SSRI Antidepressants in Treating Children with Autistic Disorder

Ana Krishnan

Penn State College of Medicine

 

I.      Overview (1)

 

Autistic disorder involves severe qualitative defects in all three of the following behavioral areas:

1. Social interaction
2. Language, communication, and play
3. Stereotypies, perseveration, and narrow range of interest and activities

Many of these patients do not tolerate changes in routine or environment, and can present with acute symptoms of anxiety, panic, irritability, or agitation.

Autism is most often identified in toddlers, mostly boys, from 18 to 30 months of age, in whom parents or pediatricians note an absence or delay of speech development and a lack of normal interest in others or a regression of early speech and sociability

Onset is usually during infancy to 30 months

Males 4:1 Females

Incidence is about 1-2/1000

 

DSM IV Criteria:

A.  A total of 6 or more items from (1), (2), and (3) below:

(1) Qualitative impairment in social interaction, as manifested by at least two of the following:

a.  Marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction

b.  Failure to develop peer relationships appropriate to developmental level

c.  Lack of spontaneous seeking to share enjoyment, interests, or achievements with other people

d.  Lack of social or emotional reciprocity

(2) Qualitative impairments in communication as manifested by at least one of the following:

a.  Delay in, or total lack of, the development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication such as gesture or mime)

b.  In individuals with adequate speech, marked impairment in the ability to initiate or sustain a conversation with others

c.  Stereotyped and repetitive use of language or idiosyncratic language

d.  Lack of varied, spontaneous make-believe play or social imitative play appropriate to developmental level

(3) Restricted repetitive and stereotyped patterns of behavior, interests, and activities, as manifested by at least one of the following:

a.  Encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus

b.  Apparently inflexible adherence to specific, nonfunctional routines or rituals

c.  Stereotyped and repetitive motor mannerisms

d.  Persistent preoccupation with parts of objects

1. Delays or abnormal functioning in at least one of the following areas, with onset prior to age 3 years: (1) social interaction, (2) language as used in social communication, or (3) symbolic or imaginative play.
2. The disturbance is not better accounted for by Rett’s Disorder or Childhood Disintegrative Disorder.

 

Why SSRI’s?

SSRI’s have been studied in depth in the treatment of OCD and have been proven to be effective in both adults and children (2).  There are similar symptoms between autism and OCD, such as the repetitive preoccupations and perseverative behaviors (3).  The similarity between some of the above symptoms and that of OCD has led to the use of SSRI’s in the management of PDDs.

 

Frequency of SSRI treatment for autistic disorder:

A recent survey (4) found that the SSRIs are commonly used to treat high functioning PDDs.  109 children and adults with high functioning PDD were surveyed.  SSRI’s were the single most commonly used class of drugs (27% of the respondents); these drugs were also identified by the patient’s families as being very useful in reducing repetitive and anxiety type symptoms.

 

II.     Evidence based studies examining SSRIs in the treatment of autism

1. Fluoxetine:  Only one placebo controlled trial that was performed in 6 adults.  Other studies showed some promise (5-8):

FLUOXETINE

Study	Subjects	Design	Rating Scale	Results	Side Effects
Cook 1992	N=23, children and adults	Prospective open trial	CGI	15/23 significantly improved	6/15 hyperactivity, restlessness, agitation, decreased appetite, insomnia
Fatemi 1998	N=7, ages 9-20 yrs	Retrospective chart review	Aberrant Behavior Checklist	Only improvement of lethargy reached statistical significance	Appetite suppression, vivid dreams, hyperactivity
Buchsbaum 2001	N=6, adults	Placebo controlled trial	YBOCS, Hamilton Anxiety scale	3 pts significantly improved, 3 pts unchanged
DeLong 2002	N=129, children ages 2-8	Prospective open trial	Childhood Autism Rating Scale	17% (22) excellent response, 52% (67) good response.  FH of bipolar disorder, intelligence, and hyperlexia correlated significantly

1. Paroxetine: No controlled studies.  A few case reports have been published regarding paroxetine.  One reported a decrease in self injurious behavior in a 15 year old boy (9), and another case report reported decreased irritability and temper tantrums in a 7 yr old boy (10).
2. Sertraline: No controlled studies.  Results from open trials suggest improvement in aggression, mainly in adults. (11-13)

SERTRALINE

Study	Subjects	Design	Rating Scale	Results	Side Effects
Hellings 1996	N=9, Adults	Prospective open trial	CGI	8/9 improved in self injury and aggression	1 pt d/c due to sever agitation and worsening of self-picking
Steingard 1997	N=9, Children age 6-12	Prospective open trial		8/9 improved in situational/environmental changes, however 3 pts response decreased after a few months.	2 pts behavior worsened
McDougle 1998	N=42, Adults	12 week open trial	CGI,Behavioral ratings	24/42 (57%) showed significant improvement, mostly in repetitive and aggressive symptoms. 68% were treatment responders.	—

 

1. Fluvoxemine:

A double blind placebo controlled study in adults (14):

This was the first controlled study examining SSRI in treatment of autism.

