4291 words excluding references
Risperidone as a treatment for
symptoms associated with Post-Traumatic Stress Disorder and Acute Stress
Reaction/Disorder. A systematic review.
Forensic Mental Health
Research Unit,
Tel. 01777 247537
Fax. 01777 247221
e-mail: Michael.Ferriter@nottshc.nhs.uk
Acknowledgements
The author wishes to acknowledge the help of Andrew Booth and Catherine Beverley of the ScHARR library service in carrying out the preliminary literature search, Bernard Huckstep, Chief Pharmacist, Rampton Hospital, in providing costs for risperidone and Jenny Roberts, health economist at ScHARR for advice on costing CPN services.
At the time of
writing, one of the authors (PM) was employed as a Research Assistant at
Background: Exposure to traumatic events accounts for a significant amount of psychological morbidity in the population. The resulting psychological disorder can be acute and time limited (Acute Stress Reaction/Disorder) or chronic (Post-Traumatic Stress Disorder). The traditional approach to these disorders has been through a range of ‘talking’ therapies though there is, at best, a limited evidence base to support their use and in one form of therapy (psychological debriefing) evidence that contraindicates its use. In contrast, the use of pharmacological therapies is a growing area of research. Risperidone is known to impact on both the serotonergic and dopaminergic neurotransmitter systems that research has shown to be altered in Post-Traumatic Stress Disorder. The purpose of this review was to see what evidence there was to support the use of risperidone in the treatment of stress disorders.
Method: The relevant databases were searched for suitable studies concerning risperidone treatment of PTSD.
Results: The results of the search were disappointing, discovering only one, unpublished, RCT, four case series and two case reports.
Conclusion: The evidence was generally in favour of the intervention but of insufficient quantity or quality to make recommendations for clinical practice. However, this is clearly a promising area for research and there is a compelling humanitarian and economic case to carry out better and larger scale trials on risperidone and other pharmacological interventions both as an adjunct and an alternative to traditional psychological approaches.
Keywords: Risperidone; Posttraumatic
Stress Disorder; systematic review
There is little doubt that there is a relationship between exposure to traumatic events and subsequent psychological morbidity. The nature of the trauma can be a single disaster affecting many (e.g. the sinking of the Herald of Free Enterprise or the Kings Cross fire), genocidal violence, torture and political violence, combat experience (where the sufferer may be victim, witness or perpetrator or any combination of these three), or more individual traumatic events such as sexual abuse and violence, road traffic accidents, abduction, hostage taking and physical violence.
Both the International Classification of Mental and Behavioural Disorders: ICD10 (W.H.O. 1992) and the Diagnostic and Statistical Manual of Mental Disorders: DSM-IV (American Psychiatric Association 1994) recognise short and long term disorders associated with exposure to traumatic events. In both classification systems the long-term disorder is referred to as Post-Traumatic Stress Disorder (PTSD), in ICD10 the short duration disorder is referred to as Acute Stress Reaction (ASR) and in DSM-IV Acute Stress Disorder (ASD). In all these definitions there must be a clear link between a known significant traumatic event and the disorder with no symptoms pre-dating the event.
Symptoms for ASR include problems of attention and consciousness and disorientation, dissociation stupor, agitation (flight reaction or fugue state) and autonomic states associated with panic anxiety. The diagnosis of ASD requires the following symptomology. At least three of the five following dissociative symptoms must be present: numbing (detachment or absence of emotional response), a reduction of awareness of surroundings (being in a ‘daze’), derealization, depersonalisation, and dissociative amnesia. The sufferer should be experiencing one of the following: recurrent images, thoughts, dreams, flashbacks, and illusions of the traumatic event. In addition there should be avoidance of stimuli associated with the traumatic event, symptoms of anxiety or arousal (e.g. sleep disturbance, impairment of concentration, hyperarousal, hypervigilence) and clinically significant impairment of social and everyday functioning.
