominent shared symptoms, such as deficits in attention (Barr, 2001; Carter et al., 2010). Additionally, substance abuse may be an important moderator of their relationship, as a history of childhood ADHD increases both the rate of substance use disorders (SUDs) (Charach et al., 2011), and the psychotogenic potential of drugs of abuse (Roncero et al., 2012; Salo et al., 2013). This increased rate of substance use disorders has also been noted in samples with first episode of SSD (Cassidy et al., 2011). Given the typical persistence of both ADHD symptoms and related impairment beyond adolescence (Faraone et al., 2006; Klein et al., 2012), it is important to understand whether patients with childhood ADHD who develop SSD represent a distinct clinical population that may require a modified approach to treatment (Bellak et al., 1987;
http://dx.doi.org/10.1016/j.schres.2015.03.031 0920-9964/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Rho, A., et al., Clinical and functional implications of a history of childhood ADHD in first-episode psychosis, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.03.031
2
A. Rho et al. / Schizophrenia Research xxx (2015) xxx–xxx
Levy et al., 2015). Two studies have compared participants with SSD with and without a history of childhood ADHD. Elman et al. (1997) investigating adolescents with early-onset schizophrenia, found that those with a history of childhood ADHD had more neurodevelopmental abnormalities and a more insidious course with poorer medication response and functional outcome. Peralta et al. (2011) on the other hand, concluded that obstetrical complications and neurodevelopmental delay explained much of the association of childhood ADHD with schizophrenia, with no further impact on psychopathology or response to treatment in schizophrenia. Additional data come from studies showing that individuals at high-risk for psychosis with ADHD fare worse compared to those without ADHD in terms of premorbid adjustment, psychotic symptoms, cognition, function, and progression into SSD (Oner and Munir, 2005; De la Serna et al., 2010; Hurtig et al., 2011; Kim et al., 2012). In the present study, we compared the characteristics of two groups of participants with FEP: one with a history of childhood ADHD (the FEP–ADHD group) and another without such a history (the FEP-alone group), on a broad range of demographical, clinical, and functional measures. We tested the hypothesis that the FEP–ADHD group would have worse clinical and functional status both at baseline and at follow-up. These hypotheses were based on previously cited studies associating higher levels of illness severity in SSD with co-morbid ADHD. Our study builds on this previous work by investigating a relatively large well-characterized FEP sample of 179 participants using rigorously-standardized methodology over a longer duration of follow-up. 2. Methods 2.1. Participants The study was conducted on FEP patients treated at the Prevention and Early intervention Program for Psychoses — Montreal (PEPP), a specialized early intervention clinical research program at the Douglas Mental Health University Institute. PEPP is the sole service for FEP patients living in a catchment area of 400,000 in south-west Montreal. This helps minimize referral bias and increases the generalizability of the study's findings. Following international guidelines for specialized early intervention services for psychosis, all PEPP patients are provided with second-generation antipsychotic treatment and psychosocial interventions for a period of two years. Full details of the program are provided elsewhere (Malla et al., 2003) and on the website (douglas.mcgill.ca/pepp). 213 patients who entered PEPP consecutively between 2007 and 2013 were considered for inclusion in this study. PEPP admits patients with a first-episode psychotic disorder as defined by the Diagnostic and Statistical Manual of Mental Disease (4th edition; DSM-IV), either non-affective or affective, aged between 14 and 35 years old, with IQ higher than 70, and less than one month of previous exposure to antipsychotics. Additionally, for the present study, we excluded patients with either suspected history of childhood ADHD (32 individuals; 15%) or history of diagnosed but not treated childhood ADHD then (2 individuals; 1%), so as to maximize the reliability of the diagnosis of the ADHD. After their exclusion, the study sample comprised 179 participants. Data collection for the study was approved by the Institute's Ethics Research Board and all patients or their legal representatives have provided written informed consent. 2.2. Study design and outcome measures This was a prospective observational study, with data collected for all cases by trained evaluators using a specific protocol (Malla et al., 2003). At baseline, a Structured Clinical Interview for DSM-IV (First et al., 1995) was conducted by staff and confirmed with a senior