•  30 adults who met autistic criteria in DSM III, ages 18-53 randomized to either fluvoxamine or placebo.  Received 50 mg at night, increased to 300 mg as needed for maximal clinical response.
• Behaviors were assessed at baseline, 4, 8, 12 weeks.  Scales used: YBOCS, Ritvo-Freeman Real Life Rating scale, Vineland Adaptive behavior scale, CGI global improvement.
• Results showed significant improvements in the CGI beginning at week 4 (p<0.006) which continued though wk 12 (p<0.001), with no significant change in placebo group.  53% vs 0% responders (p=.001)

–       YBOCS scores: Fluvoxamine was better than placebo in treating repetitive thoughs and behaviors (p<0.001).

–       Vineland maladaptive behavior subscale maladaptive behaviors: Fluvoxamine significantly better beginning at week 4

–       Brown aggression scale: a reduction in aggression from baseline (p<0.03), beginning at week 8

–       Ritvo Freeman Real life rating scale: improved behavior after 8 weeks, subscale showed improved language use.

 

In children however, there have been recent differing results:

1. McDougle 2001:  Unpublished data of a 12 week controlled study in children examining fluvoxamine 2.5-3 mg/kg.  The study was discontinued due to the adverse effects: increase in aggression, increase agitation, increased ritualistic behaviors, and anxiety.

1. Martin 2003:  Prospective study of low dose fluvoxamine in children and adolescents with PDDs.  Assessed whether a reduced dose of fluvoxamine would be better tolerated.  Examined effects of pubertal status on response, and whether platelet serotonin content was associated with a response (15).

• Ages 7-18 with at least moderate severity (>= 4 on CGI scale, >12 YBOCS scale, or >25 SCARED – screen for child anxiety related emotional disorders)

79% male. 61% prepubertal, 39% pubertal.

• 10 weeks prospective open label, behaviors assessed every other week.
• Fluvoxamine was started at 12.5mg for pts <40kg, or 25 mg for pts > 40 kg. The maximum dose used was 1.5mg/kg/day (almost half that of unpublished study.)
• Efficacy was evaluated by a change in baseline CGI.  Secondary variables examined were YBOCS and SCARED

 

Results:  18 enrolled, 14 completed study (premature termination due to behavioral activation in 4 pts)

 

• Overall changes on CGI-I were not significant
• Decreases on CYBOCS (12% change from baseline: 18.1 à 16.4 à 16.9, p=.32) and SCARED (17% change: 30.1 à 25.1 à 25.1, p=0.16) were small and not statistically significant.
• 3 were full responders (17%), 5 partial (28%), 10 were nonresponders (55%).

Full responders had a CGI score of 1 (very much improved) or 2 (much improved), AND a decrease by 25% in either CYBOCS or SCARED.  Partial responders: A score of 1 or 2 on CGI OR improvement in YBOCS and SCARED.

• There was a significant association with gender.  All of the girls were considered responders (3 full responder, 1 partial responder), versus 4/14 boys, who were all partial responders (p=0.02).
• Serotonin measurements:  Blood levels decreased by 83% during treatment.  There was no difference in absolute serotonin levels or percent change between responders and non- responders.  Serotonin levels decreased by even more (>90%) in those that were full responders, but this did not reach statistical significance.

 

Adverse events:  13 patients (72%) reported at least one adverse event.  Most frequently this was akathesia/agitation/behavioral activation (n=9, 50%).  In 4 of these patients, it was severe enough to prematurely d/c.  Other adverse effects included sleep difficulties (n=9), and headaches (n=6).

 

Conclusion:  They concluded that fluvoxamine cannot be recommended for the routine treatment of anxiety or OCD-like symptoms for most children and adolescents with PDD’s, due to the high risk of behavioral activation in this population.  However, gender differences should be further studied.  In addition, predicting the response has not been elucidated.  In this study, serotonin levels failed to distinguish responders vs. nonresponders.  Further studies may help in this aspect.