PTSD as defined by DSM-IV also requires the distressing re-experience of the traumatic events in at least one of the following forms: intrusive thoughts and memories, recurrent distressing dreams of the event, feelings that the event is recurring, distress at, and physiological reactivity to, cues associated with the event. There should also be present three or more of a range of indicators of avoidance of such cues or stimuli and symptoms of arousal. The ICD10 criteria for PTSD are very similar.
There is a large overlap between the stress disorders and dissociative disorders. As can be seen above, dissociative symptoms are important diagnostic factors for PTSD, ASR and ASD and there is speculation that in many cases the origins of dissociative disorders are in traumatic events. The stress disorders and the dissociative disorders can be thought of as two circles that significantly overlap and it is advisable that any systematic review on stress disorders or dissociative disorders should contain search terminology for both.
A Cochrane review has recently been published by Stein, Zungu-Dirwayi, van der Linden & Seedat (2000) (1) which looks at a range of pharmacological interventions for PTSD. They concluded that pharmacological interventions were effective in reducing the core symptoms of PTSD though there was insufficient data to draw firm conclusions about a drug of choice. However, the evidence to date supported the use of one class of drugs, serotonin specific re-uptake inhibitors (SSRIs). The review contained no trials of risperidone, though one such trial was noted as pending (2). This review will differ from the Cochrane review in that it will use the wider search strategy of terms for both stress and dissociative disorders and will not be limited to RCTs.
Incidence/prevalence
It has been estimated that between 30%-40% of those exposed to disasters were showing significant psychological morbidity one year after the event (3). A lifetime prevalence rate for PTSD of 5% in men and 10% in women has also been suggested (4). PTSD is therefore a more frequent psychiatric problem than schizophrenia, which is acknowledged as the most significant mental health problem worldwide, with the often-quoted prevalence rate of 1%.
Outline of current services
The standard treatment for the stress disorders is a range of psychological interventions with an, at best, limited evidence base. These therapies tend to be resource intensive and most involve recapitulation of the traumatic event, which might seem paradoxical in a disorder characterised by distressing and unwanted recollections. While steering clear of the controversy about ‘recovered memory’ of childhood abuse, most people who have suffered authenticated trauma are distressed by remembering and would wish but are unable to forget. We may contrast the position of Parkinson (1993) (5) who focuses exclusively on psychological debriefing as a treatment for, and as post-trauma prophylactic against the development of PTSD with Wessely, Rose & Bisson’s (2000) Cochrane Review (6). The authors found that post trauma psychological debriefing did not reduce psychological distress or prevent PTSD and that those who had had the treatment, though they showed no elevated risk in the short term, were at greater risk in the long term. Not surprisingly they recommend that compulsory post trauma debriefing should cease.
Proposed service
Risperidone is an ‘atypical’ antipsychotic drug developed by Janssen-Cilag in the early 1990s, one of a second generation of pharmacological interventions in the treatment of schizophrenia which has proved successful in the treatment of both the negative symptoms (e.g. apathy, anhedonia) and positive symptoms (e.g. delusions, hallucinations) of schizophrenia. The earlier generation of antispsychotics had proved less effective in the treatment of negative symptoms.
We are aware of anecdotal accounts from clinical colleagues of the successful use of risperidone for patients suffering from intrusive thoughts and flashbacks of traumatic events. Risperidone is licensed, and is normally only used, for the treatment of major mental illnesses, notably schizophrenia. However, it is also licensed as an anxiolitic and it is within this context that it has been used in these cases.
What is the scientific case for the use of risperidone with the stress disorders and how does what is known of the neurobiological alterations in these disorders relate to the psychopharmacology of risperidone? Friedman (1996) (7) lists the following neurobiological alterations found in PTSD: heightened sympathetic reactivity, excessive adrenergic activity, HPA axis abnormalities, elevated thyroid function, opioid system dysregulation, exaggerated startle response, disturbed sleep and dreaming, serotonergic abnormalities, dopaminergic abnormalities, sensitisation of limbic nuclei and immunological abnormalities. Friedman’s review particularly focuses on the evidence for abnormalities in the andrenergic, dopaminergic and serotonergic mechanisms. Green (2000) points out that risperidone impacts on both the dopamine (D2) receptor sites and the serotonin (5-HT2) receptor sites; it has a complex effect on two of the three significant neurotransmitter systems identified by Friedman as being altered in PTSD.
