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    QUEST - Attention Deficit Hyperactivity Disorder

AUTHOR
Alexandra Spessot

Long Term Treatment of ADHD

Chairman’s Rounds, October 30, 2006

Clinical Questions: How do long-term medication and behavioral treatments compare with one another? Are there additional benefits when they are used together? What is the effectiveness of systematic, carefully delivered treatments vs routine community care? 

Reference: The MTA Cooperative Group. 1999. A 14-Month Randomized Clinical Trial of Treatment Strategies for Attention-Deficit/Hyperactivity Disorder. Arch Gen Psychiatry 56:1073-86. 

Background:  ADHD has a prevalence of 3-5% in school-aged children, and accounts for 30-50% of child mental health referrals. ADHD causes impairment across most all domains of functioning. While the treatment of choice for ADHD at this point is stimulants, little is known about the long-term effectiveness of these meds, and there are wide variations in the way stimulants are used. There is also limited evidence about the effectiveness of behavioral treatments for ADHD, both alone and in combination with medication.

Methods:
Design/Setting: Randomized clinical trial using samples from 6 different sites. Referral sources for each site included mental health settings, pediatricians, advertisements, and school notices. 579  children were assigned randomly to medication mgmt, behavioral treatment, combined treatment, or community care for 14 months:

  1. Med mgmt: 28 day, double-blind, daily-switch titration of methylphenidate, using 5 randomly-prdered repeats each of  placebo, 5mg, 10mg, and  15mg/20mg.. Most effective dose determined, blind broken. If poor response to methylphenidate, then alternates tried: dextroamphetamine, pemoline, imipramine, others. Pts seen Qmonth for med mgmt.
  2. Behavioral Treatment: Parent training, total 27 group and 8 individual sessions. Child-focused treatment was an intense summer treatment program (8 wks, 5 days/week, 9 hrs/day).  School-based treatment was 10-16 sessions of biweekly teacher consultation and 12 weeks of a part-time aide working directly with the child.
  3. Combined Treatment: 1 & 2, with close collaboration between providers of each.
  4. Community Care: pts got a report of their initial assessments and a list of community mental health providers.

Population : Male and female children aged 7-9.9; in grades 1-4; living with same primary caretaker >6 months; all met DSM-IV criteria for ADHD as evaluated using DISC,  parent report, version 3.0, supplemented with up to 2 sx identified by teachers for cases falling just below the DISC diagnostic threshold.

Exclusion criteria: see Table 1

Assessment Methods/Outcomes: 6 domains; subjects assessed along these domains at baseline, 3mos, 9mos, and 14mos

  1. ADHD symptoms: parent and teacher SNAP ratings on inattention/hyperactivity-impulsivity subscales
  2. Oppositional/aggressive symptoms: parent and teacher SNAP ratings on oppositional-defiant disorder subscale
  3. Social Skills: parent and teacher completed subscale from the Social Skills Rating System (SSRS)
  4. Internalizing Sx (Anxiety, Depression): internalizing subscale of SSRS and children’s self-ratings on MASC
  5. Parent-child relations: 2 composite scales from a parent-child relationship questionnaire
  6. Academic achievement: 3 subscales from the WISC (reading, math, spelling)

Assessment of domains 1-5 were augmented by blinded ratings of school-based ADHD and ODD/aggression symptoms using the Abikoff Classroom Observational System, and social skills and peer relations using peer sociometric procedures.

Analysis: Intention-to-treat, random-effects regression analyses, with Bonferonni corrections for multiple comparisons.

Validity: F/U complete? Yes. Randomized? Yes; Intention to treat? Yes. Similar at baseline? Yes. Blinded? Yes. Equal treatment? Yes. 

Results: (See Table 5)
1. How do long-term medication and behavioral treatments compare with one another? Med mgmt > behav

for ADHD sx, as shown by parents’ and teachers’ ratings of inattention and teachers’ ratings of hyperactivity/impulsivity. No significant difference between med mgmt and behav on any other outcomes.

2. Are there additional benefits when they are used together?  Comb ≈ Med Mgmt across all domains, but comb methylphenidate doses < med mgmt doses. Comb, Behav > Med mgmt with regard to parent satisfaction. Comb > behav in ADHD sx as shown by parent/teacher ratings of inattention and parent-rated hyperactivity/impulsivity.

3. What is the effectiveness of systematic, carefully delivered treatments vs routine community care? Comb, Med mgmt  > CC, and behav≈ CC for parent and teacher-reported ADHD sx. Comb > CC on all 5 non-ADHD domains.

Comments:
Strengths:: well-organized; rigorous; generalizable; long-term F/U; looked at non-ADHD domains

Weaknesses:: behavioral intervention not necessarily realistic; limited power to detect small effect sizes

CLINICAL BOTTOM LINE: This study supports medication management as the first-line treatment for ADHD symptoms. Adding behavioral interventions may be beneficial in treating non-ADHD symptoms that are found more commonly in children with ADHD, and they may allow for lower minimum effective dosing of medications. Although the benefit of these behavioral interventions was modest in this study, further study is needed to clarify the role of behavioral interventions in treatment of ADHD throughout development.

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AUTHOR
 Doug Burgess

Adult ADHD

Chairman’s Rounds, March 19, 2007 

Citation: McCann B.S. Screening and diagnostic utility of self-report attention deficit hyperactivity disorder scales in adults. Comprehensive Psychiatry 2004; 45(3): 175-83. 

Clinical Question: How effective are standard adult ADHD scales in screening and aiding in diagnosis?  (Adult Rating Scale (ARS), Attention-Deficit Scales for Adults (ADSA) and Symptom Inventory for ADHD) 

Background: The estimated prevalence of ADHD in the adult population is between 0.3% and 5%.  Currently, there are several scales available for screening and diagnosing ADHD in adults. However, despite their frequent use, few studies have explored the validity and reliability of these scales. 

Question Type: Diagnosis. 

Validity Criteria:  In this study, the diagnosis of PTSD was uncertain in participants and there was a blind comparison between the results of the screening questionnaires and the determination of clinicians based on a semi-structured interview (gold standard).  Every participant completed all three questionnaires as well as a semi-structured interview and follow up was complete.  The main threat to validity involved the population selected for screening.  Participants were recruited from an adult specialty ADHD clinic.  Patients were either self referred secondary to significant ongoing symptoms or seeking a second opinion on a previously applied diagnosis.

Study Design: Cross Sectional
Criteria for Appropriate Design: This study was conducted in a university affiliated adult ADHD specialty clinic in the Seattle area from 1997 to 1999.  A total of 82 patients participated in the study the majority of which were Caucasian males (96.3% and 59.8% respectively).  Each participant completed three commonly utilized screening questionnaires:  the Adult Rating Scale (ARS), the Attention-Deficit Scale for Adults (ADSA) and the Symptom Inventory for ADHD. In addition, each participant underwent two semi-structured interviews conducted by a psychologist and a psychiatrist.  The consensus of these interviewers served as the gold standard of diagnosis. Based on the interviews, the clinicians were able to assign any DSM-IV diagnosis. 

Main results:
Based on the diagnostic interview, 38 patients were diagnosed with ADHD while 44 were given an alternative diagnosis. Depressive disorder (25%), dysthymia (22.7%) and bipolar disorder (11.4%) were the principal alternative diagnoses. Based on these results, the following sensitivities, specificities and likelihood ratios were determined.