 

III.     Serotonin: increased or decreased in autism?

• Elevated blood serotonin levels published since the 60’s, but not in CSF (16).
• McBride (1998) found an increase by 25% in serotonin in prepubertal autistic children as compared with controls, but less than in previous studies (17).
• Chugani (1999):  Serotonin is produced 200% greater in normal children until 5 yrs, then taper to adult values.  Unlike previous studies, they (18) demonstrated that autistic children produced less serotonin than normal children, peaking at 12 yrs at 150% that of adults.  This suggests that the normal development process of producing elevated serotonin levels is disrupted in autism.

 

IV.     Summary:

SSRI’s have been shown to be helpful in reducing aggression and repetitive behaviors in adults.  However, recent studies challenge the use of SSRI’s in treating autistic children.  Additional studies are needed in children examining response to SSRI’s, and developmental differences in serotonin regulation. 

 

References:

1. Rapin I. Autism. NEJM. 1997; 337: 97-104.
2. Geller DA, Hoog SL, Heiligenstein JH, et. al., Fluoxetine treatment for obsessive compulsive disorder in children and adolescents: a placebo controlled clinical trial. J of the Am Acad of Child and Adolesc Psychiatry. 2001; 40: 773-739.
3. McDougle CJ, Kresch LE, Goodman WK, et.al. A case-controlled study of repetitive thoughts and behavior in adults with autistic disorder and obsessive-compulsive disorder. Am J Psychiatry. 1995; 152(5): 772-777.
4. Martin A, Scahill L, Klin A et. al. Higher functioning pervasive developmental disorders: rates and patterns of psychotropic drug use. J Am Acad Child Adolesc Psychiatry. 1999; 38(7): 923-931.
5. Cook EH, Rowlett R, Jaselskis C. Fluoxetine treatment of children and adults with autistic disorder and mental retardation. J Am Acad Child Adolesc Psychiatry. 1992; 31:739-745.
6. Fatemi SH, Merz A, Realmuto GR, Khan L et.al. Fluoxetine treatment of adolescent patients with autism: a longitudinal open trial. J Autism Dev Disord. 1998; 28(4): 303-307.
7. Buschbaum MS, Hollander E, Haznedar MM et.al. Effect of fluoxetine on regional cerebral metabolism in autistic spectrum disorders: a pilot study. Ing J Neuropsychopharmacol. 2001; 4(2): 119-125.
8. DeLong GR, Ritch CR, Burch S. Fluoxetine response in children with autistic spectrum disorders: correlation with familial major affective disorder and intellectual achievement. Dev Med Child Neurol.2002; 44(10): 652-659.
9. Snead RW, Boon F, Presberg J. Paroxetine for self-injurious behaviors. J Am Acad Child Adolesc Psychiatry. 1994; 33(6): 909-910.
10. Posey DI, Litwiller M, Koburn A, et.al. Paroxetine in autism. J An Acad Child Adolesc Psychiatry. 1999; 38(2): 111-112.
11. Hellings JA, Kelley LA, Gabrielli WF. Sertraline response in adults with mental retardation and autistic disorder. J Clin Psychiatry. 1996; 57: 333-336.
12. Steingard RJ, Zimnitzky B, DeMaso DR, et.al. Sertraline treatment of transition-associated anxiety and agitation in children with autistic disorder. J Child Adolesc Psychopharmacol. 1997; 7: 9-15.
13. McDougle CJ, Brodkin ES, Naylor ST, et.al. Sertraline in adults with pervasive developmental disorders. J Clin Psychopharmacol. 1998; 18: 62-66.
14. McDougle CJ. Naylor ST, Cohen DJ, et. al. A double-blind, placebo controlled study of fluvoxamine in adults with autistic disorder. Archives of General Psychiatry. 1996; 53(11): 1001-1008.
15. Martin A, Koenig K, Anderson GM, et. al. Low-dose fluvoxamine treatment of children and adolescents with pervasive developmental disorders: A prospective, open-label study. Journal of Autism and Developmental Disorders. 2003; 33(1): 77-85.
16. Fatemi SH, Merz A, Realmuto GR.  The roles of reelin, bcl2, and serotonin in cerebellar pathology in autism.  Journal of Developmental and Physical Disabilities. 2003; 15(1): 1-22.
17. McBride PA, Anderson GM, Hertzig ME et.al. Effects of diagnosis, race, and puberty on platelet serotonin levels in autism and mental retardation. J Am Acad Child Adolesc Psychiatry. 1998; 37(7): 767-776.
18. Chugani DC, Muzik O, Behen M et.al. Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol. 1999; 45(3): 287-295.

 

See the Autism and Asperger’s Disorder page for more information.