psychiatrist (AM or RJ) to establish primary, secondary, and substance use disorder (SUD) diagnoses. The age of first psychosis onset, the length of the psychotic prodrome, as well as the duration of untreated psychosis (DUP) were determined retrospectively using the semistructured Circumstances of Onset and Relapse Schedule (CORS) interview (Norman et al., 2004) conducted by trained evaluators. The diagnoses of childhood ADHD, conduct disorder (CD) and learning disorder (LD) were also established through the CORS. Education at baseline was coded at six levels: 1 (high School non-completers), 2 (high School completers), 3 (college non-completers), 4 (college completers), 5 (university non-completers), 6 (university completers). Socioeconomic status (SES) was measured using the Hollingshead index (Hollingshead, 1975). Medication non-adherence was assessed based on information from clients and case managers. Participants who did not conform to the medication prescriptions at least 75% of the time were considered non-adherent, based on level considered to be effective in preventing re-hospitalization (Valenstein et al., 2002; Karve et al., 2009). The Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS) (Andreasen, 1983a,b) were administered at baseline and six months of follow up. In our analysis, we used a modified SANS score without the Attention Subscale items, given their overlap with ADHD symptoms (Malla et al., 2002). Premorbid functioning was measured using the Premorbid Adjustment Scale (PAS) (Cannon-Spoor et al., 1982) total score for social and educational functioning from childhood to early adolescence. Psychosocial functioning was assessed at baseline and twelve months of follow-up using the Social and Occupational Functioning Assessment Scale (SOFAS) (Spitzer et al., 2000) and the Life Skills Profile (LSP), assessing self-care, non-turbulence, social contact, communication and responsibility (Rosen et al., 1989). These scales were administered at baseline and at twelve months after follow-up. 2.3. Statistical analysis The data were analyzed using SPSS (Statistical Package for the Social Sciences, version 20.0 for Windows). Categorical variables were compared by Pearson's Χ2 for proportions analysis, using the Fisher exact test when the Χ2 test assumptions were not met. For greater statistical power, demographic variables like marital status, SES, and non-adherence were collapsed into binary variables. Continuous variables were inspected for normality both visually through histogram and quantile–quantile plots, and by using the Kolmogorov test. Most variables were skewed, even after logarithmic transformations. For normally distributed continuous variables, we used Student's t-tests for cross-sectional data, and repeated-measures ANOVA for longitudinal data. For skewed variables, group medians were compared using the non-parametric Mann–Whitney U-test, after inspection of histogram plots confirmed the two comparison groups had similarly-shaped distributions. Statistical significance was set at 5%, using a one-tailed statistic to test the hypotheses that the comorbid FEP–ADHD group had worse clinical characteristics. 2.4. Missing data Preliminary analysis showed that the fraction of missing values increased rapidly with longer duration of follow up due to missed appointments or non-completion of scales. To strike a balance between presenting a longer longitudinal span and limiting bias from missing data, we choose to analyze follow up-data for the 6 months and the 12 months visits. This approach limited missing values to less than 20% for all variables, with the exception of the PAS total score, and the SOFAS and LSP scores at 12 months. Data appeared to be missing completely at random [Little's Missing Completely At Random test: Χ2(1522) = 766.446, p = 1.000], which indicates a low risk of bias from missing values. To confirm this, we
Please cite this article as: Rho, A., et al., Clinical and functional implications of a history of childhood ADHD in first-episode psychosis, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.03.031
A. Rho et al. / Schizophrenia Research xxx (2015) xxx–xxx
3
performed a sensitivity analysis by conducting multiple imputations (SPSS Markov Chain Monte Carlo algorithm, 10 iterations with 50 case draws and 2 parameter draws resulting in 10 imputed datasets) and reanalyzing several variables; we obtained similar results as the raw data analysis presented here.
revealed a significant main effect of ADHD status [F(1,108) = 8.202, p = 0.005]. While graphically (see Fig. 1) the differences in LSP scores appear to increase with time, the interaction between group and time was not significant [F(1,108) = 2.714, p = 1.02].
3. Results
4. Discussion
3.1. Prevalence of childhood ADHD
4.1. Summary of findings
There were 213 patients in our initial PEPP sample. Out of these, 34 (15.8%) had a history of suspected childhood ADHD or a history of diagnosed but untreated childhood ADHD. This FEP–ADHD group (N = 27) was compared with the FEP-alone group (N = 152).