Method
PSYCHINFO, MEDLINE, EMBASE, National Centre for PTSD, Cochrane Library, NRR, BIOMED and Science Citation Index databases were searched using the strategy shown in Appendix A. Appendices B, and C list the included and excluded studies. The search strategy was based on pre-existing search strategies used in Cochrane reviews for risperidone and for stress disorders and dissociative disorders. RCT filters were not applied and there were no limitations on gender or age of participants.
Only one unpublished, RCT, four case series and two case reports were identified. Table 1 shows a summary of the results of the seven included studies. The references from the included and excluded studies were examined for further studies but none were identified.
Case series and case reports are the lowest form of evidence but one RCT has been identified (2). However, the issue of how much reliance can we place on that study is open to debate. There are a number of problems. It is an unpublished conference paper and, to date, is only available as a conference abstract. The participants suffered from PTSD comorbid with psychotic symptoms, which complicates the issue, and the reported reduction in PANNS rating is neither relevant nor surprising. In effect, the authors are reporting that a drug specifically developed and with a proven record of reducing psychotic symptoms is effective in reducing psychotic symptoms! The results for the re-experiencing symptom subscale are of note but what of the other PTSD subscales? In summary, although five out of seven of the studies favoured the intervention, the quantity and the quality of the studies are too poor to recommend changes to current clinical practice. The reports of side effects should be noted. The poor quantity and quality of data also means that more sophisticated methods of analysis such as meta-analysis and funnel plotting are inapplicable.
Benefits of risperidone treatment
The studies, so far, are not of sufficient quantity or quality to accurately estimate the benefits of the intervention. However, within the considerable limitations of the data, the benefit, if any, is in reduction of flashbacks, nightmares, hypervigalence, hyperarousal, intrusive thoughts and irritable aggression.
Disbenefits of risperidone treatment
Green (2000) (8) lists common side effects with risperidone of insomnia, weight gain, agitation, anxiety and headache and less frequent side effects of somnolence, tiredness, dizziness, poor concentration, nausea and sexual dysfunctions. Risperidone carries less risk, compared to other antipsychotics, of tardive dyskinesia (irreversible Parkinsonian side effects) and neuroleptic malignant syndrome (a potentially life-threatening adverse reaction to anti-psychotic medication). There has been one case report of risperidone being implicated in sudden cardiac death. However, the important issue is that although the relative risk of risperidone is good on a range of factors compared to other antipsychotics this review is concerned with the use of the drug in a group of patients most of whom would not, otherwise, be exposed to the risks of antipsychotics at all. These risks are highlighted in Chan and Silove (13) and Feeney and Klykylo’s (14) studies.
Costs
The lowest cost psychological intervention for the stress disorders
is probably a GP surgery based, community psychiatric nurse (CPN) counselling
service (treatment by a clinical psychologist, psychotherapist or psychiatrist
would be more expensive). The
Treatment by CPN = £160,800 ($246,313.44)
Treatment with risperidone = £143,080 ($219,169.95)
Note: this assumes that costs for case supervision by a psychiatrist or GP are identical in both treatments.
Savings
If one assumes equal efficacy between a CPN counselling service and the above dosage of risperidone then risperidone is clearly the cheaper option. However, we do not have the evidence base to make any such assumption, or to assume the efficacy of either intervention. We also do not know the outcome of risperidone in addition to psychologically intervention compared to risperidone or psychological intervention on their own. As a final point, the costs are deliberately weighted to the standard treatment. The figures presented are counselling at its cheapest likely cost versus a high dosage of risperidone. A more likely dosage level would be between 1 to 3 mg daily, i.e. between one half and one sixth of the above estimate.