Test

Score

Sens

Spec.

Positive Likelihood Ratio

Negative Likelihood Ratio

Symptom
Inventory

6

78.4

53.5

1.7

0.40

7

62.2

67.4

1.9

0.56

ARS

31

91.9

32.6

1.4

0.25

41

59.5

58.1

1.4

0.70

ADSA

T-score 70

81.0

46.0

1.5

0.35

Conclusions: Although many self report indices are currently available to aid in the screening and diagnosis of adult ADHD, these studies yield a large number of false positives that limit their clinical usefulness.  In particular, patients with mood disorders may share a number of characteristics with ADHD that make them more vulnerable to inappropriate diagnosis and potentially harmful medication. The results of this study clearly demonstrate the limits of self report indices in screening and diagnosing ADHD. However, their potential role in monitoring the symptoms of ADHD in patients previously diagnosed remains unclear and should be a topic for further research. 

Synopsis: In this cross-sectional study, the positive and negative predictive values of the Adult Rating Scale (ARS), the Attention-Deficit Scale for Adults (ADSA) and the Symptom Inventory for ADHD were shown to produce minimal or no change in the pretest likelihood of ADHD.  Additionally, the study showed that individuals with mood disorders were particularly vulnerable to inappropriate diagnosis.

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AUTHOR:

Kerry Landry

Methylphenidate Treatment for Preschoolers with ADHD

Chairman’s Rounds, December 4, 2006

 “Efficacy & Safety of Immediate-Release Methylphenidate Treatment for Preschoolers with ADHD,” J. Am. Acad. Child Adolesc. Psychiatry, 2006; 45(11):1284-1293.

Clinical Question: What’s the evidence out there for treating 4yo’s with ADHD?

Clinical Case or Background Info: 4yo WM is brought to an outpatient private practice clinic by his parents who are “desperate.”  “John” has always been a much more active kid than any of his 3 brothers and sisters, his parents “can’t keep up” with him at home or wherever they take him, has just been kicked out of 2 preschools in the last month for aggressive behaviors towards his peers.

Question Type: Therapy

            Validity Criteria for Therapy:

Follow-up: Follow-up was complete and all patients who entered the trial were properly accounted for and attributed at its conclusion.

Randomization: Computerized stratified randomization, 1:1:1:1 starting allocation ratio, using a randomized, balanced, crossover protocol designed to avoid order effects.  Second randomization to active MPH or to placebo was performed before entering the parallel-design, placebo-controlled phase.

Intention to treat: Pts were analyzed in the groups to which they were randomized and all randomized patient data was analyzed.

Similar groups: Pts in treatment and control groups are similar with respect to known prognostic factors.

Blinding: Clinicians remained blind to the dose sequences except in emergencies and blinding was maintained for primary dependent measures until after the best dose was determined or as needed.  Patent & teacher dose-response rating scale graphs prepared & blindly evaluated by 2 study clinicians who determined child’s best response by id’ing week with optimally minimized ADHD sx’s and medication SE’s.  Parents & child blinded throughout.  Active drug of different strengths and placebos all in same type of capsule.

Equal treatment: Aside from the intervention, groups were treated equally.

Study Design Type: Randomized Controlled Trial

            Relevant Criteria for Randomized Controlled Trial:

Blinding: see above

Duration:5-week crossover-titration phaseà1 day washoutà4-week parallel-design within an 8-phase, 70 week trial.

Setting: Academic clinics at Columbia, Duke, John Hopkins, NYU, UC-Irvine & LA

Patients/Population: 303 Preschoolers (mean age 4.4, 73% male) recruited from communities surrounding Columbia, Duke, John Hopkins, NYU, UC-Irvine & LA diagnosed with ADHD-combined or hyperactive type (DISC) with moderate impairment (CGAS-I <55) w/ IQ>70, participating in out of home structured setting, with same primary caregiver >6mos prior.  No other significant Axis I pathology requiring medication in child, cocaine/ stim. abuse in home, or h/o bipolar in both parents. ODD most common comorbidity,(1915 screenedà1272 eligibleà553 consentedà303 met criteriaà303 enrolledà165 randomized into crossover-titration phaseà114 randomized into parallel trial).  Those eligible for crossover-titration phase continued to meet ADHD severity criteria after 10wks parents training & completed 1 week sequential, open-label, safety lead-in phase.

Intervention/exposure: MPH-IR 1.25, 2.5, 5.0, or 7.5mg or placebo on TID schedule.

Outcomes:Primary outcome for titration phase (set a priori)-composite formed by standardizing & combining parent & teacher CLAM and SKAMP rating scales to reflect overall medication response for each dose across settings.  Primary efficacy measure for parallel phase-met “excellent responder”criterion using combination of parent and teacher SNAP rating scales.

Main Results:  Crossover phase-Sig linear trend w/ dose on SKAMP/CLAM scores and statistically sig reduced ADHD symptom scores for TID doses of 2.5, 5.0, and 7.5mg compared to placebo.   No significant correlation b/w age and MPH absolute dose or MPH dose by weight.  Effect sizes relative to placebo for scalar composite SKAMP/CLAM ratings during titration w/ doses 1.25, 2.5, 5, & 7.5 TID were 0.16, 0.34, 0.43, & 0.72.  Parallel phase- Only22% on best dose MPH and 13% placebo met “excellent responder” criteria (non-sig diff). Effect sizes for composite ratings were 0.22, 0.48, 0.52, & 0.87 (same respective dose order).  Safety & Tolerability Data:  92% tolerated MPH in open safety lead-in phase.  14 left d/t AE’s (9-emotionality/irritability).  % AE’s more common at higher doses (appetite loss, trouble sleeping, stomach aches, social w/d, lethargy).  Some elevated BP & tachycardia during crossover-titration phase.  Weight velocity decreases seen in kids who completed titration & parallel phases.  8 serious AE’s during entire study, but only one (seizure) thought to be d/t medication.  No mania, hypomania, depression or suidicality.

Conclusions: Preschoolers with severe ADHD respond to 7.5 to 30mg MPH, with mean optimal dose around 14+/-8mg/d.  Although degree of response by effect size was less than that seen in MTA trial, this may have been d/t limitations on dose range imposed by regulatory agency, difficulty in assessing attention in preschoolers, and increased length and complexity of the whole PATS trial which required multiple reconsenting, “skip out” option for direct path to maintenance trt, and increased attrition during controlled phases.

Synopsis:  

This NIMH-funded, 6-center, randomized, controlled 70 week trial that included 2 double-blind, controlled phases (crossover titration trial followed by placebo-controlled parallel trial) of 165 preschoolers with severe ADHD, MPH-IR was effective in the treatment of severe ADHD, but somewhat less so than previous studies investigating school-age children.  Replication of this finding with a study design that includes higher doses is needed.

