Psychosis in adulthood is associated with high rates of ADHD and CD problems during childhood
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ARNE DALTEG, ANDERS ZANDELIN, EVA TUNINGER, STEN LEVANDER
Dalteg A, Zandelin A, Tuninger E, Levander S. Psychosis in adulthood is associated with high rates of ADHD and CD problems during childhood. Nord J Psychiatry 2014;68:560–566. Background: Patients diagnosed with schizophrenia display poor premorbid adjustment (PPA) in half of the cases. Attention deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) are common child psychiatric disorders. These two facts have not previously been linked in the literature. Aims: To determine the prevalence of ADHD/CD problems retrospectively among patients with psychoses, and whether and to what extent the high frequency of substance abuse problems among such patients may be linked to ADHD/CD problems. Method: ADHD and CD problems/diagnoses were retrospectively recorded in one forensic (n 149) and two non-forensic samples (n 98 and n 231) of patients with a psychotic illness: schizophrenia, bipolar or other, excluding drug-induced psychoses. Results: ADHD and CD were much more common among the patients than in the general population—the odds ratio was estimated to be greater than 5. There was no significant difference in this respect between forensic and non-forensic patients. Substance abuse was common, but substantially more common among patients with premorbid ADHD/CD problems. Conclusions: Previous views regarding PPA among patients with a psychotic illness may reflect an association between childhood ADHD/CD and later psychosis. The nature of this association remains uncertain: two disorders sharing some generative mechanisms or one disorder with two main clinical manifestations. Childhood ADHD and particularly CD problems contribute to the high frequency of substance abuse in such groups. • ADHD, Conduct disorder, Forensic, Psychosis, Schizophrenia, Substance abuse. Sten Levander, Department of Criminology, Malmö University, SE 20506 Malmö, Sweden, E-mail: [email protected]; Accepted 4 February 2014.
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ome 40 years ago, researchers became aware that many patients with schizophrenia had a poorer premorbid adjustment than controls (1, 2). Instruments to assess poor premorbid adjustment (PPA) were developed, i.e. the Premorbid Asocial Adjustment Scale (PAAS) (1) and the Premorbid Adjustment Scale (PAS) (3). This approach fitted well with the vulnerability–stress model (4, 5) and fuelled interest in the nature of the vulnerabilities linked to PPA. In terms of causal factors, the most well-researched candidates so far are genes (6, 7), epigenetic mechanisms (8) and adverse factors during pregnancy and delivery (9)), including infections and auto-immune mechanisms (10). There is a reasonable consistency in research findings regarding how these vulnerabilities manifest during childhood and adolescence— and studies are still being pursued with this issue in focus (11–13). In summary, PPA individuals who later develop schizophrenia are in childhood/ adolescence
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characterized by poor social skills, academic underachievement that is not necessarily linked to low IQ, and certain personality traits. Psychosis onset is earlier in these cases, there are more negative symptoms and social outcomes are poorer. It is somewhat curious that few researchers have considered whether certain child psychiatric syndromes might be the cause of PPA. A PubMed search yielded only a handful of hits over the last 20 years (14). In more recent studies, nobody has suggested that attention deficit/hyperactivity disorder (ADHD) might be a risk factor for schizophrenia, as an alternative to the assumption that PPA is an early manifestation of schizophrenia (15–17). Interest among PPA researchers has been focused on the symptom level, looking at ADHD symptoms as well as those characteristic of oppositional defiance disorder and conduct disorder (CD). Such symptoms are rather unspecific when considered in DOI: 10.3109/08039488.2014.892151
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isolation, which might explain why findings in the PPA literature have so far been difficult to interpret. Reflecting on the degree to which symptoms of ADHD/CD in childhood are associated with the characteristic pattern of failure to reach milestones, peer problems and academic underachievement described in the PPA literature, there is actually a good match. For the past two decades, it has been possible to diagnose ADHD in adulthood. CD is closely associated with antisocial personality disorder (ASPD) in adulthood. For both diagnoses, there is continuity from childhood to adulthood with respect to diagnostic criteria. The most common instruments used to assess PPA were developed prior to the publication of the DSMIII—and there were at that time major differences in the US and European views of ADHD. In Europe, hyperkinetic child disorder was rare (0.5%) by comparison with the rate of ADHD, which based on the current DSM-IV-TR definition is found in around 2% of girls and 6% of boys, conservatively estimated, with little variation between countries and cultures. An increase in prevalence is expected with the proposed criteria included in the DSMV (18). In adulthood, a majority of these individuals continue to have problems, including difficulties linked to substance abuse (19). What about psychoses other than schizophrenia in this respect? ADHD in adulthood shares features with bipolar disorders (20, 21): is this a question of comorbid disorders or of shared generative mechanisms with two different clinical manifestations? Kraepelin’s view of two major and distinct functional psychoses has been challenged in the recent literature (22). If bipolar disorder is somehow linked to ADHD, schizophrenia may also be linked to ADHD (23). Childhood ADHD problems, as well as such problems that persist into adulthood, are common in prison populations (24, 25), where many individuals have a major mental illness, particularly in countries that employ the M’Naghten strict criteria of criminal nonresponsibility (26). The link between criminality and CD is even stronger. It is therefore of interest to compare the rate of premorbid ADHD and CD problems in forensic and non-forensic patients diagnosed with a major mental illness. The main aim of this study was to assess the prevalence of retrospectively identified childhood ADHD and CD problems and corresponding diagnoses among patients diagnosed with schizophrenia and other functional psychoses. This issue was analyzed in two materials: one general psychiatric sample, and one forensic sample with matched non-forensic controls from general psychiatry. Another aim was to document the association between childhood ADHD and/or CD and alcohol/drug abuse in adulthood in these samples. NORD J PSYCHIATRY·VOL 68 NO 8·2014
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Method Analytical strategy and statistical methods This report concerns two unrelated studies with partially overlapping sets of data indices, some of which are identical and some related. The studies are reported together because the same main issues can be analyzed, no similar studies have previously been conducted, and because it is important to verify both the concurrent and construct validity of the findings described immediately, in order to encourage further empirical studies. Our main focus is directed at effect size (Cohen’s d (27)). We use the mean as the preferred index of central tendency because it is robust and commonly used. We do not present standard deviation as an index of variability unless the distribution is normal—standard deviation is a non-robust statistic. In these cases, the range is an appropriate measure. We prefer to use the non-parametric Kendall’s tau as the main index of association. We have kept our statistical analyses rather basic, and have restricted ourselves to the use of standard methods—in order to answer the main research issues examined in the paper. The calculations were conducted using the SPSS 18 package.