Implications for other parties
Stein et. al.’s (2000) (1) review indicates a role for pharmocotherapy in PTSD but also points out that more data is needed. As they point out, there is a need for more and better quality trials of a whole range of pharmacological interventions and there is a good scientific case for including risperidone within this range. The case for more and better research is made more compelling by the high prevalence rates of the disorders, the amount of distress to the sufferers and high comparative costs of psychological interventions. Any future programme of research should explore not just differences between types of drugs but also compare pharmacological intervention combined with, or as an alternative to, psychological treatment. However, any analysis should also be mindful of the known risks and side effects of risperidone and other pharmacological interventions.
Conclusion
The evidence available so far, though supportive, is of too poor a quality to provide a definitive answer to the question of whether risperidone should be an intervention of choice for stress disorders. However, there is a strong case for further research on a number of pharmacological interventions, including risperidone, for the treatment of the stress disorders.
References
1. Stein, D J, Zungu-Dirwayi,
N, van der Linden, G J H, Seedat
S. (2000) .
Pharmacotherapy for Posttraumatic
Stress Disorder (Cochrane Review). The Cochrane Library, Issue 4.
2. Hamner M B, Frueh B C, Huber M G, Twomey T J,
Meason M O, Ulmer, H G, Tyson, C, Johnson, R H.
( 1999). A randomised controlled trial of Risperidone for psychotic features in PTSD. 152nd
Annual Meeting
of the American Psychiatric Association.
3. Raphael, B. (1986). When Disaster
Strikes: A Handbook for Caring Professionals.
4. Kessler, R, Somnnega,
A, Bromet, E, and Nelson, C (1993). Post-traumatic stress disorder in the National
Comorbidity Survey. Institute for Social
Research.
5. Parkinson, F. (1993) Post-Trauma
Stress.
6. Wessely, S,
Rose, S and Bisson, J. (2000) Brief psychological interventions
(“debriefing”) for trauma-related
symptoms and the prevention of post traumatic
stress disorder. The Cochrane Library,
Issue 3.
Update Software.
7. Friedman M.J (1996). Neurobiological
alterations in PTSD. In Giller E L and Weisaeth L (eds)
Bailliere’s
Clinical Psychiatry International Practice and Research. Post-traumatic Stress Disorder, 2
(2).
8. Green B. (2000). Focus on risperidone. Curr. Med. Res. Opin.,
16(2):57-65
9. Krashin D,
Oates E W. (1999). Risperidone as an adjunct therapy for post-traumatic stress disorder. Military-
Medicine,
164/8, 605-606.
10. Monnelly, E
P, Ciraulo, D A. (1999) Risperidone
effects on irritable aggression in posttraumatic stress
disorder. Journal of Clinical Psychopharmacology, 19 (4), 377-378
11. Leyba C M, Wampler
T P. (1998). Risperidone in ptsd. Psychiatric Services, 49 (2), 245-246.
12. Eidelman I, Seedat S, Stein D J.
(2000). Risperidone in the treatment of acute
stress disorder in physically
traumatized in-patients. Depression and
Anxiety, 11 (4),
187-188.
13. Chan A O M, Silove
D. (2000). Nosological implications of psychotic
symptoms in patients with established
posttraumatic stress disorder. Australian and
14. Feeney, D J and Klykylo,
W. Risperidone and tardive dyskinesia
(letter). Journal of the
of Child and Adolescent Psychiatry, 36
(7), 867.
15. Cardoni A A. (1997). New directions in clinical
psychopharmacology.
595.
16. Dieperink M
E, Drogemuller L. (1999). Zolpidem
for insomnia related to PTSD. Psychiatric Services, 48,
50 (3), 421.
17. Donnelly C L, Amaya
Jackson L, March J S. (1999). Psychopharmacology of paediatric posttraumatic
stress
disorder. Journal of Child and Adolescent
Psychopharmacology, 9 (3), 203-220.
18.Dubovsky S
L. (1994). Beyond the serotonin reuptake
inhibitors: Rationales for the development of new
serotonergic agents. Journal of
Clinical Psychiatry,
55 (2) SUPPL., 34-44.
19. Friedman M J. (1998). Current and Future Drug Treatment for Posttraumatic Stress Disorder
Patients.
Psychiatric Annals, 28 (8), 461-468.