We found a higher prevalence of childhood ADHD in our FEP sample than rates in the general population (Faraone et al., 2003), consistent with previous studies of ADHD prevalence in FEP samples (Gomez et al., 1981; Dalteg et al., 2014). Our comparative analysis generally confirmed the hypothesis that FEP–ADHD individuals have worse outcomes. We found that participants with and without a history of ADHD did not differ at baseline on symptoms. However, the FEP–ADHD group had an earlier onset of psychosis, as well as lower life skills at baseline. Further, FEP–ADHD participants also had a more severe illness trajectory. During the premorbid period, they had poorer functioning, lower educational achievement, more comorbid childhood conduct and learning disorders, and a trend toward higher rates of SUD. They also had a poorer prognosis at follow-up, with more severe positive and negative symptoms, and poorer social and occupational functioning, despite starting from a similar baseline in terms of symptoms. The rates of lifetime SUD and adherence at follow-up did not differ significantly between the two groups, Therefore, the differences in symptom scores appear to indicate a poorer response to treatment in the FEP–ADHD group, which also displayed lower life skills at follow-up, as well as an opposite trend in the evolution of life-skills over the course of the follow-up. As shown in Fig. 1, a decline over the first year in the FEP–ADHD group is observed compared to a steady improvement in the FEP-alone group. The exact mechanisms through which a history of ADHD may lead to poorer treatment response in FEP remain unclear. Recent work suggests that patients with schizophrenia and limbic hyperdopaminergia have better response to antipsychotic medications than patients without elevated mesolimbic dopamine levels (Howes and Kapur, 2014). While the profile of dopamine activity in FEP–ADHD patients has not yet been characterized, we may expect generally lower dopamine activity, given the possible deficits in mesolimbic dopamine activity found in ADHD (Volkow et al., 2007). Thus, differences in dopamine activity between the FEP-alone and FEP–ADHD groups may hold the key to explaining the poorer response to antipsychotics in FEP–ADHD patients. Overall, the FEP–ADHD group demonstrated poorer functioning in all phases (premorbid, at baseline and at one year follow-up) in terms of clinical characteristics, impairment and comorbidity. The lack of difference at baseline on the SOFAS between the two groups may be related to floor effects on this scale leading to loss of sensitivity in assessing participants with very poor functioning, as indicated in the heavy skewing on the low end on this scale. The earlier age of onset of psychosis in the FEP–ADHD group may be partly related to the higher
3.2. Baseline demographic characteristics As seen in Table 1, the two groups did not differ in terms of age, marital status, or SES, but there were significantly more males in the FEP–ADHD group. The FEP–ADHD participants had significantly lower academic achievement (p = 0.007). The median participant in the FEP–ADHD group had not completed high school, whereas the median participant in the FEP-alone group had completed high school. 3.3. Measures of psychopathology The differences in psychopathology are summarized in Table 2. While the average length of prodrome and DUP did not differ between the two groups, the FEP–ADHD group experienced the onset of psychosis on average two years earlier (p = 0.01). In regards to symptom severity, SAPS and SANS scores did not differ at baseline, but the FEPADHD group had significantly higher scores at six (p = 0.002 and p = 0.023, respectively). At baseline, 93% of patients in both groups were prescribed antipsychotic medication. No significant differences were observed in medication non-adherence both at baseline, six and twelve months of follow-up. Regarding comorbidity, there was a non-significant trend toward higher lifetime SUD rates among FEP–ADHD participants (75% vs 56% for FEP-alone participants, p = 0.066). The rates of affective and nonaffective psychosis did not differ between the two groups. Finally, FEP–ADHD individuals had significantly higher rates of childhood conduct disorder and learning disorder (44% and 35%, respectively, vs 11% and 11% in the FEP-alone group). 3.4. Measures of functioning As seen in Table 3, FEP–ADHD participants had poorer premorbid functioning than FEP-alone participants (p = 0.003). In terms of functioning, the SOFAS scores did not differ at baseline, but the FEP– ADHD group had significantly lower SOFAS scores at twelve months (p = 0.005). On cross-sectional analysis, the LSP scores were poorer in the FEP–ADHD group both at baseline and at twelve months (p = 0.009 and p = 0.002, respectively). Repeated-measures ANOVA
Table 1 Baseline demographic data in participants with and without a history of childhood ADHD.
