# Presentation: 902510

**Paula Riggs, MD**
**Associate Professor Psychiatry **
**University Colorado School of Medicine**
- Supported by: NIDA 5U10DA13716, NIDA 5R01DA13176

**Clinical Implications and Applications of Advances in Addiction Research to the Evaluation and Treatment of Adolescents**

**Substance Abuse in Your Patients:  **
**Beyond What is Taught in Your Residency**

## Learning Objectives

- What does research tell us about:
- Developmental pathways and neurobiological underpinnings of  adolescent addiction?
- Common co-occurring disorders ?
- Assessment and treatment ?
- What are the clinical implications of addiction research?

**Notes:**
1.	Understand the key developmental risk factors that increase the risk of mental health problems, substance abuse and other behavioral pathology in adolescents
2.	Understand the clinical implications of scientific advances in our understanding of adolescent brain development and the neuro-developmental processes underpinning addiction and commonly associated psychiatric comorbidity
1.	Understand the key developmental risk factors that increase the risk of mental health problems, substance abuse and other behavioral pathology in adolescents
2.	Understand the clinical implications of scientific advances in our understanding of adolescent brain development and the neuro-developmental processes underpinning addiction and commonly associated psychiatric comorbidity

##           Individual                                                       

-           Individual

- ADHD

- Mood / Anxiety

- School

- ODD             CD               ASP

- Experimentation (90%)       SUD
- (drug 3-9%; alcohol 5-8%)

- Family

- 0

- 10

- 20

- 5

- 15

- PEERS

- LD

- Fetal exposure
- Attachment

- Genetics

- Resilience

**Verbal IQ; school performance; **
**hobby; empathic gatekeeper , **
**second chance**** **

**SUD, abuse, neglect**

**Failure; truancy**

**Deviant, drug involved**

**Gene-environ****m****ent interactions**

**Temperament and **
**co morbidity**

** ****Impedes development of :**
**Coping skills**
** ****Social /interpersonal skills**
** ****Communication skills**
** ****Identity, values consolidation**
** ****Affect identification/regulation**
** ****Self-Efficacy/external locus control**
** ****Pro-social network**

**Notes:**
This slide schematically shows the developmental risk factors that increase the risk for adolescent substance abuse.
Survey research indicates that the majority of adolescents will experiment with drugs of abuse before graduating from high school(85%)
However, those with the developmental vulnerabilities indicated in this slide are the ones at greatest risk for progression from experimentation to substance abuse and dependence 
Understanding the developmental risk factors and pathways to adolescent substance use disorders underscores the importance of obtaining a longitudinal, lifetime timeline approach to assessment of all developmental domains when taking a  medical history in  adolescents in primary care, mental health , and substance treatment settings. 
The “yellow ‘ bubble indicates how an understanding of developmental arrest from substance use can be effectively addressed in treatment. That is ...if adolescents learn to use drugs/alcohol as their primary mechanism for coping with life stressors (loss, failure, relationship, family problems), this interferes with the development of more adaptive or a broader range of coping skills to deal with environmental stressors. 
For example adolescents who become dependent upon marijuanaduring their early adolescent years have “one tool in the coping skills toolbag”
When they present for drug treatment during mid-late adolescence ----an important component of treatment will be teaching them a broader range of non-drug coping skills if they are to be successful in reducing or abstaining from drugs of abuse. 

## Gray Matter Development

*Gogtay et al., 2004*

**Notes:**

Much brain development during adolescence, when substance use typically starts.
Gray matter volumes typically reduce due  to synaptic pruning during adolescence.

White matter and gray matter volumes are important due  to the critical changes that typically occur during adolescence, with white matter volumes typically increasing (myelination) and gray matter volumes typically decreasing (synaptic refinement) The process of gray matter maturation (represented by the blue color) begins initially in the dorsal parietal cortices in the primary sensorimotor areas near the interhemispheric margin spreading rostrally over the frontal cortex, and caudally and laterally over the parietal, occipital, and finally the temporal cortex. The side bar shows a color representation in units of gray matter volume.

This study, by researchers at UCLA and the National Institutes of Mental Health , shows how gray matter volumes actually decrease during adolescence, due  to synaptic pruning.
(Gray matter refers the brain cell bodies/nuclei, dendrites, synapses; while white matter refers  to the axons, which appear “white” in brain images due to the fatty myelin coating.)
The blue areas show brain areas with major changes in gray matter thickness, which are maturing and refining into late adolescence.
The process of gray matter maturation begins initially in the dorsal parietal cortices in the primary sensory and motor areas spreading forward over the frontal cortex, and then over the parietal, occipital, and finally the temporal cortex. 