 

 

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AUTHOR:
Leigh Fylstra

Bupropion SR vs. Methylphenidate vs. Placebo for ADHD in Adults

Chairman’s Rounds, November 27, 2006

Citation:  Bupropion SR vs. Methylphenidate vs. Placebo for Attention Deficit Hyperactivity Disorder in Adults, Kuperman et al, Annals of Clinical Psychiatry, Vol 13, No 3, Sept 2001

Clinical Question: Alternatives to stimulants in adults w/ ADHD

Question Type: Therapy

Validity Criteria for Appropriate Question Type:            

·         Follow-up: complete, all pt’s accounted for, 37 enrolled, 5 dropped out during placebo lead-in, 2 during 1st week of randomization (3 d/t not wanting risk of placebo, 3 d/t AE (2 M, 1 Pl), 1 d/t non-compliance

·         Randomization: Randomized after 1 week placebo lead in period

·         Intention to treat: Pts analyzed in groups assigned to, outcome data analyzed using a carried forward approach for pts completing at least 1 week of double-blind treatment

·         Similar groups: no significant differences observed bet groups, see table 1

·         Blinding: double- blind 

·         Equal treatment: all TID dosing: Bupropion: titrated over 2 wks to max 200mg 8am/placebo noon/100mg 4pm, Methylphenidate titrated over 1 wk to 0.9mg/kg/day div 8am/noon/4pm, and placebo dosed similarly.

Study Design Type: Randomized Controlled Trial, Relevant criteria:

·         Duration: 8 weeks: 1 week placebo lead-in, then 7 weeks randomized

·         Setting: assumption: Outpt clinic Dept Psychiatry, Univ Iowa, Iowa city

·         Patients/Population:  n= 30, 9 F, 21 M, Mean ed: 15.2 years, 4/30 had professional training: 2PhDs, 1MD, 1 lawyer; Incl: full DSMIV criteria, Chronic: childhood to adulthood, Moderate/severe impairment.  Excl: reasonable

·         Intervention/exposure:  Bupropion, Methylphenidate, or Placebo x 7 weeks  

Outcomes:

Primary

Secondary

Primary: CGI- baseline and endpt

 

ADHD symptom checklist severity scale: 0 to 42                     Hamilton Depression Scale- 21 item, BL and endpt                                                                      Hamilton Anxiety Scale: 14 item, BL and endpt                                                   Neuropsychological testing:                                                                                                     Hopkins Verbal Learning Test: verbal learning & delayed recall                                                      Digit Ordering Test: attention & working memory                                                                   Trails A & B: attention, sequencing, & cognitive flex                                                        Verbal Fluency: verbal initiation and maintenance effort                                                               Conners’ Continuous Perform Test: sustained & selective attention

Main Results: 

·         Primary outcome: CGI responders:

o        Bupropion: 64%

o        Methylphenidate: 50%

o        Placebo: 27%

·         However: p = 0.14, not significantly greater response rate in active treatment vs. placebo

·         Secondary: all groups showed improvement, no significant diff bet groups

 Conclusions:

According to the study, high placebo response rate accounted for the lack of clinically significant difference between pharmacologic intervention and placebo.  However, the more likely reason is lack of power; the sample size was too small, because the power was calculated using a placebo response rate of 10% found in a previous study.  As was evident in this study, normal placebo response rates are between 20-30%.  However, Bupropion and Methylphenidate did show high response rates similar to previous studies.  The study reported reasons for large placebo response rate: no co-morbid psych diagnosis, highly educated and employed, Mean baseline CGI = 4 (moderately ill).  Interestingly, Bupropion showed a trend toward equivalent, if not better response rate, when compared to Methylphenidate on CGI.  However, no conclusions can be made at this time, and further investigation is needed w/ a larger sample size. Neuropsych preliminary results: pharmacologic intervention increased verbal learning, immediate recall, and maintenance of focus, so potential for future investigation.  No adverse events w/ Bupropion, but 2 adverse events with Methylphenidate.

Synopsis: In this 8 week RCT of 30 pts randomized to Bupropion, Methylphenidate, or placebo, the efficacy of pharmacologic intervention did not differ from placebo due to small sample size, and thus lack of power.  However, if larger studies could show statistical significance for the findings in this study, that Bupropion showed equivalent to greater response than Methylphenidate on CGI as well as having a low AE profile, it may be a promising alternative to stimulants in adults with ADHD, especially when providers are reluctant to prescribe stimulant. 

 

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AUTHOR:
Ana Carla Smith, MD         

Characteristics of Adult ADHD

Chairman’s Rounds

 

                        

General Facts About Adult ADHD:

-as many as 67% of kids w/ ADHD continue to have sx that significantly interfere w/ academic, vocational or social fxn’g in their adult lives.  Approximately 2-4% of adults are affected by ADHD.  Gender ratio = 2:1 (male:female).

-core sx: inattention, impulsivity, hyperactivity usu appear by age 7.  In adults, sx are often obscured by problems w/ relationships, organization, mood disorders, substance abuse, employment or other difficulties.

-research suggests that hyperactivity declines w/ age, attentional problems remain fairly constant, and executive function problems increase in adulthood.  Many adults remain unidentified & untreated.

-ADHD is first recognized in some adults b/c of problems w/ depression, anxiety, SA, impulse control, or after their child is diagnosed.                         

Characteristics of Adults w/ ADHD:                         

  1. Fail to give close attention to details or make careless mistakes at work
  2. Fidget with hands or feet or squirm in seat
  3. Have difficulty sustaining attention in tasks or fun activities
  4. Leave seat in situations where seating is expected
  5. Don’t listen when spoken to directly
  6. Feel restless
  7. Don’t follow through on instructions and fail to finish work
  8. Have difficulty engaging in leisure activities quietly
  9. Have difficulty organizing tasks and activities
  10. Feel “on the go” or “driven by a motor”
  11. Avoid, dislike, or are reluctant to engage in work that requires sustained mental effort
  12. Talk excessively
  13. Lose things necessary for tasks and activities
  14. Blurt out answers before questions have been completed
  15. Easily distracted
  16. Have difficulty awaiting turn (impatient)
  17. Forgetful in daily duties
  18. Interrupt or intrude on others

Associated problems & consequences that coexist w/ Adult ADHD:

  1. Problems with self-control and regulating behavior
  2. Poor working memory
  3. Poor persistence of efforts toward tasks
  4. Difficulties with regulation of emotions, motivation and arousal
  5. Greater than normal variability in task or work performance
  6. Chronic lateness and poor time perception
  7. Easily bored
  8. Low self-esteem
  9. Anxiety
  10. Depression
  11. Mood swings                                                          
  12. Employment difficulties
  13. Relationship problems
  14. Substance abuse
  15. Risk-taking behaviors
  16. Poor time management                                               
  17. Antisocial behavior & criminality
  18. Poor social skills or deficits in self-awareness

Causes:

-heredity is the largest contributer

-other factors that contribute to ADHD to varying degrees: difficulties during pregnancy, prenatal exposure to alcohol and tobacco, premature delivery, significantly low birth weight, excessively high body lead levels, and postnatal injury to the prefrontal regions of the brain 

Diagnosis in Adults:

-comprehensive clinical interview surveying past & present ADHD symptomatology, developmental & medical hx, school, work & psych hx (including meds & level of functioning).

-first ID core ADHD sx, & then ensure the hx of these sx is both chronic & pervasive

-corroborate hx w/ additional informants (if possible a parent or significant other), & review any past objective records (report cards, transcripts, prior testing/evaluation reports)

-survey behavior from multiple settings (school, work, home)

-rule in or out other psych diagnoses

-may use psychological testing to determine any cognitive or learning weaknesses that may underlie functional impairment. 

Treatment:

-greatest improvement in sx results from tx w/ stimulant medication combined w/ counseling; some antidepressants may also be effective:

1.  Psychopharmacology -

a.  Stimulants: response rate over 15 studies (systematic review) ranged from 25-78%

Methylphenidate (Ritalin) – 7 wk RCT crossover study showed favorable response in 78% (18/23) of subjects while taking drug vs 4% (1/23) while taking placebo; some adults need scheduled dosing, while others do well w/ as-needed dosing.