Subjects GOTLAND GENERAL PSYCHIATRY SAMPLE Gotland is a large island in the Baltic Sea with a residential population both in the medieval town of Visby (20,000 inhabitants) and in rural areas (35,000 inhabitants). Psychiatric services are provided by a single clinic, located in Visby. The current patients were recruited consecutively from an inpatient ward that also served outpatients with more serious problems—including neuro-psychiatric and substance abuse disorders. During the years 1993–2005, data for patients who were subjected to a more comprehensive clinical assessment procedure were entered into a database comprising clinical, neuropsychological and other kinds of relevant information (n 616). The aim was to systematize the needs of such patients in order to improve the quality of the care. Among the 616 patients in the database, which has been anonymized, there were 119 inpatients who met DSM-IV criteria for schizophrenia, 73 had bipolar disorder and 39 patients had other psychoses (n 231). These represent almost all psychosis patients known to the psychiatric services during the years of data collection. Substance dependence/ abuse was ascertained, and if present was subdivided into alcohol and substance abuse with or without alcohol abuse. A number of clinical characteristics for the three psychosis groups are presented in Table 1.
AFTERCARE MIXED SAMPLE The international multicenter AfterCare study included 120 patients from Canada, 78 from Finland, 79 from Germany and 31 patients from Sweden, for the years
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Table 1. Socio-demographic and clinical characteristics (means/ percentages) of the Gotland psychosis group. Schizophrenia
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n Age Age/onset Age/range Abuse Alcohol Substance
Bipolar
Other psychoses
Men
Women
Men
Women
Men
Women
67 37 26 16–68
52 41 28 20–60
38 42 30 19–67
35 43 28 20–57
25 34 28 16–58
14 41 35 18–63
22% 30%
15% 29%
21% 24%
14% 17%
16% 44%
29% 14%
1997–2001 (28). Index patients were consecutively recruited from forensic psychiatric clinics at four sites, when patients were released from compulsory care. For 122 of the 186 index patients, it was possible to recruit a control patient from nearby general psychiatric clinics, i.e. a person of the same sex, age and diagnosis, and who had been released concurrently from inpatient treatment. Most of the patients (84%) were diagnosed with schizophrenia. Only 11 of the patients were women. For the current study, men with a 295 diagnosis (DSMIVTR schizophrenia) were considered, 149 forensic and 98 general psychiatry cases (Table 2). Of these, 19% were diagnosed with schizoaffective disorder.
Retrospective assessment of ADHD and ODD/CD problems THE GOTLAND SAMPLE All subjects were interviewed and assessed clinically by the first author (AD), an experienced psychologist and clinical researcher (Ph.D.). All subjects were also interviewed with respect to childhood problems, particularly those characteristic of ADHD and ODD/CD. Childhood and adolescence problems, if present, were classified as ADHD, CD, autism spectrum/tics disorders, internalizing (anxiety/depression) problems and low IQ. The classification was not mutually exclusive. Diagnoses in adulthood were made according to DSM-IV criteria. ADHD problems in adulthood were assessed by self-reports, using the Malmo questionnaire (unpublished). This self-report questionnaire (76 items, four-step Likert response format) has been used in the current as well as in a number of Table 2. A number of clinical characteristics of the AfterCare male patients diagnosed with schizophrenia.
n Age Age range Age 1st hospitaliz. Abuse Alcohol only Substance
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Forensic
Non-forensic
149 40 20–75 25
98 36 19–63 24
28% 46%
22% 44%
other (also unpublished) studies as a practical way of collecting data in the clinic. It includes the 18 DSM criteria, followed by 24 items from the Brown ADD instrument (29), the 25 items from Broadbent and colleagues’ “Cognitive failure questionnaire” (30) and finally nine items to assess “short fuse problems”. Subscales are homogenous (alpha range 0.77–0.91) and strongly intercorrelated (median 0.75) in samples of “normals” among whom the prevalence of ADHD might be expected to be higher than in the general population, for instance “unemployed”. It should be noted that problems described by the items may be manifestations of a psychosis (21). The validity of the retrospective childhood clinical ADHD diagnoses was backed up by scores in another self-report questionnaire, using the 25-item version of the Wender– Utah Rating Scale (WURS-25) (31) in our translation (32). Symptoms relevant for the diagnosis of CD were assessed by a self-report version of the DSM-III Axis 2 symptom definitions, the SCID-II-Screen, similar to the DIP-Q instrument developed and used in Sweden (33). This includes subscales on antisocial symptoms both prior to age 15 and subsequent to age 18. ASPD was diagnosed according to DSMIV criteria, recognizing the overlap in symptom descriptions between the Axis I and II disorders (34). In order to assess the validity of the ADHD indices, inter-correlations (tau) were computed between WURS and the indices of the Malmo questionnaire. All coefficients were significant and most of them were highly significant. The median correlation was 0.33 among men and 0.47 among women. Correlations between the clinical assessment of ADHD in childhood and the Malmo questionnaire subscales are presented in Table 3 for men and women. Most coefficients are significant, and are substantially higher for women. The correlation between a retrospective CD diagnosis, the number of self-rated CD symptoms according to SCID-II-Screen, and an ASPD diagnosis was 0.64 and 0.50 respectively (Kendall’s tau, both P 0.001).