Age at study entry: M (SD) Gender: Ns — % males Marital status: Ns — % singles Lower SES: % lower Education: Md
FEP-alone group (n = 152)
FEP–ADHD group (n = 27)
Analyses
23.8 (4.7) 104 — 69% 139 — 92% 0–0% 3 (HS completer)
22.3 (3.7) 25 — 93% 26 — 96% 2–7% 2 (HS non-completer)
t(177) = 1.528; p = 0.13 Χ2(1) = 6.376; p = 0.007⁎ FET, p = 0.402 FET, p = 0.391 U = 1159, p = 0.003⁎
Abbreviations: HS: high school; M (SD): mean (standard deviation); Md (R): median (range); Ns — %: number — percentage. t: Student's t-test; U: Mann–Whitney U-test; Χ2: Χ2 test for proportions; FET: Fisher's Exact test. ⁎ Result significant at 5% level.
Please cite this article as: Rho, A., et al., Clinical and functional implications of a history of childhood ADHD in first-episode psychosis, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.03.031
4
A. Rho et al. / Schizophrenia Research xxx (2015) xxx–xxx
Table 2 Psychopathology at baseline and follow-up in participants with and without a history of childhood ADHD.
Age at psychosis onset: M (SD) Prodrome: Md in weeks (R) DUP: Md in weeks (R) Medication non-adherence at baseline: % Medication non-adherence at 6 months: % Medication non-adherence at 12 months: % SAPS at baseline: Md ® SAPS at 6 months: Md ® SANS at baseline: Md ® SANS at 6 months: Md ® Non-affective psychosis: % SUD (lifetime diagnosis) at baseline: % Childhood LD: % Childhood CD: %
FEP-alone group (n = 152)
FEP–ADHD group (n = 27)
Analyses
23.2 (4,7) 26.1(0–965) 15(0.1–1049.4) 9.2% 27.4% 20.9% 36(5–90) 3(0–41) 28(0–61) 16(0–61) 64% 56% 11% 11%
21.3 (3.5) 39.1 (0–424.1) 16.1 (0.57–476.9) 19.2% 26.9% 25.0% 40 (15–79) 11 (0–51) 24 (6–67) 23,5 (4–49) 82% 75% 35% 44%
t(44.9) = 2.436; p = 0.01⁎ U = 1602, p = 0.237 U = 1568.5, p = 0.104 Χ2(1) = 2.332; p = 0.121 Χ2(1) = 0.003; p = 0.584 Χ2(1) = 0.194; p = 0.421 U = 1977, p = 0.423 U = 955.5, p = 0.002⁎ U = 1825, p = 0.479 U = 1124, p = 0.023⁎ Χ2(1) = 3.211; p = 0.081 Χ2(1) = 2.95; p = 0.066 Χ2(1) = 9.773; p = 0.005⁎ Χ2(1) = 19.989; p = b0.0005⁎
Abbreviations: DUP: duration of untreated psychosis; SAPS: Scale for Assessment of Positive Symptoms; SANS: Scale for Assessment of Negative Symptoms; SUD: substance use disorder; LD: learning disorder; CD: conduct disorder; M (SD): mean (standard deviation); Md (R): median (range); %: percentage. t: Student's t-test; U: Mann–Whitney U-test; Χ2: Χ2 test for proportions; FET: Fisher's Exact test. ⁎ Result significant at 5% level.
proportion of males in this group, who typically have an earlier onset (Eranti et al., 2013).
4.2. Comparison with past research Our results generally replicate those of Elman et al. (1997) who also found that a history of childhood ADHD was associated with poorer premorbid function, earlier onset, and poorer response to treatment. However, we did not find a longer prodrome in the FEP–ADHD group. While conducted in a different clinical sample, our findings are generally concordant with the literature on individuals at high-risk for SSD, where worse outcomes have been associated with comorbid ADHD (Oner and Munir, 2005). More recently, Peralta et al. (2011) found that obstetrical complications and neurodevelopmental delay mediated most of the association between recollected childhood ADHD symptoms and SSD. These variables are not regularly assessed at PEPP, so we were not able to test their influence in our study. The finding that the FEP–ADHD group also was more likely to have been diagnosed with CD and LD in childhood is in agreement with the high rates of CD and LD comorbidity in the general ADHD population (Biederman et al., 1991). Finally, our findings, especially those related to treatment response, are compatible with the hypothesis (Elman et al., 1997; Levy et al., 2015) that FEP patients with comorbid ADHD represent a special clinical group within the larger FEP population which may not be adequately served by our current treatments. We believe this underscores the need for future research into tailored treatment approaches for patients with FEP and comorbid ADHD.