Modafinil (Provigil)

Dextroamphetamine (Dexedrine)

Mixed amphetamine salts

b. Antidepressants:

Desipramine (Norpramin) – TCA, most data from controlled trials supports efficacy of this antidepressant over others

Atomoxetine (Strattera) – SNRI, less effective than desipramine

Buproprion (Wellbutrin) – SS, SN, SDRI, efficacy unclear, one 7 wk RCT showed 64% response rate vs 27% for placebo for sustained-release buproprion

Venlafaxine (Effexor) – SS, SN, SDRI, initial published open data suggest response rate of 50-78%.

2.  Other treatments –

counseling & education about ADHD, vocational assessment & guidance to find the most suitable work environment, time management & organizational assistance, behavior skill-building (list-making, day planners, filing systems & other routines), coaching, academic or workplace accommodations, behavior management strategies

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Author:
Alyson Kuroski, DO

ADHD WITH BIPOLAR DISORDER IN GIRLS

Reference: Faraone SV, et al, 2001. Attention deficit hyperactivity disorder with bipolar disorder in girls: further evidence for a familial subtype?  Journal of Affective Disorders 64, 19-26.

Background: Prior work has shown a relationship between ADHD and bipolar disorder (BPD). Systematic studies of children and adolescents show that the rates of ADHD range from 57 to 98% in pts with bipolar disorder (Borchardt and Bernstein, 1995; Geller et al., 1995; West et al., 1995; Wozniak et al., 1995a) and that the rates of bipolar disorder range from 11 to 22% in ADHD pts (Butler et al., 1995; Biederman et al, 1996b). However, there is little information known about the relationship and presence of both ADHD and BPD in pts, which the authors term ADHD + BPD. They began to investigate this issue in a sample of consecutively referred pre-adolescent children with BPD. Would these children and their relatives be at high risk for ADHD? Also, could ADHD + BPD be a familiarly distinct subtype of BPD? Their original work was on boys, which did suggest that comorbid ADHD with BPD is familiarly distinct from other forms of ADHD. Then they began investigating this relationship in girls.

Methods:
Subjects: 140 ADHD probands and 122 non-ADHD comparisons with 417 and 369 first degree biological relatives respectively. The two ADHD proband groups and the control group were similar in terms of SES, intactness of family, gender, and age of relatives.

Procedures: DSM-III-R based structured interviews and diagnostic assessments of parents were based on direct interviews with each parent using the SCID or through an indirect interview with the available parent from that family. Ninety two percent of the control parents and 88% of the ADHD parents were directly interviewed.

Hypotheses to be tested:
1) ADHD and BPD are independent and co-occur due to chance.
2) ADHD + BPD is a distinct subtype or a completely separate condition. Also, co segregation should be found: among relatives of ADHD + BPD children, the presence of one disorder should predict the presence of the other. 3) ADHD and BPD co-occur due to nonrandom mating.
4) Predicts higher risks for ADHD and BPD among relatives of ADHD + BPD compared with relatives of ADHD w/o BPD probands. 
5) ADHD children with and w/o BPD share common familial etiologic factors, but differ due to environmental effects. 
6) Posits that the BPD among ADHD children is secondary to ADHD.
7) Posits that the ADHD among BPD children is secondary to BPD.

Statistical analysis: Adjusted analyses for the non-independence of siblings by using the Huber formula and then logistic regression to compare groups on the prevalence and family history of the disorders of interest. Additionally, to test for assertive mating they used the entire ADHD sample to determine if ADHD in one spouse was predictive of BPD in the other spouse.

Results: Fifteen (11%) of the ADHD probands met criteria for BPD.
-Rates of ADHD were elevated among relatives of both types of ADHD probands compared to controls (P value <0.001), but BPD was elevated only among relatives of ADHD + BPD probands compared to controls.
-The risk for any ADHD + BPD was highest among relatives of ADHD + BPD probands, but the difference was not statistically significant.
-ADHD w/o BPD was highest among relatives of ADHD probands w/o BPD (P < 0.001). 
-Weak evidence for co segregation between ADHD and BPD.
-No evidence for a trend of random mating between ADHD parents and those with mania.

Comments/Limitations: Partially consistent with hypothesis number two. Results reject hypotheses that assume all ADHD children have some familial risk for BPD. Findings also reject hypotheses that attribute either disorder to be a secondary manifestation of the other. It is important to recognize that further work investigating the validity of a syndrome that exhibits childhood onset BPD, ADHD and high familial risks for ADHD + BPD is necessary. Limitations include the fact that only 5 of the 15 probands with ADHD + BPD were directly interviewed, other psychiatric illnesses which may have accounted for some of the s/s reported were not assessed (ex. PTSD), and there was a limited number of pts included with ADHD + BPD. Further work is necessary to determine the full relationship between ADHD, BPD, and a possible subtype. This will have clinical and research implications which may be very critical in the future

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Tomoxetine in Adult ADHD

Bottom line: Tomoxetine may be a beneficial drug for adult ADHD, but better studies need to be done.

Clinical Question: A 34-year-old white female appears to have ADHD. She does not want to take methylphenidate or desipramine. What therapy can be offered to her as an alternative? Article: Spencer, et al. "Effectiveness and Tolerability of Tomoxetine in Adults With Attention Deficit Hyperactivity Disorder" American Journal of Psychiatry vol. 155 (5) May 1998 pp693-695 

Background:
-Some follow-up studies have suggested that ADHD in childhood/adolescence continues into adulthood in 10-60%. Its persistence is associated with a myriad of psychosocial pathology. 
-Current treatments have their limitations (methylphenidate - abusable, short acting; desipramine - wide range of adverse effects).
-Tomoxetine is a highly selective noradrenergic reuptake inhibitor with little affinity for other systems (muscarinic, cholinergic, histamine, etc). Little effect on cardiac conduction/ function. 
-Because of its limited spectrum of adverse effects/ abuse potential, tomexetine might be beneficial in ADHD.

Methods: A placebo controlled, double blind crossover study.

3-week treatment periods with one-week washout in between.
Dose of Tomoxetine - 40mg/day by wk 1, 40mg bid by wk 2, and maintained if no adverse effects. Average dose for tomoxetine was 76mg/day by week 3. 
Exclusion Criteria - chronic mental disorders, MR, ETOH, pregnancy, active psychiatric 22 outpatients - between 19-60 years of age (mean age = 34, sd = 9)

Inclusion - DSM IIIR criteria met by the age of 7 as well as having chronic features, reporting detriment from.
Patients - 13 patients had at least one lifetime co morbid psychiatric disorder. Only 2 had current ratings of depression or anxiety that were severe. 20 patients had family hx of ADHD. 9 patients needed tutoring in school, 6 needed to repeat

Scales/tests - ADHD rating scale, Ham D (depression and  

 anxiety), Beck.Wisconsin Card Sorting, Rey- Osterrieth,

 Stroop test, auditory Continuous Performance Test.

Blinding: Not explained

Responders: 30% reduction in symptoms on ADHD rating scale.

Analysis: McNemar, Wilcoxon, t test given continuous data. Random effects model used, cross sectional time series model.