THE AFTERCARE SAMPLE All patients were assessed by trained and clinically experienced interviewers (23) concerning psychiatric Table 3. Intercorrelations (Kendall’s tau) between the retrospective clinical diagnosis of attention deficit/hyperactivity disorder (ADHD) and the Malmo ADHD questionnaire subscales among Gotland psychosis patients. Scale DSM criteria Brown items Broadbent items Short fuse items Total
Men (n 140) 0.32** 0.20 0.12 0.30* 0.24**
Women (n 101) 0.49*** 0.53*** 0.39** 0.52*** 0.52***
*p .05; **p .01; ***p .001. NORD J PSYCHIATRY·VOL 68 NO 8·2014
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symptoms in childhood, e.g. behavior and other relevant problems at school, home or in the community, particularly symptoms characteristic of ADHD. Their answers were, as far as possible, checked against information in e.g. hospital records or from parents. A retrospective diagnosis of childhood ADHD was based on the presence of a typical pattern of problems (data collection was carried out at a time when there was no ADHD SCID interview). Current (adulthood) ADHD was not specifically diagnosed. CD and ASPD were diagnosed by SCID interviews according to DSM IV. Furthermore, the number of CD problems was tallied.
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Table 5. Alcohol and drug abuse among men and women (Gotland material) subdivided according to presence of childhood attention deficit/hyperactivity disorder (ADHD) and conduct disorder (CD).
Men (n 140) ADHD No ADHD CD No CD Women (n 101) ADHD No ADHD CD No CD
No abuse
Alcohol
Drug abuse
33% 63% 31% 59%
25% 16% 25% 18%
41% 26% 43% 23%
53% 70% 33% 69%
17% 16% 17% 17%
29% 14% 50% 14%
Results The Gotland sample The proportions with ADHD in childhood and adulthood, and CD among Gotland psychosis patients are displayed in Table 4. For ADHD, there were no significant effects of sex, childhood vs. adulthood, or diagnostic subgroups (χ2 tests). The frequency of CD was lower than for ADHD for all comparisons except for men with “other psychoses”. Furthermore, CD was less common among women with “other psychoses”. Bipolar men displayed the highest percentage of adult ADHD problems. The largest sex difference was obtained for CD/ASPD among patients with “other psychoses”. Findings regarding alcohol and substance abuse are displayed in Table 5. Among men, those with childhood ADHD had more abuse (χ2 (2) 11.4, P 0.01). This difference was non-significant for women. With respect to CD, both men and women with CD had significantly more abuse (men: χ2 (2) 9.48, P 0.01; women: χ2 (2) 14.1, P 0.001).
The AfterCare sample Among all patients, 23% were diagnosed with CD, and 50% had either attention (24%) or impulsivity/hyperactivity (4%) or both problems (23%), suggestive of childhood ADHD. There were no significant differences (χ2) between forensic and general patients for any comparison. The Table 4. Percentage with attention deficit/hyperactivity disorder (ADHD) in childhood and adulthood (Ch and Ah), conduct disorder (CD) and antisocial personality disorder (ASPD) among Gotland psychosis patients (n=231). Schizophrenia
n ADHD-Ch ADHD-Ah* CD ASPD
Bipolar
Other psychoses
Men
Women
Men
Women
Men
Women
67 53% 48% 40% 15%
52 62% 46% 31% 19%
38 42% 63% 26% 11%
35 57% 46% 20% 6%
35 56% 38% 44% 36%
14 43% 40% 7% 7%
*7% missing values. NORD J PSYCHIATRY·VOL 68 NO 8·2014
percentages for attention problems were 40% vs. 41%, for hyperactivity symptoms 19% vs. 20% and for CD 26% vs. 17%, respectively. The mean number of conduct symptoms (DSMIV) was 1.84 and 1.36 for forensic and general patients respectively. This difference was also non-significant (two-way analysis of variance with site as the other independent variable), as was the interaction. Abuse problems subdivided according to the presence of childhood ADHD and CD among forensic and nonforensic patients are displayed in Table 6. Among nonforensic patients, abuse was more common for those with childhood CD (χ2 (2) 9.91, P 0.01). All the other differences were non-significant.
Discussion The first aim was to assess the frequency of childhood ADHD type problems in our groups of patients diagnosed with psychosis. The pattern of correlations among the various independent indices of ADHD and CD suggest that the assessments yielded valid data. Retrospectively diagnosed ADHD and CD were much more common among the patients, regardless of diagnosis, than in the general population (34, 35)—the odds ratio (OR) can be conservatively estimated at 5 for men and as being higher still for women. In arriving at these estimations, we have taken into account that even if such problems were reported, this does not mean that the diagnostic criteria for ADHD or CD were fulfilled (36). Table 6. Abuse problems among the AfterCare patients subdivided with respect to presence of childhood attention deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) diagnoses. Forensic
ADHD No ADHD CD No CD
Non-forensic
No
Alc.
Subst.
No
Alc.
Subst.