4.3. Study strengths and weaknesses Our study is the first to compare FEP individuals with and without a history of ADHD over a significant duration of follow-up (up to one year) by using a mostly prospective, systematic, and wellstandardized assessment protocol. We compared the two groups on a broad range of domains, paying attention not only to illness symptoms, but also to their level of functioning. In the FEP–ADHD group, we only included participants who had reported receiving a clear diagnosis (and treatment) of ADHD as children. By doing so, we avoided the dangers of making retrospective diagnoses, which are overestimated in this population by recall bias and by the overlap between prodromal inattention and ADHD symptoms. This approach, however, may have led to the exclusion of some participants whose ADHD went undiagnosed in childhood. A potential limitation is the reliance on recalled information for the variables pertaining to the period prior to the index episode. We attempted to mitigate against recall bias and incomplete information by gathering data from multiple informants using structured interview-based instruments, such as the CORS. While including all FEP patients with a broad list of DSM-IV diagnoses results in a more naturalistic sample and increases statistical power, it does limit the generalizability of our finding to schizophrenia alone samples. The lack of data on current ADHD status of participants has made it necessary to rely on past history of diagnosis for our analysis. While we acknowledge this as a significant limitation, we note that pediatric ADHD persists into adulthood in around two-thirds of patients according to a large number of follow up studies, with higher persistence in patients with psychiatric comorbidities (Kooij et al., 2010). Therefore,
Table 3 Functioning at baseline and follow-up in participants with and without a history of childhood ADHD.
PAS: M (SD) SOFAS at baseline: Md (R) SOFAS at 12 months: Md (R) LSP at baseline: M (SD) LSP at 12 months: M (SD)
FEP-alone group (n = 152)
FEP–ADHD group (n = 27)
Analyses
0.27 (0.013) 35 (20–70) 60 (23–91) 132.4 (15.1) 136.6 (12.5)
0.37 (0.42) 35 (15–70) 50 (31–80) 123.8 (13.5) 127.91 (11.1)
t(109) = −2.899; p = 0.003⁎ U = 1951.5, p = 0.446 U = 880.5, p = 0.005⁎ t(143) = 2.405; p = 0.009⁎ t(130) = 2.972; p = 0.002⁎
Abbreviations: PAS: Premorbid Adjustment Scale; SOFAS: Social and Functional Assessment Scale; LSP: Life Skills Profile; M (SD): mean (standard deviation); Md (R): median (range); %: percentage. t: Student's t-test; U: Mann–Whitney U-test. ⁎ Result significant at 5% level.
Please cite this article as: Rho, A., et al., Clinical and functional implications of a history of childhood ADHD in first-episode psychosis, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.03.031
A. Rho et al. / Schizophrenia Research xxx (2015) xxx–xxx
5
Fig. 1. LSP evolution from baseline to 12 months in participants with or without a history of childhood ADHD.
we estimate that the symptoms of ADHD were still present in most patients from the FEP–ADHD group. Due to lack of information, we were unable to control our analysis for some potential mediators of the relationship between ADHD and FEP, including obstetric complications and developmental deficits. Moreover, it might have been informative to conduct symptom-level analyses for the SAPS and SANS, but given our sample size, this analysis would have had limited validity. Finally, given that the territory of FEP and ADHD is relatively unchartered, we chose not to adjust our significance level for multiple comparisons. We acknowledge that this increases the risk of spurious results, but believe this risk is low given the plurality of our findings consistently showing worse outcomes for the FEP–ADHD group. 4.4. Conclusion FEP participants who were diagnosed with ADHD in childhood had poorer premorbid function, earlier onset of illness, and poorer clinical and functional outcomes up to one year after follow-up, suggesting a poorer response to treatment compared to participants without ADHD. This suggests the necessity of further studies to clarify the association between ADHD and FEP and to test the efficacy of treatments tailored for this population. Role of funding source No funding source.