Validity

1. Randomization - ?
2. Follow up of patients sufficiently long and complete?
3. Were all patients analyzed in the groups to which they were randomized? Yes
4. Were the groups similar at the start of the trial? Yes
5. Were groups treated equally, apart from the experimental therapy?

Results:
1. One Dropout due to anxiety,. irritability during second week of tomoxetine tx.

Mean Score__  SD______ End Score______ SD

Tomoxetine__30________6.7_______ 21.4__   10.1 (p= 0.001) Placebo         29.4           6.3              29.7                8.8

2. Hedges G (Effect Size) - 0.85 (CI - 1.48 to 0.22).
3. Odds Ratio - 4.5
4. Using pre-established 30% improvement criteria, 11 of 21 showed improvement with Tomoxetine, vs 2 with placebo (52.3% vs. 9.5%, no intention to treat). 
5. NNT = 2.44 (using all 22 patients).
6. Adverse Effects = Insomnia, anxiety in less than 3 patients.

Comments:
Promising Study, but too much fuzzy math given crossover design and lack of follow-up. Good pilot type study, however.

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ATOMOXETINE IN CHILDREN WITH ADHD

Bottom line: Atomoxetine may or may not be a reasonable alternative to ritalin for kids with ADHD

Clinical Question: In your clinic, you see an 11 year old boy with ADHD who is not responding to ritalin. Increasing the dosage causes the child to have insomnia and headaches. Is there an alternative tx?

Article: Kratochvil, Christopher, et al. Atomoxetine and Methylphenidate Treatment in Children with ADHD: A Prospective Randomized, Open Label Trial

Background:
1. ADHD affects 3-7 percent of school age children
2. Affecting the dopaminergic and noradrenergic pathways have resulted in improved impulse control and concentration.
3. Atomoxetine is a potent inhibitor of the presynaptic norepinephrine transporter with minimal affinity for other neurotransmitters.

Methods:
1. Design - 10 week randomized, open label tx with either atomoxetine or ritalin. 319 patients were entered, and 228 were randomized (44 for ritalin, 184 for atomoxetine). 24 were dropped off in the Duke ER by parents and were lost to follow up.
2. Randomization - 3:1 (atomoxetine to ritalin) for first block, then 5:1 blocks (atomoxetine to ritalin)
3. Inclusion - boys 7-15 and girls 7-9 (pregnancy issues) who met ADHD DSM criteria. All children had severity score at least 1.5 SD from average.
4. Exclusion - Bipolar, psychosis, motor tics/ tourettes, substance abuse, prior failure with methylphenidate.

Efficacy Variables:
1.        Primary scale was ADHD RS - an 18 item DSM IV based scale. Based on interview with parent.
2.        Parent rated scale also implemented as a "T-score." 50 was the norm and every 10 points represented one SD.
3.    Other scales include the conners parent rating scale (CPRS -R), CTRS-R (conners teacher), CGI severity
4.    CYP2d6 status - pt's grouped under poor and extensive metabolizers (homozygotes at any of 6 alleles in a gene were deemed poor metabolizers. Poor metabolizers had dose titration of 1mg/kg per day, vs. 2mg/kg per day for extensive metabolizers. Ritaline pushed up for clinical need, not to exceed 60mg/day

Analysis: ANCOVA, LOCF

Validity:
1.    Randomization - yes, but not blinded.
2.    Follow up of patients sufficiently long and complete? decent
3.       Were all patients analyzed in the groups to which they were randomized? yes
4.       Were the groups similar at the start of the trial? OPEN LABEL
5.       Were groups treated equally, apart from the experimental therapy? OPEN LABEL

Results:
1.  66/184 in atomoxetine and 19/44 ritalin patients dropped out (see table one for demographic info).
2. Of 228 patients, 218 came for at least one f/u and were included in results
3. Final mean dose for atomoxetine among extensive metabolizers (n= 174) was 1.40mg/kg/day. Poor metabolizers (n=10) had average dose of 0.48mg/kg/day.
4.    Adverse Events - 5.4% of atomoxetine and 11.4% of ritalin group withdrew secondary to adverse effects.
4.    Adverse Effects - Statistically significant increase in pulse and BP for both atomoxetine and ritalin. Headache the most common side effect in each group. Atomoxetine group lost 0.63kg in 10 wks, compared to 0.13 wks in Methylphenidate.

Comments:
Open label trial, so difficult to say if bias was properly accounted for, but authors claim that placebo effect in ADHD trials are low to begin with. With the exception of weight, atomoxetine may at least be as safe as methylphenidate. French Fries are good.

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CHILDHOOD DIAGNOSIS OF ADHD AND ADULT PSYCHIATRIC DISORDERS

Clinical Question: Are adults who were diagnosed in childhood with ADHD more prone to psychiatric disorders such as antisocial personality disorder, non alcoholic substance abuse. ADHD syndromes, mood and anxiety disorders?

Reference: Salvatore Mannuzza PhD, Rachel Kelin PhD et a1, "Adult Psychiatric Status of Hyperactive Boys Grown Up" The American Journal of Psychiatry. 4/1998, volume 155 (4), 493-498.

Introduction: Previous studies of young adults who have grown up with ADHD have shown that arrest history, conduct problems, poor academic history, and continued ADHD symptoms are common. To the date of this article there have been 2 published controlled prospective studies of psychiatric status into late adolescence and young adulthood. One of these studies was by Manuza et al. Between 1970 to 1977, they evaluated 1.000 children between 6-12 years of age. Of these, 207 subjects met inclusion criteria (under methods). 103 of these subjects had reached age 16 by the time of an adolescent flu study published in 1985. These 103 subjects were then studied in adulthood (avg. 25y/o). and were found to have higher prevalence of ongoing ADHD, antisocial personality, and drug abuse, but not mood and anxiety disorders. The other study by Weiss et al took 61 previously diagnosed childhood ADHD patients and evaluated them at the average age of 25. They found increased prevalence of at least one symptom of ADHD. This article follows Manuza's 104 subjects who had not yet reached age 16 at time of his previous study to gain further understanding of the natural course of ADHD.

Methods:
Design: Prospective cohort study
Subjects:
-Predominantly middle class, white hyperactive boys of average intelligence (mean full scale IQ 105, SD 13) referred to a no cost child psychiatric research clinic.
-207 subjects met the following 8 criteria (104 of these subjects targeted for this study): 1)Referred by a teacher because of behavior problems, 2)Judged hyperactive by a teacher with a score of at least 1.8 on Conners Teacher Rating Scale, 3)Judged hyperactive by parents or clinic staff; 4)dx. as having DSM-II hyperkinetic reaction of childhood by a psychiatrist, 5) IQ of at least 85.6) free of psychosis and neurological d/o, 7) Without clinically significant presenting problems involving aggression or other antisocial behaviors, 8) English speaking parents with phone.
-Comparison Subjects: 64 from nonpsychiatric outpatient clinics within the medical center. Charts reviewed for white middle class males of appropriate age. Those treated for accidental injuries or chronic serious illnesses or those with behavior problems before age 13 were not included. Parents of selected subjects were called. If school teachers had complained about the child's behavior, they were not included. An additional 14 recruited from community sampling service using same inclusion/exclusion criteria. Mean age 18.6 SD 1.5.
-Adult Vu: 85 (of 104) probands administered semistructured interview that included DSM-III antisocial personality, attention deficit, anxiety. mood, substance use, and psychotic d/o. Probable and definitive diagnoses were included in this study. Blind assessments were conducted by a clinical psychologist and a psychiatric social worker (written narratives reviewed by senior investigator) with correlative kappa values as follows: ADHD (0.70), Antisocial (0.69), substance use d/o (0.80), major depression (.1.00). Analysis: Logistic regression analyses. Odds ratio adjusted for age and socioeconomic status since probands had lower SES and age was older (24.1. SD1.2).
Outcome:
1. Probands had more ongoing mental do than comparison (33% v. 19%)
2. The most common dx. in probands were antisocial personality (OR 4.0, CI 1.01-15.65) and substance use d/o (Nonalcohol OR3.8, CI 1.18-13.12). Antisocial and substance abuse aggregated significantly (60% of antisocial probands displayed substance abuse v. only 13% of non antisocial probands) 
3. The rates of mood and anxiety dlo didn't differ significantly (MDD OR 1.0, CI 0.2-5.55). 
4. Only 4% of probands had full ADHD syndrome (OR 49. CI 0.61-38.96. not statistically significant).