22% 29% 18% 29%
23% 33% 26% 29%
55% 39% 56% 42%
29% 36% 6% 40%
17% 24% 18% 24%
54% 40% 77% 37%
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Contrary to expectations, there were no significant differences in the prevalence of ADHD/CD between forensic and non-forensic patients. It should be noted that the same kind of problems were also common in adulthood, but then in combination with a psychotic illness. It appears that there may be a substantial correlation between childhood ADHD/CD and a functional psychosis in adulthood, and a persistence of ADHD/CDrelated symptoms/problems over the life course among such patients, i.e. co-morbidity. This association appears to be much stronger for women, or alternatively to be less “diluted” by symptoms of the psychotic illness. The nature of these associations remains unclear, i.e. whether they reflect shared generative mechanisms or are rather a manifestation of a single disorder with multiple clinical presentations. The AfterCare material has previously been employed for analyses of a related issue: the consequences of childhood CD for schizophrenia in adulthood with respect to aggression and criminality (37, 38). Here we have examined the same issue in reverse, i.e. starting in adulthood and looking back. None of the findings in the two earlier reports contradicts the findings of the present study. This study was conducted for specific reasons. One was that we were puzzled by a previous finding—among a group of 80 borstal school children, all with severe CD and 70% of whom had ADHD, who were aged 13–17 at data collection, and then followed up at age 30; of these, seven had developed schizophrenia, an OR of approximately 10. In addition, eight were dead and all deaths were violent (suicide, homicide, accidents). Among those, there may have been even more cases of psychoses (39). The present findings are in a way neither unexpected, nor new. The PPA type of research has provided consonant empirical data for over three decades. What is new is the interpretation of these findings, and the much higher degree of persistence of ADHD symptoms over the life course found among women. Cross-validation by other research groups is needed. However, the field appears to believe that it has already been done: in a recent study (40), the authors refer to the “well-known link between ADHD and schizophrenia/bipolar disorder” in their study of relatives of people with ADHD but provide no reference to this statement. Recently the first follow-up study of children diagnosed with ADHD and schizophrenia in adulthood was published (41). The relative risk (OR) was 4, corroborating our findings. The over-representation of the two childhood disorders did not differ between the three diagnostic groups in the Gotland sample. An increased frequency of ADHD/CD in bipolar patients has been reported previously (20, 21). The statistical power of the comparison between patients with schizophrenia and bipolar disorder
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(n 119 and n 73, respectively) in our study is good enough to detect even small differences with respect to clinical significance in these respects. Thinking twice, a link between the two major and often comorbid externalizing child psychiatric syndromes on the one hand, and psychoses in adulthood on the other, is not unlikely. The meso-limbic dopamine system (ML-DS) is implicated in both sets of disorders. One set is typically treated with dopamine agonists, the other set with antagonists. A unifying assumption would be the presence of an age-specific dysregulation of the ML-DS system. The prime candidate for involvement in ML-DS dysregulation is the glutamate system—this is only one hypothesis and many more could be developed if our findings hold (42). Our findings appear to be appropriate to analyze further according to the RDoC recommendations (Research Domain Criteria; www.nimh.nih.gov/ research-priorities/rdoc/index.shtml). The long-term effects of central stimulant (CS) treatment of ADHD in childhood are largely unknown. We are currently analyzing Norwegian material suggesting that such treatment appears to offer protection against many negative outcomes in adulthood: abuse, depression, certain anxiety disorders and criminality (submitted manuscript). These effects appear to be large (Cohen’s d 0.8). Would such treatment also provide protection against later psychoses or might it perhaps increase the risk? We do not know, in spite of 75 years of CS treatment of children with ADHD.1 The second aim of the study was to document the association between childhood problems and substance abuse in adulthood. Substance abuse was common in all three samples. CD contributed more than childhood ADHD to abuse in adulthood, in line with previous studies (37, 42). There might be a sex difference with respect to ADHD and substance abuse (i.e. a still more increased risk among men).
Limitations THE GOTLAND SAMPLE The diagnostic process was a standard clinical one, involving the team at the unit and cross-checked by one experienced clinician before being entered into the database. DSM-IV criteria were used, in retrospect for patients assessed prior to 1995. The diagnoses for psychoses and abuse may be expected to be more reliable than the retrospective diagnoses for ADHD and CD. These latter clinical diagnoses, together with the ASPD diagnosis, were therefore corroborated via a set of selfrating scales. Correlations were generally high and highly significant.
THE AFTERCARE SAMPLE This study is exemplary with respect to its rigorous assessment of the relevant patient characteristics. However, NORD J PSYCHIATRY·VOL 68 NO 8·2014
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the matched controls from general psychiatry were recruited somewhat differently—at one site, the researchers tried to find matches who were also similar to the index patients with respect to clinical history. This was not the case at the other sites. However, there were no significant effects of site on our main findings. For some index patients no match could be found. This does not threaten the validity of the findings.
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Conclusions Retrospectively reported ADHD and CD type problems were much more common than expected among patients diagnosed with schizophrenia and bipolar disorder. With respect to schizophrenia, these problems have previously been viewed as prodromal rather than comorbid with ADHD and CD diagnoses. There were no differences between the two psychoses in respect of frequency of childhood ADHD and CD problems. Forensic patients might be expected to display more ADHD and CD childhood problems with reference to the association between these problems and later criminality. This was not the case compared with non-forensic patients. Women diagnosed with schizophrenia and bipolar disorder reported more childhood ADHD and CD problems than men. Substance use problems were more common among patients who reported childhood ADHD/CD problems, men being more vulnerable to this outcome. In the future, two research approaches may be used: the comorbidity one (think diagnostically) and the RDoC one (focus on common problems and their generative mechanisms on a more fundamental level). Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Note 1 The DSMIII criteria of ADHD were based on clinical descriptions of children infected by the von Economo influenza type virus during the epidemic of 1915–1926 in Europe and North America, Encephalitis lethargica. The clinical syndromes, which differed in children and adults, were probably caused by auto-immune mechanisms in vulnerable individuals (cf. 10). Such a mechanism, targeting the basal ganglia, is probably involved in the recent 10-fold increase in narcolepsy in Sweden associated with Swine flu and the corresponding vaccine. Treatment by central stimulants for “minimal CP children” was found to be effective in the mid-1930s (Bradley C, The behaviour of children receiving Benzedrine. Am J of Psychiatry1937;94:577–585). NORD J PSYCHIATRY·VOL 68 NO 8·2014
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criteria of attention deficit/hyperactivity disorder and hyperkinetic disorder? Parent-based prevalence rates in a national sample— Results of the BELLA study. Eur Child Adolesc Psychiatry 2008; 17 Suppl 1:59–70. Anckarsäter H, Lundström S, Kollberg L, Kerekes N, Palm C, Carlström E, et al. The Child and Adolescent Twin Study in Sweden (CATSS). Twin Res Hum Genet 2011;14:495–508. Moran P, Hodgins S. The correlates of comorbid antisocial personality disorder in schizophrenia. Schizophr Bull 2004;30: 791–802. Hodgins S, Tiihonen J. The consequences of conduct disorder for males who develop schizophrenia: Associations with criminality, aggressive behaviour, substance use, and psychiatric services. Schizophrenia Res 2005;78:323–35. Hodgins S, Cree A, Alderton J, Mak T. From conduct disorder to severe mental illness: Associations with aggressive behaviour, crime and victimization. Psychological Medicine 2007;38:975–89. Dalteg A, Levander S. Twelve thousand crimes by 75 boys: A 20-year follow-up study of childhood hyperactivity. J Forens Psychiatry 1998;9:39–57. Larsson H, Rydén E, Boman M, Långström N, Lichtenstein P, Landén M. Risk of bipolar disorder and schizophrenia in relatives of people with attention-deficit hyperactivity disorder. Br J Psychiat 2013;203:103–6. Dalsgaard S, Mortensen PB, Frydenberg M, Maibing CM, Nordentoft M, Thomsen PH. Association between attention-deficit hyperactivity disorder in childhood and schizophrenia later in adulthood. Eur Psychiatry 2013; doi: 10.1016/ j.eurpsy.2013.06.004. Wu J, Xiao H, Sun H, Zou L, Zhu LQ. Role of dopamine receptors in ADHD: A systematic meta-analysis. Mol Neurobiol 2012;45:605–20.