Contributors Aldanie Rho, Alexandru Traicu and Ridha Joober designed the study and wrote the protocol. Aldanie Rho and Alexandru Traicu performed the literature search and statistical analyses, and wrote the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest All authors declare that they have no conflicts of interest.
Acknowledgements We would like to acknowledge Nicole Pawliuk for the assistance with data access, Serge Gallant for the assistance with the statistical analysis and reviewing the manuscript, as well as the PEPP—Montreal staff for their help with participants' recruitment and evaluation.
References Andreasen, N.C., 1983a. Scale for the Assessment of Negative Symptoms. University of Iowa, Iowa City. Andreasen, N.C., 1983b. Scale for the Assessment of Positive Symptoms. University of Iowa, Iowa City. Barr, W.B., 2001. Schizophrenia and attention deficit disorder. Two complex disorders of attention. Ann. N. Y. Acad. Sci. 931, 239–250. Bellak, L., Kay, S.R., Opler, L.A., 1987. Attention deficit disorder psychosis as a diagnostic category. Psychiatr. Dev. 5 (3), 239–263. Biederman, J., Monuteaux, M.C., Mick, E., Spencer, T., Wilens, T.E., Silva, J.M., Snyder, L.E., Faraone, S.V., 2006. Young adult outcome of attention deficit hyperactivity disorder: a controlled 10-year follow-up study. Psychol. Med. 36 (2), 167–179. Biederman, J., Newcorn, J., Sprich, S., 1991. Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am. J. Psychiatry 148, 564–577. Cannon-Spoor, H.E., Potkin, S.G., Wyatt, R.J., 1982. Measurement of premorbid adjustment in chronic schizophrenia. Schizophr. Bull. 8 (3), 470. Carter, J.D., Bizzell, J., Kim, C., Bellion, C., Carpenter, K.L., Dichter, G., Belger, A., 2010. Attention deficits in schizophrenia—preliminary evidence of dissociable transient and sustained deficits. Schizophr. Res. 122 (1–3), 104–112. Cassidy, C.M., Joober, R., King, S., Malla, A.K., 2011. Childhood symptoms of inattention– hyperactivity predict cannabis use in first episode psychosis. Schizophr. Res. 132 (2–3), 171–176. Charach, A., Yeung, E., Climans, T., Lillie, E., 2011. Childhood attention-deficit/ hyperactivity disorder and future substance use disorders: comparative metaanalyses. J. Am. Acad. Child Adolesc. Psychiatry 50 (1), 9–21. Cornblatt, B.A., Lencz, T., Smith, C.W., Correll, C.U., Auther, A.M., Nakayama, E., 2003. The schizophrenia prodrome revisited: a neurodevelopmental perspective. Schizophr. Bull. 29 (4), 633–651. Dalsgaard, S., Mortensen, P.B., Frydenberg, M., Maibing, C.M., Nordentoft, M., Thomsen, P.H., 2014. Association between Attention-Deficit Hyperactivity Disorder in childhood and schizophrenia later in adulthood. Eur. Psychiatry 29 (4), 259–263. Dalteg, A., Zandelin, A., Tuninger, E., Levander, S., 2014. Psychosis in adulthood is associated with high rates of ADHD and CD problems during childhood. Nord. J. Psychiatry 68 (8), 560–566. De la Serna, E., Baeza, I., Toro, J., Andres, S., Puig, O., Sanchez-Guistau, V., Romero, S., Bernardo, M., Castro-Fornieles, J., 2010. Relationship between clinical and neuropsychological characteristics in child and adolescent first degree relatives of subjects with schizophrenia. Schizophr. Res. 116 (2–3), 159–167. Elman, I., Sigler, M., Kronenberg, J., Lindenmayer, J., Doron, A., Mendlovic, S., Gaoni, B., 1997. Characteristics of patients with schizophrenia successive to childhood attention deficit hyperactivity disorder (ADHD). Isr. J. Psychiatry Relat. Sci. 35 (4), 280–286. Eranti, S., Maccabe, J., Bundy, H., Murray, R., 2013. Gender difference in age at onset of schizophrenia: a meta-analysis. Psychol. Med. 43 (01), 155–167. Faraone, S.V., Biederman, J., Mick, E., 2006. The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies. Psychol. Med. 36 (2), 159–165. Faraone, S.V., Sergeant, J., Gillberg, C., Biederman, J., 2003. The worldwide prevalence of ADHD: is it an American condition? World Psychiatry 2 (2), 104. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B., 1995. Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition, January 1995 FINAL. SCID-I/P Version 2.0. Biometrics Research Department, New York State Psychiatric Institute, New York, NY.