Completeness of follow-up: Duration of follow up ranged from 15-21 years (mean 17, SD 1.4). Of the original 104 probands, 85 were interviewed (of those not interviewed, 15 refused to participate, 3 couldn't be located, and 1 died). Of the 78 comparison subjects, 73 were interviewed (5 refused to participate).

Validity:
1. Patient sample was clearly defined (age and criteria for inclusion stated), representative of clinical practice.
2. All patients accounted for.
3. Outcome criteria objective (blinded social worker and psychologist) and unbiased relative to the prognostic factors (used DSMIII-R criteria).
4. Was their adjustment for linked prognostic factors?
5. Were patients in the study treated similarly? Appear to have been since all were interviewed by same clinicians under the same blinded conditions.
6. Do the study population characteristics describe your patient? No. No ethnic, gender, socioeconomic diversity. Clinic-referred patients tend to be more ill. Only "Pure" ADHD children's adult outcome were included in this study (no comorbid conduct d/o children)..

Results:
Antisocial and nonalcoholic substance abuse are the only diagnoses with P values less than 0.05 indicating a significant difference between probands and comparison in these two categories. At the same time, the CI is wide. A larger sample size would have provided more power to the study. There's no indication by this study that ADHD children would have a higher prevalence of mood or anxiety d/o.  

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Chairman’s Rounds 11-29-04, Georgette De Jesus, M.D.
Therapy Article: Atomoxetine in Adults with ADHD

Bottom Line: This article describes two identically designed multicenter, double-blind, randomized, placebo-controlled studies looking at the efficacy and tolerability of atomoxetine when used to treat adults suffering from ADHD, using larger sample sizes studied than previous studies in this population. Atomoxetine showed superiority to placebo and was generally well tolerated, but it is questionable whether the study subjects are representative of the general adult population with ADHD. 
Background: 
- Many children with ADHD will continue to suffer from the condition as adults, resulting in significant comorbidity and distress. 
-Medications effective in children with ADHD appear to be effective in adults, but the literature is limited, and the few studies available all have small sample sizes.
-Treatments for ADHD include amphetamines and methylphenidate, but they can be addictive.  Desipramine has shown to be effective in small studies with adults.  However, desipramine has a low therapeutic index and can have dangerous cardiac side effects.
-Atomoxetine is a potent inhibitor of the presynaptic norepinephrine transporter, with little affinity for other systems. It is not associated with adverse effects on cardiac conduction and does not appear to be addictive.
-Atomoxetine has been shown to be effective in treating children and adolescents with ADHD. Because of its limited spectrum of adverse effects and low abuse potential, atomoxetine might also be beneficial in adults.
Clinical Question: A 45 year old male comes to your office because of attention problems that have been present since childhood and are now affecting him at work.  After a full evaluation, you diagnose him with ADHD.  He does not want to take methylphenidate or amphetamines, because he has read that these can be addictive.  He does not want to take bupropion or desipramine because he has a family history of seizures and heart problems. What therapy can be offered to him as an alternative?
Reference: Michelson D, et al. Atomoxetine in Adults with ADHD: Two Randomized, Placebo-Controlled Studies. Biological Psychiatry  2003; 53:112-120.
Methods: 
Design- Two identically designed, 10-week long, multicenter, double-blind, placebo-controlled, parallel design studies comparing atomoxetine (with flexible dosing from 60mg-120mg/day) vs. placebo.  2-week double-blind placebo lead-in phase.
Setting- Study I involved 17 outpatient sites in North America, while study II involved 14 outpatient sites.
Patient Population- All patients met criteria for ADHD clinically and confirmed by the CAAR-D.  They were recruited from clinics and by advertisement. Diagnosis had to be corroborated by a second reporter. Exclusion criteria: Current major depression, anxiety disorder, current or past bipolar or psychotic disorder, serious medical illness, alcohol dependence, actively using drugs of abuse, no second reporter to corroborate diagnosis.

Study I. 448 patients signed consent, 280 were randomized, 141 to atomoxetine, 139 to placebo (see figure 1).

Study II. 388 patients signed consent, 256 were randomized, 129 to atomoxetine, 127 to placebo (see figure 2).