Arne Dalteg, Psychiatric Clinic, SE-57228, Oskarshamn, Sweden. Anders Zandelin, Child and Youth Psychiatric Unit, SE-57228 Oskarshamn, Sweden. Eva Tuninger, Clinical Sciences/Psychiatry, Lund University, SE-22900 Lund, Sweden. Sten Levander, Department of Criminology, Malmö University, SE-20506, Malmö, Sweden.
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Dalteg A, Zandelin A, Tuninger E, Levander S. Psychosis in adulthood is associated with high rates of ADHD and CD problems during childhood. Nord J Psychiatry 2014;68:560–566. Background: Patients diagnosed with schizophrenia display poor premorbid adjustment (PPA) in half of the cases. Attention deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) are common child psychiatric disorders. These two facts have not previously been linked in the literature. Aims: To determine the prevalence of ADHD/CD problems retrospectively among patients with psychoses, and whether and to what extent the high frequency of substance abuse problems among such patients may be linked to ADHD/CD problems. Method: ADHD and CD problems/diagnoses were retrospectively recorded in one forensic (n 149) and two non-forensic samples (n 98 and n 231) of patients with a psychotic illness: schizophrenia, bipolar or other, excluding drug-induced psychoses. Results: ADHD and CD were much more common among the patients than in the general population—the odds ratio was estimated to be greater than 5. There was no significant difference in this respect between forensic and non-forensic patients. Substance abuse was common, but substantially more common among patients with premorbid ADHD/CD problems. Conclusions: Previous views regarding PPA among patients with a psychotic illness may reflect an association between childhood ADHD/CD and later psychosis. The nature of this association remains uncertain: two disorders sharing some generative mechanisms or one disorder with two main clinical manifestations. Childhood ADHD and particularly CD problems contribute to the high frequency of substance abuse in such groups. • ADHD, Conduct disorder, Forensic, Psychosis, Schizophrenia, Substance abuse. Sten Levander, Department of Criminology, Malmö University, SE 20506 Malmö, Sweden, E-mail: [email protected]; Accepted 4 February 2014.
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ome 40 years ago, researchers became aware that many patients with schizophrenia had a poorer premorbid adjustment than controls (1, 2). Instruments to assess poor premorbid adjustment (PPA) were developed, i.e. the Premorbid Asocial Adjustment Scale (PAAS) (1) and the Premorbid Adjustment Scale (PAS) (3). This approach fitted well with the vulnerability–stress model (4, 5) and fuelled interest in the nature of the vulnerabilities linked to PPA. In terms of causal factors, the most well-researched candidates so far are genes (6, 7), epigenetic mechanisms (8) and adverse factors during pregnancy and delivery (9)), including infections and auto-immune mechanisms (10). There is a reasonable consistency in research findings regarding how these vulnerabilities manifest during childhood and adolescence— and studies are still being pursued with this issue in focus (11–13). In summary, PPA individuals who later develop schizophrenia are in childhood/ adolescence
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characterized by poor social skills, academic underachievement that is not necessarily linked to low IQ, and certain personality traits. Psychosis onset is earlier in these cases, there are more negative symptoms and social outcomes are poorer. It is somewhat curious that few researchers have considered whether certain child psychiatric syndromes might be the cause of PPA. A PubMed search yielded only a handful of hits over the last 20 years (14). In more recent studies, nobody has suggested that attention deficit/hyperactivity disorder (ADHD) might be a risk factor for schizophrenia, as an alternative to the assumption that PPA is an early manifestation of schizophrenia (15–17). Interest among PPA researchers has been focused on the symptom level, looking at ADHD symptoms as well as those characteristic of oppositional defiance disorder and conduct disorder (CD). Such symptoms are rather unspecific when considered in DOI: 10.3109/08039488.2014.892151
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isolation, which might explain why findings in the PPA literature have so far been difficult to interpret. Reflecting on the degree to which symptoms of ADHD/CD in childhood are associated with the characteristic pattern of failure to reach milestones, peer problems and academic underachievement described in the PPA literature, there is actually a good match. For the past two decades, it has been possible to diagnose ADHD in adulthood. CD is closely associated with antisocial personality disorder (ASPD) in adulthood. For both diagnoses, there is continuity from childhood to adulthood with respect to diagnostic criteria. The most common instruments used to assess PPA were developed prior to the publication of the DSMIII—and there were at that time major differences in the US and European views of ADHD. In Europe, hyperkinetic child disorder was rare (0.5%) by comparison with the rate of ADHD, which based on the current DSM-IV-TR definition is found in around 2% of girls and 6% of boys, conservatively estimated, with little variation between countries and cultures. An increase in prevalence is expected with the proposed criteria included in the DSMV (18). In adulthood, a majority of these individuals continue to have problems, including difficulties linked to substance abuse (19). What about psychoses other than schizophrenia in this respect? ADHD in adulthood shares features with bipolar disorders (20, 21): is this a question of comorbid disorders or of shared generative mechanisms with two different clinical manifestations? Kraepelin’s view of two major and distinct functional psychoses has been challenged in the recent literature (22). If bipolar disorder is somehow linked to ADHD, schizophrenia may also be linked to ADHD (23). Childhood ADHD problems, as well as such problems that persist into adulthood, are common in prison populations (24, 25), where many individuals have a major mental illness, particularly in countries that employ the M’Naghten strict criteria of criminal nonresponsibility (26). The link between criminality and CD is even stronger. It is therefore of interest to compare the rate of premorbid ADHD and CD problems in forensic and non-forensic patients diagnosed with a major mental illness. The main aim of this study was to assess the prevalence of retrospectively identified childhood ADHD and CD problems and corresponding diagnoses among patients diagnosed with schizophrenia and other functional psychoses. This issue was analyzed in two materials: one general psychiatric sample, and one forensic sample with matched non-forensic controls from general psychiatry. Another aim was to document the association between childhood ADHD and/or CD and alcohol/drug abuse in adulthood in these samples. NORD J PSYCHIATRY·VOL 68 NO 8·2014
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Method Analytical strategy and statistical methods This report concerns two unrelated studies with partially overlapping sets of data indices, some of which are identical and some related. The studies are reported together because the same main issues can be analyzed, no similar studies have previously been conducted, and because it is important to verify both the concurrent and construct validity of the findings described immediately, in order to encourage further empirical studies. Our main focus is directed at effect size (Cohen’s d (27)). We use the mean as the preferred index of central tendency because it is robust and commonly used. We do not present standard deviation as an index of variability unless the distribution is normal—standard deviation is a non-robust statistic. In these cases, the range is an appropriate measure. We prefer to use the non-parametric Kendall’s tau as the main index of association. We have kept our statistical analyses rather basic, and have restricted ourselves to the use of standard methods—in order to answer the main research issues examined in the paper. The calculations were conducted using the SPSS 18 package.