Please cite this article as: Rho, A., et al., Clinical and functional implications of a history of childhood ADHD in first-episode psychosis, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.03.031
6
A. Rho et al. / Schizophrenia Research xxx (2015) xxx–xxx
Gogtay, N., Vyas, N.S., Testa, R., Wood, S.J., Pantelis, C., 2011. Age of onset of schizophrenia: perspectives from structural neuroimaging studies. Schizophr. Bull. 37 (3), 504–513. Gomez, R.L., Janowsky, D., Zetin, M., Huey, L., Clopton, P.L., 1981. Adult psychiatric diagnosis and symptoms compatible with the hyperactive child syndrome: a retrospective study. J. Clin. Psychiatry 42 (10), 389–394. Hamshere, M.L., Stergiakouli, E., Langley, K., Martin, J., Holmans, P., Kent, L., Owen, M.J., Gill, M., Thapar, A., O'Donovan, M., Craddock, N., 2013. Shared polygenic contribution between childhood attention-deficit hyperactivity disorder and adult schizophrenia. Br. J. Psychiatry 203 (2), 107–111. Hollingshead, A.B., 1975. Four Factor Index of Social Status. Howes, O.D., Kapur, S., 2014. A neurobiological hypothesis for the classification of schizophrenia: type A (hyperdopaminergic) and type B (normodopaminergic). Br. J. Psychiatry 205 (1), 1–3. Hurtig, T.M., Taanila, A., Veijola, J., Ebeling, H., Maki, P., Miettunen, J., Kaakinen, M., Joukamaa, M., Therman, S., Heinimaa, M., Jarvelin, M.R., Moilanen, I., 2011. Associations between psychotic-like symptoms and inattention/hyperactivity symptoms. Soc. Psychiatry Psychiatr. Epidemiol. 46 (1), 17–27. Karve, S., Cleves, M.A., Helm, M., Hudson, T.J., West, D.S., Martin, B.C., 2009. Good and poor adherence: optimal cut-point for adherence measures using administrative claims data. Curr. Med. Res. Opin. 25 (9), 2303–2310. Kieling, C., Kieling, R.R., Rohde, L.A., Frick, P.J., Moffitt, T., Nigg, J.T., Tannock, R., Castellanos, F.X., 2010. The age at onset of attention deficit hyperactivity disorder. Am. J. Psychiatr. 167 (1), 14–16. Kim, S.J., Lee, Y.J., Jang, J.H., Lim, W., Cho, I.H., Cho, S.J., 2012. The relationship between psychotic-like experiences and attention deficits in adolescents. J. Psychiatr. Res. 46 (10), 1354–1358. Klein, R.G., Mannuzza, S., Olazagasti, M.A., Roizen, E., Hutchison, J.A., Lashua, E.C., Castellanos, F.X., 2012. Clinical and functional outcome of childhood attentiondeficit/hyperactivity disorder 33 years later. Arch. Gen. Psychiatry 69 (12), 1295–1303. Kooij, S.J.J., Bejerot, S., Blackwell, A., Caci, H., Casas-Brugué, M., Carpentier, P.J., Edvinsson, D., Fayyad, J., Foeken, K., Fitzgerald, M., Gaillac, V., Ginsberg, Y., Henry, C., Krause, J., Lensing, M.B., Manor, I., Niederhofer, H., Nunes-Filipe, C., Ohlmeier, M.D., Oswald, P., Pallanti, S., Pehlivanidi, A., Ramos-Quiroga, J.A., Rastam, M., Ryffel-Rawak, D.R., Stes, S., Asherson, P., 2010. EUropean consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD. BMC Psychiatry 10, 67 (Sep 3). Levy, A., Traicu, A., Iyer, S., Malla, A., Joober, R., 2015. Psychotic disorders co-morbid with ADHD: an important knowledge gap. Can. J. Psychiatry 1;60 (3 Suppl 2), S48–52. Malla, A., Takhar, J.J., Norman, R., Manchanda, R., Cortese, L., et al., 2002. Negative symptoms in first-episode non-affective psychosis. Acta Psychiatr. Scand. 105 (6), 431–439. Malla, A., Norman, R., McLean, T., Scholten, D., Townsend, L., 2003. A Canadian programme for early intervention in non-affective psychotic disorders. Aust. N. Z. J. Psychiatry 37 (4), 407–413.