SO, Much brain development occurs during adolescence, when substance use typically starts. 
It has been unclear what the influence of heavy drinking and other drug use during these processes   might be on the adolescent and the adult brain.

Brain areas implicated in acute and chronic response to drugs of abuse similar to those implicated in depression; ADHD 
Hippocampus, amygdala (memory and conditioned learning
Ventral cingulate (mood regulation) 
Thalamus (arousal in acute response to drugs of abuse)

Adolescents 
Orbitofrontal (< grey matter)
Ventral tegmentum and thalamus (< white matter) 

Increased anterior cingulate activity 
Important in monitoring response for errors; 
Emotional evaluation of how well performing; appropriateness of response under conditions of conflict
Giedd et al work indicates that most used circuits are preferentially spared during adolescent pruning; least utilized more likely to be pruned.
Jay Giedd’s example paraphrased: “..so If you spend your adolescence playing video games , those circuits spared at expense of those that may be more dedicated to math, logic, physics problems ...”  Generalized to drug using teens embedded in drug culture; peers; and over learning related to drug activities ---circuits spared ...which may ‘engrave’ neural substrate supporting ongoing/progression of drug abuse into adulthood....?? Area for future research

## Brain Mechanisms in ADHD

- Posner MI, et al. *Images of Mind*. 1st ed. New York, NY: Scientific American Library; 1997.

- Neuropathology overlap
- ADHD, SUD

**Notes:**
Brain Mechanisms in ADHD suggest overlap with areas of the brain involved in neuropathology of SUD in adolescents
Researchers do not yet know 
what is attributable to ADHD alone; SUD alone 
 what is overlapping
Pre existing vs substance induced as seen in later slides

There is a considerable body of research to indicate the role of catecholamine mechanisms in ADHD. The posterior attention center in the parietal cortex is responsible for scanning the environment for relevant stimuli, and communicating this information to the anterior fronto-striatal system, which is more involved with executive control and focusing attention. The posterior center is primarily under noradrenergic control, while the anterior center receives both dopaminergic and noradrenergic projections. The system is interactive, with considerable noradrenergic-dopaminergic interaction in specific regions, such as the prefrontal cortex. The precise way in which the cerebellum interacts with this system is unknown, although it is known that the cerebellum sends projections anteriorly to the PFC, via thalamus. In addition, findings from structural MRI studies have consistently found that cerebellar size is smaller in children with ADHD. And, while the size of other brain regions in ADHD and control subjects converge in adolescence, the smaller cerebellar size remains.

**Comorbidity  **     **Prevalence**      ** ****        risk SUD   **     **Effective Tx**** ****          Tx with SUD**

|  ADHD | 30-50%

vs 10% | Yes | Stimulants 
Lower abuse
  pemoline*           Atomoxetine
 Bupropion
 Modafinil** | 1 RCT n=69
 Efficacy > PBO
 Good safety profile
 No impact on  SUD
   absent SUD tx |
| --- | --- | --- | --- | --- |
| Depression | 15-25%

vs 5-7% | Yes | 
    SSRIs*
Psychotherapy
   CBT 
   Interpersonal | 1 RCT  n=126
 *fluoxetine + CBT
      for SUD
  Efficacy > PBO 
  Good safety profile

  |
|    Bipolar | 10-15%

vs 1% | Yes | mood 
stabilizers | 1 RCT lithium n=22
Good safety profile
Treats bipolar
Not  SUD |
|  Anxiety
 | 15-35%
vs 5-10% | Yes | SSRI /CBT | No RCTs
 |

**Notes:**
This slide indicates the most common co -occurring psychiatric disorders in adolescents with SUD
The second column shows the higher prevalence of the disorder in adolescents with SUD compared to the general population
Column 3 indicates that there are some data supporting that the disorder increases the risk of developing  SUD in adolescence
In general, treatment of a psychiatric disorder in childhood reduces the increased risk that it imparts for development of adolescent SUD. However even effective treatment does not necessarily decrease risk to the prevalence those youths without the psychiatric disorder (see wilens’ et al re: adhd ) 
Column 4 shows the practice  standard of  care  regarding evidence based treatments for the psychiatric disorder in youths without SUD
Column 5 indicates the results of randomized controlled trials that have been conducted in adolescents with SUD and the psychiatric comorbidity --related to research supported treatment of comorbidity with ASUD

## Study Flow Diagram

**Study Flow Diagram**

**Randomized Controlled Trial**** ****Fluoxetine vs Placebo     + 16 weeks CBT **

**Notes:**
This slide presents more detailed data from recently completed RCT of Fluoxetine + CBT (for SUD) vs Placebo + CBT in adolescents with MDD and SUD (Riggs et al in press Archives Pediatric Adol Med)