Subjects GOTLAND GENERAL PSYCHIATRY SAMPLE Gotland is a large island in the Baltic Sea with a residential population both in the medieval town of Visby (20,000 inhabitants) and in rural areas (35,000 inhabitants). Psychiatric services are provided by a single clinic, located in Visby. The current patients were recruited consecutively from an inpatient ward that also served outpatients with more serious problems—including neuro-psychiatric and substance abuse disorders. During the years 1993–2005, data for patients who were subjected to a more comprehensive clinical assessment procedure were entered into a database comprising clinical, neuropsychological and other kinds of relevant information (n 616). The aim was to systematize the needs of such patients in order to improve the quality of the care. Among the 616 patients in the database, which has been anonymized, there were 119 inpatients who met DSM-IV criteria for schizophrenia, 73 had bipolar disorder and 39 patients had other psychoses (n 231). These represent almost all psychosis patients known to the psychiatric services during the years of data collection. Substance dependence/ abuse was ascertained, and if present was subdivided into alcohol and substance abuse with or without alcohol abuse. A number of clinical characteristics for the three psychosis groups are presented in Table 1.
AFTERCARE MIXED SAMPLE The international multicenter AfterCare study included 120 patients from Canada, 78 from Finland, 79 from Germany and 31 patients from Sweden, for the years
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Table 1. Socio-demographic and clinical characteristics (means/ percentages) of the Gotland psychosis group. Schizophrenia
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n Age Age/onset Age/range Abuse Alcohol Substance
Bipolar
Other psychoses
Men
Women
Men
Women
Men
Women
67 37 26 16–68
52 41 28 20–60
38 42 30 19–67
35 43 28 20–57
25 34 28 16–58
14 41 35 18–63
22% 30%
15% 29%
21% 24%
14% 17%
16% 44%
29% 14%
1997–2001 (28). Index patients were consecutively recruited from forensic psychiatric clinics at four sites, when patients were released from compulsory care. For 122 of the 186 index patients, it was possible to recruit a control patient from nearby general psychiatric clinics, i.e. a person of the same sex, age and diagnosis, and who had been released concurrently from inpatient treatment. Most of the patients (84%) were diagnosed with schizophrenia. Only 11 of the patients were women. For the current study, men with a 295 diagnosis (DSMIVTR schizophrenia) were considered, 149 forensic and 98 general psychiatry cases (Table 2). Of these, 19% were diagnosed with schizoaffective disorder.
Retrospective assessment of ADHD and ODD/CD problems THE GOTLAND SAMPLE All subjects were interviewed and assessed clinically by the first author (AD), an experienced psychologist and clinical researcher (Ph.D.). All subjects were also interviewed with respect to childhood problems, particularly those characteristic of ADHD and ODD/CD. Childhood and adolescence problems, if present, were classified as ADHD, CD, autism spectrum/tics disorders, internalizing (anxiety/depression) problems and low IQ. The classification was not mutually exclusive. Diagnoses in adulthood were made according to DSM-IV criteria. ADHD problems in adulthood were assessed by self-reports, using the Malmo questionnaire (unpublished). This self-report questionnaire (76 items, four-step Likert response format) has been used in the current as well as in a number of Table 2. A number of clinical characteristics of the AfterCare male patients diagnosed with schizophrenia.
n Age Age range Age 1st hospitaliz. Abuse Alcohol only Substance
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Forensic
Non-forensic
149 40 20–75 25
98 36 19–63 24
28% 46%
22% 44%
other (also unpublished) studies as a practical way of collecting data in the clinic. It includes the 18 DSM criteria, followed by 24 items from the Brown ADD instrument (29), the 25 items from Broadbent and colleagues’ “Cognitive failure questionnaire” (30) and finally nine items to assess “short fuse problems”. Subscales are homogenous (alpha range 0.77–0.91) and strongly intercorrelated (median 0.75) in samples of “normals” among whom the prevalence of ADHD might be expected to be higher than in the general population, for instance “unemployed”. It should be noted that problems described by the items may be manifestations of a psychosis (21). The validity of the retrospective childhood clinical ADHD diagnoses was backed up by scores in another self-report questionnaire, using the 25-item version of the Wender– Utah Rating Scale (WURS-25) (31) in our translation (32). Symptoms relevant for the diagnosis of CD were assessed by a self-report version of the DSM-III Axis 2 symptom definitions, the SCID-II-Screen, similar to the DIP-Q instrument developed and used in Sweden (33). This includes subscales on antisocial symptoms both prior to age 15 and subsequent to age 18. ASPD was diagnosed according to DSMIV criteria, recognizing the overlap in symptom descriptions between the Axis I and II disorders (34). In order to assess the validity of the ADHD indices, inter-correlations (tau) were computed between WURS and the indices of the Malmo questionnaire. All coefficients were significant and most of them were highly significant. The median correlation was 0.33 among men and 0.47 among women. Correlations between the clinical assessment of ADHD in childhood and the Malmo questionnaire subscales are presented in Table 3 for men and women. Most coefficients are significant, and are substantially higher for women. The correlation between a retrospective CD diagnosis, the number of self-rated CD symptoms according to SCID-II-Screen, and an ASPD diagnosis was 0.64 and 0.50 respectively (Kendall’s tau, both P 0.001).