Marsh, P.J., Williams, L.M., 2006. ADHD and schizophrenia phenomenology: visual scanpaths to emotional faces as a potential psychophysiological marker? Neurosci. Biobehav. Rev. 30 (5), 651–665. Mehler-Wex, C., Riederer, P., Gerlach, M., 2006. Dopaminergic dysbalance in distinct basal ganglia neurocircuits: implications for the pathophysiology of Parkinson's disease, schizophrenia and attention deficit hyperactivity disorder. Neurotox. Res. 10 (3–4), 167–179. Norman, R., Malla, A., Verdi, M., Hassall, L., Fazekas, C., 2004. Understanding delay in treatment for first-episode psychosis. Psychol. Med. 34 (02), 255–266. Oner, O., Munir, K., 2005. Attentional and neurocognitive characteristics of high-risk offspring of parents with schizophrenia compared with DSM-IV attention deficit hyperactivity disorder children. Schizophr. Res. 76 (2–3), 293–299. Peralta, V., de Jalon, E.G., Campos, M.S., Zandio, M., Sanchez-Torres, A., Cuesta, M.J., 2011. The meaning of childhood attention-deficit hyperactivity symptoms in patients with a first-episode of schizophrenia-spectrum psychosis. Schizophr. Res. 126 (1–3), 28–35. Roncero, C., Ros-Cucurull, E., Daigre, C., Casas, M., 2012. Prevalence and risk factors of psychotic symptoms in cocaine-dependent patients. Actas Esp. Psiquiatr. 40 (4), 187–197. Rosen, A., HadziPavlovic, D., Parker, G., 1989. The life skills profile. Schizophr. Bull. 15 (2), 325–337. Salo, R., Fassbender, C., Iosif, A.M., Ursu, S., Leamon, M.H., Carter, C., 2013. Predictors of methamphetamine psychosis: history of ADHD-relevant childhood behaviors and drug exposure. Psychiatry Res. 210 (2), 529–535. Spitzer, R., Gibbon, M., Endicott, J., 2000. Global assessment scale (GAS), global assessment of functioning (GAF) scale, social and occupational functioning assessment scale (SOFAS). Handbook of Psychiatric Measures. American Psychiatric Association, Washington, pp. 96–100. Valenstein, M., Copeland, L.A., Blow, F.C., McCarthy, J.F., Zeber, J.E., Gillon, L., Bingham, C.R., Stavenger, T., 2002. 2002 pharmacy data identify poorly adherent patients with schizophrenia at increased risk for admission. Med. Care 40 (8), 630–639. Volkow, N.D., Wang, G.-J., Newcorn, J., Telang, F., Solanto, M.V., Fowler, J.S., Logan, J., Ma, Y., Schulz, K., Pradhan, K., 2007. Depressed dopamine activity in caudate and preliminary evidence of limbic involvement in adults with attention-deficit/ hyperactivity disorder. Arch. Gen. Psychiatry 64 (8), 932–940. Williams, N.M., Zaharieva, I., Martin, A., Langley, K., Mantripragada, K., Fossdal, R., Stefansson, H., Stefansson, K., Magnusson, P., Gudmundsson, O.O., Gustafsson, O., Holmans, P., Owen, M.J., O'Donovan, M., Thapar, A., 2010. Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genomewide analysis. Lancet 376 (9750), 1401–1408.
Please cite this article as: Rho, A., et al., Clinical and functional implications of a history of childhood ADHD in first-episode psychosis, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.03.031