## Demographics

| Demographic Characteristic | Placebo
(n=63) | Fluoxetine
(n=63) | Overall
(n=126) |
| --- | --- | --- | --- |
| Gender n (%)       Female
Male | 20 (31.7)
43 (68.3) | 21 (33.3)
42 (66.7) | 41 (32.5) 85(67.5) |
| Age:                   mean (SD) | 17.02 (1.49) | 17.29 (1.81) | 17.16 (1.66) |
| Ethnicity n(%)  Caucasian
      African American
         Native American 
                         Asian
                   Hispanic
                         Other | 28 (44.4)
9 (14.3)
3 (4.8)
1 (1.6)
17 (27.0)
5 (7.9) | 33 (52.4)
9 (14.3)
1 (1.6)
0 (0)
17 (27.0)
3 (4.8) | 61 (48.4)
18 (14.3)
4 (3.2)
1 (0.8)
34 (27)
8 (6.3) |
| SES: group IV category | 43.98 (15.49) | 44.56 (17.60) | 44.27 (16.5) |
| Referral Source: n (%)
     Court-Ordered
     Non Court-Ordered | 
12 (19.0)
51(81.0) | 
14 (22.2)
49 (77.8) | 
26 (20.6)
100 (79.4) |

**Notes:**
Demographic data from the aforementioned RCT fluoxetine /placebo + CBT in adolescents with MDD and SUD

## Fluoxetine vs. Placebo Compliance: Medication & CBT 

**%**

***NS***

***NS***

***NS***

- N=52
- N=54

**Notes:**
Outcome data regarding compliance with medication and CBT attendance in the aforementioned RCT in adolescents with MDD, SUD

## Fluoxetine vs. Placebo Depression Remission

**70%**

**52%**

- P<.05

***Final CDRS < 29***

**Fluoxetine**** vs. ****Placebo**** ****Depression Remission**

- Riggs et al Archives of Pediatric and Adolescent Medicine in press

**Notes:**
Differential rates of depression remission in placebo vs fluoxetine treatment groups in Fluoxetine /Placebo RCT
Results indicate that CBT (even though targeting SUD, not depression ) was probably active in treatment of depression given high remission rates in placebo treatment arm 
Data indicate that remission was not largely due to abstinence since only 12% of study participants achieved sustained abstinence (plus other supporting data from study results)

## Pbo NR 

**Pbo NR**

**Flx NR**

**Pbo R**

**Flx R**

**REMITTERS **

**NON REMITTERS**

**Notes:**
Results showed high rates of remission of depression (defined as final CDRS R raw score < 29) in both fluoxetine and placebo treatment groups 

## Change in Drug Use 

**Pbo R**

**Flx NR**

**Pbo N R**

**Flx R**

**Remitters’ pre post     drug use (p<.001) (0.5 effect size)**** (U/A R> NR p<.02)**** **
**Non-Remitters: no change in drug use (NS)**

**Change in Drug Use**

**REMITTERS**

**NON REMITTERS**

**Notes:**
After controlling for medication group assignment; remission of depression was > predictor of decrease in drug use than medication group 
Remitters’ drug use decreased significantly from baseline levels/pre-post treatment ; whereas non remitters’ drug use did not change from baseline 

## Conclusions and Clinical Implications 

** ****Fluoxetine > Placebo for MDD in non-abstinent adolescents with active SUD; ****good safety profile**
** ****Remission was better predictor of reduced drug use than medication group**
**Remitters showed significant       in drug use N**
**Non-remitters’ drug use did not decrease from baseline levels**
**CBT probably active ingredient in treatment of MDD despite focus on SUD, not depression **
**Increased access to treatment (80% not court-mandated)**
**Empirical support for integrated SUD/mental health tx**
**Depression outcomes as good or better than controlled trial in depressed teens without SUD**
**Change in drug use, compliance, retention as good or better than substance treatment in adolescents without comorbidity / < severe psychopathology**

**Notes:**
Results from this first randomized controlled trial of pharmacotherapy for MDD and CBT for SUD support integrated /concurrent treatment of both disorders 

## family) 

- Treatment
- Pharmacotherapy
- Psychotherapy
- (individual, behavioral,
- family)

- Neuropathology
- Pre existing ?
- Substance induced?

- Changes with treatment?
-  Differences in neuroplasticity:
-     adolescents vs adults?
-  What recovers? What doesn’t ?

