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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