Blinding- Raters were blind to all the details of the study design and were not allowed to evaluate or ask about side effects. 
Analysis- Intention-to treat basis.  Primary analysis: MIXED procedure in SAS.  For the CAARS, if more than one item of a subscale was missing, the whole score for the subscale was also considered missing.  If only a single item was missing, the mean score for all other items in the subscale was given as the missing score.  Self-reported CAARS values were given as t scores.  Secondary analysis: Included all patients with at least one postbaseline measurements.  Safety analysis- all patients who took at least 1 dose.  LOCF using ANOVA.  Treatment differences in binary measures assess by Fisher’s Exact Test.  Two-sided significance level= 0.05.
Outcomes- Primary: Sum of the Inattention and Hyperactivity/Impulsivity subscales of the investigator-rated CAARS( Conners’ Adult ADHD Rating Scales).  Other: CGI-S, self-reported CAARS, WRAADDS (Wender-Reimherr Adult Attention Deficit Disorder Scale), Sheehan Disability scale.  They also measured anxiety and depressive symptoms through the HAM-A and HAM-D 17. Safety and tolerability were assessed at each visit by open ended questions and monitoring of vital signs and labs. 
Dosing- Atomoxetine was administered in evenly divided doses in the AM and early PM, beginning at a total of 60mg.  Afterwards, dose could be titrated up if residual symptoms remained and if dose was well tolerated: after 2 weeks, increase to 90mg/day, after 4 weeks increase to 120mg/day.
Follow-up: 10-week study.  Patients had visits q2weeks. If pt dropped out, LOCF was used for the purpose of analysis.
Validity:
Randomization? Yes.  Concealed list? Yes.  Treatment groups similar at baseline? Yes. Patients starting trial accounted for at conclusion? Yes (see figure 1 and figure 2). Patients and clinicians blinded to treatment? Patients and raters were blinded, not clear whether PI’s were blinded. Groups treated similarly outside of intervention? Hard to tell, it was a multicenter trial and possible differences between raters and between centers could have been present. Do the study characteristics describe our patients? Yes and no. Although demographically the patients were similar to our pt population, most patients had had previous stimulant exposure, which is not always the case.  Pts with comorbidities such as depression, anxiety disorders and substance abuse, common for ADHD patients, were excluded.
Results: Patient characteristics (table 1): Mean age in all groups was 40-43 y/o (with SD’s ranging from 10.3-11.7).  The majority of pts were male (83-91%).  Baseline ADHD severity scores based on the CARRS-inv, CARRS-self, CGI-ADHD-S and WRAADDS were not significantly different between groups. Dose: Most common dose was 90mg/day, followed by 120mg and 60mg.  
Primary outcome: CAARS-inv scores were significantly reduced from baseline in the atomoxetine group (Study I: -9.5 (SD=10.1, %dec=28%) atomoxetine vs. –6.0 (SD=9.3, %dec=18%,)placebo, p= .005; Study II: -10.5 (SD=10.9, %dec=30%) atomoxetine vs. –6.7 (SD=9.3, %dec=19%) placebo, p= .002.
Effect size for primary outcome: 0.35 in study I and 0.40 in study II (medium effect). Atomoxetine showed significantly separated from placebo as early as the first post-randomization visit, but scores continued to decline through the study.
Statistically significant change in secondary outcome measures (CAARS-self, CGI-S and WRAADS) were also observed, but the effect sizes for these variables were small.
RRR,ARR, NNT- N/A, cannot be calculated because outcome is point reduction in a severity scale. 
Please see table 2 for CI’s, and other outcome variables.
Compliance with therapy: A greater proportion of pts taking atomoxetine discontinued from study II but not study I due to adverse events. Completers: Study I- 103 (73%) in the atomoxetine group vs. 107 (77%) of the placebo group; Study II- 94(73%) of the atomoxetine group vs. 104 (81.9%) of the placebo group.  See table 3 for patient disposition.
Safety and Tolerability:  The most common side effects with atomoxetine were dry mouth (57%) and insomnia (56%).  Others include nausea, decreased appetite, constipation, decreased libido, dizziness, erectile difficulties and sweating, all significantly more common in the atomoxetine group. Atomoxetine was associated with clinically insignificant increases in blood pressure and heart rate.
Comments: These two studies, overall were well designed.  Limitations include recall bias by the patients, since the diagnosis of ADHD requires the onset of symptoms before age 7.  Patients don’t necessarily represent the adult population with ADHD, since common comorbidities were excluded. Strengths include good design, large sample size, separate safety and efficacy raters who were blinded to treatment and study design and double-blind placebo-lead in.  The end-point dose (90mg/day, corresponding to 1.3mg/kg/day in a 70kg adult) is similar to that one that has been found effective in children (1.2mg/kg/day). Although atomoxetine significantly differentiated from placebo early on, longer periods of time seemed to be required to obtain maximum response.  Alhough not described in this article, at the end of the 10-week trial 384 of the patients, elected to enter an open-label extension study for 34 weeks [described in Spencer TJ, ADHD Treatment Across the Life Cycle, Journal of Clinical Psychiatry 2004;65(suppl 3)], where CAARS:inv scores decreased by 43.5%. At present, atomoxetine is the only FDA approved medication for adult ADHD.

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Chairman’s Rounds                                                  Vidya Krishnan  29th Nov 04

ReferencE
Wilens TE, Spencer TJ, Bierderman J, Girad K, Doyle R, Prince J, Polisner D, Solhkhah R, Comeau S, Monteaux MC, Parekh A: A controlled trial of Bupropion for Attention Deficit Hyperactive Disorder in Adults. Am J Psychiatry; 2001; 158: 282-288.
METHODS
Design: Double blind placebo controlled, randomized, parallel 6 week trial comparing SR Bupropion (up to 200 gm BID, N=21) to placebo (N=19) in adults with DSM-IV ADHD. 
Setting: Massachusetts General Hospital - Clinical Psychopharmacology Unit. Study approved by IRB.
Patient Population: 20-59 yr adults recruited from advertisements and referrals to unit. Mean age 38, SD 11. 38 completed, 2 dropouts because of side effects.
Exclusion Criterion: Clinically significant chronic medical conditions,  h/o cardiac arrhythmias or seizures, mental retardation IQ < 75, organic brain syndrome, clinically unstable psychiatric condition, bipolar disorder, drug or alcohol abuse or dependence within 6 months preceding the study, or current use of psychotropics.
Screening: 154 subjects, 40 enrolled. 30 not interested, 27 no FU, 17 subs abuse, 11 psychotropics, 10 no ADHD, 9 BPAD or psychotic d/o, 6 medical CI, 4 previous bupropion use.
Diagnosis: Psych eval, physical and neuro exam, EKG, SGOT. Diagnostic interview – structured clinical interview for DSM- III R and DSM –IV supplemented for childhood disorders by unmodified modules from the SADS for school age children – epidemiological version. For diagnosis – fully meet criteria for ADHD by age 7 and well as current past month, chronic course from child to adult, moderate to severe impairment.  Diagnostic reliability was excellent between raters and board certified psychiatrists (kappa 1 with 95% CI of 0.8-1). WAIS-R, Wide Range Achievement Test -3 was used for IQ and SE status by Hollingshead Four Factor Index of social status. 
Outcome measures: Efficacy: Overall severity by CGI – severity and improvement.  For ADHD – ADHD Rating Scale, good correlation with ADHD Symptom Check List.  Dep  by HAM-D & BDI, for anxiety HARS.  Inattentive type 23 (58%), Combined 14 (35%), Hyperactive / Impulsive 3(8%). 89% had at least one comorbid psychiatric d/o, 49% had symptoms in the last month. For ADHD 11 had taken meds, 7 had counseling, 7 both. Despite av. intelligence 17 needed tutoring, 11 repeated a grade. Smoking status did not differ. CGI, ADHD at baseline and each FU. Depression and anxiety at baseline and end. Safety: FU was weekly, adverse events and VS each visit.
Intervention: Up to 200 mg BID Bupropion SR. Started at 100mg QAM and increased by 100 mg weekly in BID doses to a total of 400 mg, unless adverse effects present.  
 Analysis: Stata (Stata Corp, College Park , Tex. ): Projected group size 20 per treatment arm, a bupropion response rate of 60%, placebo response rate of 10% and alpha 0.05, statistical power 0.89. Probability of type II error was 0.11. Improvement in ADHD was defined as ADHD rating score improvement of 30% or better & CGI score of  1 or 2.  Comparing improvement:  Fisher’s exact. Ordinal data between 2 time points: Wilcoxon signed-rank test for paired data. Ordinal and continuous data at baseline and end point Wilcoxon rank-sum test for paired data. Study groups on binary outcomes Fishers exact test. For continuous variables, group differences was tested using linear regression and generalized estimation equation used for main effect of the drug and time and any relationship between the variables. p 0.05 was significant.
 Randomization  Yes; Blinding Yes; Baseline characteristics seem equal on those shown in table 1; Equal Treatment yes; Analyzed in group randomized to seems so, but not specifically mentioned Follow up 57% continued Bupropion, other details not available.

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 Sarah Richey, May 9, 2005
Chairman's Rounds

Bottom line: In this unsystematic review article, the authors compare the diagnostic advantages and disadvantages of the Wender Utah Criteria, the DSM-IV criteria, and various laboratory assessment strategies in the diagnosis of adult ADHD. While raising the issue of diagnostic challenge in this disorder, the evidence included in the article is at the discretion of the authors and is not comprehensive; therefore, this article would not qualify as a systematic review. The authors’ conclusions are that adult ADHD should remain a clinical diagnosis and that much broader areas of functioning need to be assessed when evaluating adults for this disorder.