**Notes:**
Although we know that drugs of abuse cause neuropathology, we do not always know whether neuropathological findings in drug abusers were pre existing or caused by drugs of abuse
It is known that some common comorbid psychiatric conditions arise before drug abuse and are associated with characteristic neuropathology 
ADHD is primary example with onset before age of 7 (before drug abuse; see next slide) 
Researchers currently little is known about potential changes in the brain that may occur with treatment 
Reversal of neuroplastic changes caused by drug abuse
Recovery with abstinence
Neuropathological changes that may recover function with treatment of comorbid psychiatric conditions
? Neuropathological changes common to both addiction and psychiatric comorbidity
? Pharmacotherapies and/or behavioral interventions that may taqrget both disorders ??   
Known examples :    Bupropion ---data support efficacy for MDD, ADHD, nicotine dependence; recent research support preliminary efficacy reducing craving and use of methamphetamine, cocaine, marijuana 
An important direction for future research in medication development will be to find medications that hold promise for targeting both addiction and psychiatric comorbidity . This is also an important principle of parsimony ...that is little is known about interactions of drugs of abuse and medications ..such that monotherapy   vs poly pharmacy is prudent clinical approach 
Also need to continue active investigation of effects of behavioral interventions/psychotherapeutic interventions on brain neuroplasticity /pre post treatment changes as seen in subsequent slides 

## On STROOP test: Substance dependent adolescents exhibited activation in the rostral & caudal  ACC...

- ...and **R orbito-frontal cortex (OFC)**
-  **Non-dependent controls did not**
**...****..but are differences pre-existing or caused by drug use?**

##    Greater Pretreatment Brain Activation Drug > Food  

**Ventral Tegmentum**
** ****Nucleus accumbens**
** ****Amygdala**
** ****Thalamus**
** ****Anterior Cingulate**
** ****Medial frontal cortex**
** ****Midbrain**
** ****Posterior visual cortex**
** ****Cerebellum**

- Preliminary results in 11 adolescents with cannabis and other substance use disorders suggests greater activation of reward circuit in response to drug cues than food before treatment

**Notes:**
Presented CPDD 2006 SASATE Workshop
 Riggs et al in press Drug and Alcohol Dependence

## Greater post-treatment activation Drug > Food  in areas of cognitive control* compared to pre-treatment (n=10 post scans; n=6 valid; p < .01)

-                      Pretreatment		            Post-treatment
*** ACC and cortical regions --medial frontal, lateral inferior frontal, dorsolateral, prefrontal**

## Clinical Implications

- Directions for future research
-  Decrease barriers to treatment access
-  Expand integrated /coordinated continuum of care
-   ( medical, psychiatric, substance treatment)
-  Earlier interventions & improved continuing care
-  school based, indicated prevention
-  parity for mental health and SUD treatment
-  utilization of  existing community based resources
-  Relapse Prevention : build “internalized motivation “ to maintain treatment gains by involvement in positively rewarding activities incompatible with drug use during treatment

**Notes:**
Controlled clinical trials conducted by the presenter (Riggs et al 2004 RCT pemoline for ADHD in adolescents with SUD; Riggs et al 2007 in press fluoxetine/placebo + CBT) are the first RCT to support the safety and efficacy of psychostimulants (pemoline)for ADHD and SSRIs (fluoxetine) in non abstinent adolescents with active SUD
Results from these studies and others are part of growing body of evidence indicating that comorbid disorders such as ADHD and MDD may be more responsive to medications in non-abstinent adolescents compared to dually diagnosed adults in whom  controlled pharmacotherapy trials have been negative , equivocal, or shown minimal responsiveness of comorbidity in non-abstinent adults with more chronic drug abuse careers (Levin et al; Nunes et al  ) 

## Clinical Implications

**Directions for Future Research **
- Medication Development
-  Monotherapy better than polypharmacy
-  Clinical trials using medications that target both SUD and comorbidity such as bupropion
-  controlled trials support efficacy for ADHD, MDD, nicotine dependence
-  reducing methamphetamine craving and use

**Notes:**
Riggs et al. 2004; Barrickman et al 2001, Wilens et al 2003, Newton et al 2006, 2007  

## Practice

- Research

- Primary care
- Medical services

- Substance
- treatment

- Mental Health

- Primary care
- Mental Health
- Substance
- treatment

**Research **

**Align**
**Economic **
**Incentives***

**NIDA Clinical Trials Network CCTN**

**Translational **
**Research**
**CTSA**

**Training **
**NIDA AACAP K 12**

**Assessment**
**of **
**SUD**
**(eg CRAFFT)**

**Screening**
**Dx Assessment**
**Psychiatric**
**Comorbidity**

**Practice**

** **
**   ****internalized motivation **
**  ****involve in positive activities, **
**incompatible with drug use**
**    ****use of existing community **
**resources to augment  **
**treatment  services**