20. Gupta S, Popli
A, Bathurst E, Hennig L, Droney
T, Keller P. (1998). Efficacy of cyproheptadine for
nightmares associated with posttraumatic stress
disorder. Comprehensive Psychiatry, 290, 39 (3), 160-164.
21. Marshall R D, Pierce D. (2000).
Implications of recent findings in posttraumatic stress disorder and the role
of pharmacotherapy. Harvard Review of
Psychiatry, 7 (5), 247-256.
22. Torem, M. S.
(1995). Medication in
the treatment of dissociative identity disorder.
In Spira, J.L. & Yalom,
I.D. (eds) Treating dissociative
identity disorder. The Jossey-Bass
library of current clinical technique, pp.
99-132. San Francisco, Jossey
Bass Inc.
23. Verhoeven W M
A, Marijnissen G, Van Ooy J
M, Tuinier S, Van Den Berg Y W M M,
Pepplinkhuizen L,
Fekkes D. (1999). Dysperceptions and serotonergic parameters in borderline personality
disorders: Effects
of treatment with risperidone. New
Trends in Experimental and Clinical Psychiatry, 15
(1), 9-16.
|
Study |
Study type |
Participants |
Interventions |
Outcomes |
|
Hamner et al (1999) (1) |
Double blind, RCT |
40 patients with PTSD and comorbid psychotic features. Randomly allocated to placebo or treatment group. One participant dropped out of both groups leaving 19 in each group. |
Placebo v ‘flexible dose’ of 2.8 mg +/- 1.7 mg daily for one week. |
Preliminary analysis showed a reduction in psychotic symptoms in terms of PANNS rating (positive and negative symptoms) in the risperidone and not the placebo group and also a reduction in the re-experiencing symptom subscale of the PTSD scale (caps) in the risperidone group. |
|
Krashin and Oates (1999) (9) |
Case series |
1. Female, 38, with PTSD 2. Male, 33, with PTSD |
0.5 mg twice daily increased to 3 mg twice daily 1 mg twice daily then on as-needed basis |
As dose increased reported greater relief from flashbacks and intrusive thoughts. Reported relief from intrusive thoughts and emotional reactions to thoughts. |
|
Monnelly and Ciraulo (1999) (10) |
Case report |
Male, 48, with PTSD |
0.5 mg daily increased to 1 mg daily |
Reported decrease in irritable aggression. |
|
Leyba and Wampler (1998) (11) |
Case series |
1. Male, 47, with PTSD and major depression 2. Male, 43, with PTSD, alcohol dependence and major depression. 3. Male, 45, with PTSD, alcohol dependence and personality disorder. 4. Male, 46, with PTSD and major depression. |
1mg risperidone in addition to other medication. 1 mg risperidone in addition to other medication. 1 mg morning and 2 mg bedtime in addition to other medication. 1 mg morning and 2 mg bedtime in addition to other medication. |
Reported flashbacks stopped after commenced taking risperidone. Reported considerable decrease in nightmares after commenced taking risperidone. Reported significant decrease in nightmares and flashbacks but these returned when patient discontinued medication. Reported ‘dramatic’ decrease in nightmares and flashbacks. |
|
Eidelman et al (2000) (12) |
Case series |
1. Female, 72, with ASD 2. Male, 26, with ASD 3. Male, 50, with ASD 4. Male, 30, with ASD |
1 mg twice daily 1 mg twice daily 2 mg nightly 0.5 mg nightly |
Decrease in symptoms of numbing/avoidance, hyperarousal, insomnia and flashbacks. Decrease in flashbacks and numbing/ avoidance and hyperarousal symptoms. Decrease in symptoms of flashbacks, motor agitation and hypervigalence. Decrease in symptoms of flashbacks, hyperarousal and avoidance/numbing. |
|
Chan & Silove (2000) (13) |
Case series |
1. Male, 402, PTSD and major depression with later persecutory delusions and hallucinations. 2. Male, 49, PTSD with later persecutory delusions and hallucinations. Note: a third patient in this case series did not receive risperidone but was given other antipsychotics. She too developed severe akithisia. |
1 mg daily in addition to other antipsychotics. 1 mg nocte increased to 1 mg twice daily. |
No beneficial effects recorded and patient discontinued treatment because of severe side effects (akathisia). “Marginal relief only from his psychotic symptoms.” On increase of dosage patient developed severe akithisia and refused to continue. |
|
Feeney & Klykylo (1996) (14) |
Case report |
Female, 14, with PTSD, ADDS/hyperactivity disorder, depressive and eating disorders |
Dosage of risperidone not recorded and receiving other psychotropic medication. |
No beneficial effects recorded. The authors report side effects of tardive dyskenesia. |
Appendix A. Search Strategy
PSYCHINFO, MEDLINE, EMBASE, National Centre for PTSD, Cochrane Library, NRR, BIOMED and Science Citation Index databases were searched using the following strategy (EMBASE format).