Background: Attention Deficit Hyperactivity Disorder that spans into adulthood is increasingly becoming a recognized and valid entity; however, the diagnostic criteria long-used for childhood ADHD is being questioned as to whether it is relevant for an adult population.

Clinical question: What are the controversies surrounding the diagnosis of adult ADHD?

Reference: McGough, J.J., Barkley, R.A. Diagnostic Controversies in Adult Attention Deficit Hyperactivity Disorder. 2004. American Journal of Psychiatry 161:11.

Methods: Design: This is an unsystematic article comparing what the authors see as the advantages and disadvantages of the Wender Utah Criteria, the DSM-IV criteria, and various laboratory assessment strategies in the diagnosis of adult ADHD. All relevant and available current evidence was not summarized; the information included was at the discretion of the authors. This review had a methods section in the abstract, but not in the body of the article. No explicit methodology was mentioned.

Validity: A focused clinical question was not addressed. Highlighting the diagnostic controversies in adult ADHD is quite a broad topic. The authors make no mention of any diagnostic techniques that were excluded from the review, nor do they critically appraise primary research studies to backup their points of view.

Results:

Wender Utah Criteria: The patient & an informant (eg parent) are interviewed to retrospectively assess a childhood diagnosis of ADHD via the Wender Utah Rating Scale. The patient is interviewed for ongoing symptoms of hyperactivity and inattention. Wender describes seven symptom clusters: inattentiveness, hyperactivity, mood lability, irritability and hot temper, impaired stress intolerance, disorganization, and impulsivity. The diagnosis is made if 1)a retrospective diagnosis of childhood ADHD can be made, 2)ongoing difficulties with inattentiveness and hyperactivity and demonstrated, 3)and two of the other symptoms listed above are present. The authors state that Wender was important in establishing the need for third-party informants, restrospective childhood diagnosis as well as careful description of current symptoms. They do point out, though, that these criteria have diverged from the DSM over the years, specifically mentioning that substantial research has not closely linked irritability & hot temper with ADHD and that this conflicts with diagnoses of oppositional defiant d/o and conduct d/o. Also, the inclusion of "mood lability" in the diagnostic criteria might cause difficulties in distinguishing between other mood disorders. Lastly, the Utah criteria exclude the diagnosis of ADHD when there is coexisting major depression, psychosis or severe personality disorder. The authors state that significant numbers of patients with these coexisting diagnoses who also suffer from marked inattention and hyperactivity could be missed and not therefore not receive treatment that could be helpful.

DSM-IV Criteria:

Criterion A: The limitations mentioned include the fact that no adults were included in the DSM field trial, the work group that wrote the criteria were concerned with childhood disorders, and that several of the criteria ("runs & plays excessively" and "has difficulty playing…quietly") do not pertain to adults. Secondly, the authors state that 6 of the 9 criteria might be too strict and fail to identify adults with impairment.

Criterion B: The authors question whether the criteria for age of onset should be before 7 years of age. They state that many adults cannot accurately recollect that many years ago, and that a "significant percentage" of children thought to have ADHD did not display symptoms prior to age 7. They propose that the criteria should be abandoned or the age should be increased to 12.

Criterion C & D: The authors suggest that adults can manifest difficulties of functioning in many different areas that children cannot, including marital relationships, child rearing, financial management, etc and that these possibilities are not reflected in the criteria.

Criterion E: The authors question whether several of the DSM ADHD symptoms (concentration difficulties, restlessness, increased speech & acting "on the go"), can be clearly differentiated from other diagnoses of anxiety, depression & mania.

Subtypes: They state that these subtype classifications have never been validated in adults with ADHD & that there is insufficient empirical evidence to use these subtypes after childhood. The DSM does not state if the adult subtype should be based on the child or adult symptom presentation.

Laboratory-Based Diagnostic Methods: Many neuropsychiatric tests (eg EEG, SPECT, continuous performance tests, and neuropsychological batteries) have been proposed as a basis for the diagnosis of adult ADHD. The authors argue that most of these studies are limited to single research groups & small #’s of subjects. The authors state that there is insufficient data to support the use of these mechanisms in the diagnosis.

Conclusions: The authors have several points of conclusion. They state that they believe the disorder should remain a clinical diagnosis. They argue for a set universally accepted diagnostic criteria that can prevent over and underdiagnoses and can increase the comparability and generalizability of research data. They argue that the age of onset should be increased to 12. They argue that clinicians should make every effort to obtain third-part corroboration. They caution clinicians to be watchful for abuse of the stimulants they might prescribe. Lastly, they argue that clinicians should be particularly watchful of coexisting psychiatric conditions and treat accordingly.

Comments: Strengths: This article reminds us of the current diagnostic limitations for adult ADHD and the need for further work in this area, as well as highlighting some of the specific deficiencies of the diagnostic criteria. Weaknesses: This was in no way a systematic review. They do reference many primary research articles, but they do not critically appraise any of them. They simply discuss the conclusions of the research. In addition, the information in the article was at the author’s discretion, and the bulk of the article was the authors’ opinions.

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Cori Burdine, May 11, 2005
Chairman's Rounds

Hervey A, Epstein J, Curry F.  Neuropsychology of Adults with Attention-Deficit/Hyperactivity Disorder: A Meta-Analytic Review. Neuropsychology  2004; 18(3): 485-503

The primary objective of this meta-analysis was to perform a comprehensive review of the entire body of published neuropsychological test results in patients with ADHD.

A total of 33 studies using over 25 different neuropsychological tests were identified and analyzed in this study.  The authors grouped these tests into 7 cognitive domains (attention, response inhibition, executive function, memory, processing speed, intelligence and “other”) and calculated effect sizes to measure each test’s ability to discriminate between a group of pts. w/ ADHD and a control group.  Weighted mean effect sizes were calculated whenever more than one study employed the same neuropsychological test.

Here is a brief summary of selective results:
In the attention, response inhibition and intelligence domains, the effect sizes for the different neuropsychological tests were largely in the medium range, suggesting these domains are significantly impaired in adults w/ ADHD when compared to controls.  In the executive function domain, the Wisconsin Card Sorting Test demonstrated a small effect size, an interesting finding given the WCST has been used extensively in the child literature to document ADHD deficits in executive functioning.  In the memory domain effect sizes were also largely in the medium range, although ADHD patients appeared to have less deficits on tests which used visual stimuli, e.g. parts of the Wechsler Memory Scale.  The processing speed domain yielded mostly small effect sizes.

Study limitations:  Confidence intervals for the effect sizes were not included, variability in effect sizes between 2 studies performing the identical test was often large, the study question was broad, there was no assessment of the validity of specific tests, no test of heterogeneity was done before pooling results, control groups were usually unmatched, there was no assessment of unpublished studies.

Commentary: While an in-depth explanation of each neuropsychological test and an exhaustive analysis of the results was beyond the scope of the presentation, Dr. Susan Johnson, our expert discussant, was able to clarify some important points.  The neuropsychological tests reviewed in the study were by and large well established, validated tests.  The authors’ decision to study each test in a discreet domain was problematic since a single test may actually measure factors in more than one domain (the authors mention this as well).  With respect to the large variability in effect sizes observed when the same test was performed in different studies, Dr. Johnson stated that a large degree of variability often occurs when a given neuropsychological test is administered by different persons.

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