THE AFTERCARE SAMPLE All patients were assessed by trained and clinically experienced interviewers (23) concerning psychiatric Table 3. Intercorrelations (Kendall’s tau) between the retrospective clinical diagnosis of attention deficit/hyperactivity disorder (ADHD) and the Malmo ADHD questionnaire subscales among Gotland psychosis patients. Scale DSM criteria Brown items Broadbent items Short fuse items Total
Men (n 140) 0.32** 0.20 0.12 0.30* 0.24**
Women (n 101) 0.49*** 0.53*** 0.39** 0.52*** 0.52***
*p .05; **p .01; ***p .001. NORD J PSYCHIATRY·VOL 68 NO 8·2014
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symptoms in childhood, e.g. behavior and other relevant problems at school, home or in the community, particularly symptoms characteristic of ADHD. Their answers were, as far as possible, checked against information in e.g. hospital records or from parents. A retrospective diagnosis of childhood ADHD was based on the presence of a typical pattern of problems (data collection was carried out at a time when there was no ADHD SCID interview). Current (adulthood) ADHD was not specifically diagnosed. CD and ASPD were diagnosed by SCID interviews according to DSM IV. Furthermore, the number of CD problems was tallied.
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Table 5. Alcohol and drug abuse among men and women (Gotland material) subdivided according to presence of childhood attention deficit/hyperactivity disorder (ADHD) and conduct disorder (CD).
Men (n 140) ADHD No ADHD CD No CD Women (n 101) ADHD No ADHD CD No CD
No abuse
Alcohol
Drug abuse
33% 63% 31% 59%
25% 16% 25% 18%
41% 26% 43% 23%
53% 70% 33% 69%
17% 16% 17% 17%
29% 14% 50% 14%
Results The Gotland sample The proportions with ADHD in childhood and adulthood, and CD among Gotland psychosis patients are displayed in Table 4. For ADHD, there were no significant effects of sex, childhood vs. adulthood, or diagnostic subgroups (χ2 tests). The frequency of CD was lower than for ADHD for all comparisons except for men with “other psychoses”. Furthermore, CD was less common among women with “other psychoses”. Bipolar men displayed the highest percentage of adult ADHD problems. The largest sex difference was obtained for CD/ASPD among patients with “other psychoses”. Findings regarding alcohol and substance abuse are displayed in Table 5. Among men, those with childhood ADHD had more abuse (χ2 (2) 11.4, P 0.01). This difference was non-significant for women. With respect to CD, both men and women with CD had significantly more abuse (men: χ2 (2) 9.48, P 0.01; women: χ2 (2) 14.1, P 0.001).
The AfterCare sample Among all patients, 23% were diagnosed with CD, and 50% had either attention (24%) or impulsivity/hyperactivity (4%) or both problems (23%), suggestive of childhood ADHD. There were no significant differences (χ2) between forensic and general patients for any comparison. The Table 4. Percentage with attention deficit/hyperactivity disorder (ADHD) in childhood and adulthood (Ch and Ah), conduct disorder (CD) and antisocial personality disorder (ASPD) among Gotland psychosis patients (n=231). Schizophrenia
n ADHD-Ch ADHD-Ah* CD ASPD
Bipolar
Other psychoses
Men
Women
Men
Women
Men
Women
67 53% 48% 40% 15%
52 62% 46% 31% 19%
38 42% 63% 26% 11%
35 57% 46% 20% 6%
35 56% 38% 44% 36%
14 43% 40% 7% 7%
*7% missing values. NORD J PSYCHIATRY·VOL 68 NO 8·2014
percentages for attention problems were 40% vs. 41%, for hyperactivity symptoms 19% vs. 20% and for CD 26% vs. 17%, respectively. The mean number of conduct symptoms (DSMIV) was 1.84 and 1.36 for forensic and general patients respectively. This difference was also non-significant (two-way analysis of variance with site as the other independent variable), as was the interaction. Abuse problems subdivided according to the presence of childhood ADHD and CD among forensic and nonforensic patients are displayed in Table 6. Among nonforensic patients, abuse was more common for those with childhood CD (χ2 (2) 9.91, P 0.01). All the other differences were non-significant.
Discussion The first aim was to assess the frequency of childhood ADHD type problems in our groups of patients diagnosed with psychosis. The pattern of correlations among the various independent indices of ADHD and CD suggest that the assessments yielded valid data. Retrospectively diagnosed ADHD and CD were much more common among the patients, regardless of diagnosis, than in the general population (34, 35)—the odds ratio (OR) can be conservatively estimated at 5 for men and as being higher still for women. In arriving at these estimations, we have taken into account that even if such problems were reported, this does not mean that the diagnostic criteria for ADHD or CD were fulfilled (36). Table 6. Abuse problems among the AfterCare patients subdivided with respect to presence of childhood attention deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) diagnoses. Forensic
ADHD No ADHD CD No CD
Non-forensic
No
Alc.
Subst.
No
Alc.
Subst.
22% 29% 18% 29%
23% 33% 26% 29%
55% 39% 56% 42%
29% 36% 6% 40%
17% 24% 18% 24%
54% 40% 77% 37%
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Contrary to expectations, there were no significant differences in the prevalence of ADHD/CD between forensic and non-forensic patients. It should be noted that the same kind of problems were also common in adulthood, but then in combination with a psychotic illness. It appears that there may be a substantial correlation between childhood ADHD/CD and a functional psychosis in adulthood, and a persistence of ADHD/CDrelated symptoms/problems over the life course among such patients, i.e. co-morbidity. This association appears to be much stronger for women, or alternatively to be less “diluted” by symptoms of the psychotic illness. The nature of these associations remains unclear, i.e. whether they reflect shared generative mechanisms or are rather a manifestation of a single disorder with multiple clinical presentations. The AfterCare material has previously been employed for analyses of a related issue: the consequences of childhood CD for schizophrenia in adulthood with respect to aggression and criminality (37, 38). Here we have examined the same issue in reverse, i.e. starting in adulthood and looking back. None of the findings in the two earlier reports contradicts the findings of the present study. This study was conducted for specific reasons. One was that we were puzzled by a previous finding—among a group of 80 borstal school children, all with severe CD and 70% of whom had ADHD, who were aged 13–17 at data collection, and then followed up at age 30; of these, seven had developed schizophrenia, an OR of approximately 10. In addition, eight were dead and all deaths were violent (suicide, homicide, accidents). Among those, there may have been even more cases of psychoses (39). The present findings are in a way neither unexpected, nor new. The PPA type of research has provided consonant empirical data for over three decades. What is new is the interpretation of these findings, and the much higher degree of persistence of ADHD symptoms over the life course found among women. Cross-validation by other research groups is needed. However, the field appears to believe that it has already been done: in a recent study (40), the authors refer to the “well-known link between ADHD and schizophrenia/bipolar disorder” in their study of relatives of people with ADHD but provide no reference to this statement. Recently the first follow-up study of children diagnosed with ADHD and schizophrenia in adulthood was published (41). The relative risk (OR) was 4, corroborating our findings. The over-representation of the two childhood disorders did not differ between the three diagnostic groups in the Gotland sample. An increased frequency of ADHD/CD in bipolar patients has been reported previously (20, 21). The statistical power of the comparison between patients with schizophrenia and bipolar disorder
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(n 119 and n 73, respectively) in our study is good enough to detect even small differences with respect to clinical significance in these respects. Thinking twice, a link between the two major and often comorbid externalizing child psychiatric syndromes on the one hand, and psychoses in adulthood on the other, is not unlikely. The meso-limbic dopamine system (ML-DS) is implicated in both sets of disorders. One set is typically treated with dopamine agonists, the other set with antagonists. A unifying assumption would be the presence of an age-specific dysregulation of the ML-DS system. The prime candidate for involvement in ML-DS dysregulation is the glutamate system—this is only one hypothesis and many more could be developed if our findings hold (42). Our findings appear to be appropriate to analyze further according to the RDoC recommendations (Research Domain Criteria; www.nimh.nih.gov/ research-priorities/rdoc/index.shtml). The long-term effects of central stimulant (CS) treatment of ADHD in childhood are largely unknown. We are currently analyzing Norwegian material suggesting that such treatment appears to offer protection against many negative outcomes in adulthood: abuse, depression, certain anxiety disorders and criminality (submitted manuscript). These effects appear to be large (Cohen’s d 0.8). Would such treatment also provide protection against later psychoses or might it perhaps increase the risk? We do not know, in spite of 75 years of CS treatment of children with ADHD.1 The second aim of the study was to document the association between childhood problems and substance abuse in adulthood. Substance abuse was common in all three samples. CD contributed more than childhood ADHD to abuse in adulthood, in line with previous studies (37, 42). There might be a sex difference with respect to ADHD and substance abuse (i.e. a still more increased risk among men).
Limitations THE GOTLAND SAMPLE The diagnostic process was a standard clinical one, involving the team at the unit and cross-checked by one experienced clinician before being entered into the database. DSM-IV criteria were used, in retrospect for patients assessed prior to 1995. The diagnoses for psychoses and abuse may be expected to be more reliable than the retrospective diagnoses for ADHD and CD. These latter clinical diagnoses, together with the ASPD diagnosis, were therefore corroborated via a set of selfrating scales. Correlations were generally high and highly significant.
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the matched controls from general psychiatry were recruited somewhat differently—at one site, the researchers tried to find matches who were also similar to the index patients with respect to clinical history. This was not the case at the other sites. However, there were no significant effects of site on our main findings. For some index patients no match could be found. This does not threaten the validity of the findings.
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Conclusions Retrospectively reported ADHD and CD type problems were much more common than expected among patients diagnosed with schizophrenia and bipolar disorder. With respect to schizophrenia, these problems have previously been viewed as prodromal rather than comorbid with ADHD and CD diagnoses. There were no differences between the two psychoses in respect of frequency of childhood ADHD and CD problems. Forensic patients might be expected to display more ADHD and CD childhood problems with reference to the association between these problems and later criminality. This was not the case compared with non-forensic patients. Women diagnosed with schizophrenia and bipolar disorder reported more childhood ADHD and CD problems than men. Substance use problems were more common among patients who reported childhood ADHD/CD problems, men being more vulnerable to this outcome. In the future, two research approaches may be used: the comorbidity one (think diagnostically) and the RDoC one (focus on common problems and their generative mechanisms on a more fundamental level). Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Note 1 The DSMIII criteria of ADHD were based on clinical descriptions of children infected by the von Economo influenza type virus during the epidemic of 1915–1926 in Europe and North America, Encephalitis lethargica. The clinical syndromes, which differed in children and adults, were probably caused by auto-immune mechanisms in vulnerable individuals (cf. 10). Such a mechanism, targeting the basal ganglia, is probably involved in the recent 10-fold increase in narcolepsy in Sweden associated with Swine flu and the corresponding vaccine. Treatment by central stimulants for “minimal CP children” was found to be effective in the mid-1930s (Bradley C, The behaviour of children receiving Benzedrine. Am J of Psychiatry1937;94:577–585). NORD J PSYCHIATRY·VOL 68 NO 8·2014
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Arne Dalteg, Psychiatric Clinic, SE-57228, Oskarshamn, Sweden. Anders Zandelin, Child and Youth Psychiatric Unit, SE-57228 Oskarshamn, Sweden. Eva Tuninger, Clinical Sciences/Psychiatry, Lund University, SE-22900 Lund, Sweden. Sten Levander, Department of Criminology, Malmö University, SE-20506, Malmö, Sweden.
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