((risperidone) or (risperidone.af)
or (risperdal) or (risperidal)
or (rispolin) or (belivon)
or (r64766))
AND
((post traumatic stress disorder) or (ptsd) or (post traumatic stress disorder) or (dissociative disorders) or (depersonalization) or (stress
disorder$) or (post-trauma or post trauma) or (flashback) or (fugue) or (derealisation or derealization)
or (dissociative identity disorder) or (personality
disorder) or (psychphysiologic disorder) or (psychophysiologic disorder$) or (somatoform disorder$) or
(somnambulism) or (amnesia) or (hallucination$) or (automatic talk$) or
(automatic writ$) or (dual conscious$) or (duality experienc$)
or (automatism) or (trance-like) or (psychogenic) or (alienation) or (split
personality) or (derealisation) or (dissociative identity disorder) or (multiple personality)
or (eating disorders) or (impulse control disorders) or (somatoform disorders)
or (anxiety disorders) or (consciousness disorders) or (self mutilation) or
(self-injurious beh$))
The strategy identified the following number of studies per database.
Database Number of studies
PSYCHINFO 74
MEDLINE 80
EMBASE 186
National Centre for PTSD 7
Cochrane Database of Systematic Reviews 1
CCTR 1
NRR 0
BIOMED 201
Science Citation Index 0
Taking into account overlaps in the search the total number of identified studies was 396.
The search strategy errs considerably on the side of over-inclusivity and the results were hand searched using the following exclusion criteria, studies that were not primarily about pharmacological interventions or where the intervention was primarily about the treatment of the following disorders: schizophrenia, bipolar or unipolar affective disorder, obsessive compulsive disorder, developmental disorders (e.g. autism), physical trauma (e.g. major head injury), organic brain disease (e.g. Parkinson’s disease), substance abuse, deliberate self-harm, movement disorders (e.g. Tourette's syndrome, tics) and dementia. This dramatically reduced the number of studies to 17 of which 7 studies were included and 10 studies were excluded. The references from all 17 studies were examined for further studies but none were identified.
Appendix B. Table of Included Studies
Study Study Type
Hamner M B, Frueh
B C, Huber M G, Twomey T J, Meason
M O,
Ulmer, H G, Tyson, C, Johnson, R H.
(1999) (2) RCT
Chan A O M, Silove
D. (2000) (13) Case
series
Eidelman I, Seedat S,
Stein D J. (2000) (12) Case
series
Feeney, D J, and Klykylo,
W. (1996) (14) Case
report
Krashin D, Oates E W. (1999) (9) Case
series
Leyba C M, Wampler T
P. (1998) (11) Case
series
Monnelly, E P, Ciraulo, D
A. (1999) (10) Case
report
Appendix C. Table of Excluded Studies
Study Reason for Exclusion
Cardoni A A. (1997) (15) Review of a
range of pharmacological interventions but no specific information on risperidone and stress or dissociative
disorders.
Dieperink M E, Drogemuller
L. (1999) (16) Intervention
not risperidone.
Donnelly C L, Amaya Jackson L, March J S. (1999) Review of a range of pharmacological
interventions for paediatric PTSD. Contains one reference to a case report
already identified in this review. (17)
Dubovsky S L. (1994) (18) A review of
medications that act as serotonergic agents. Refers to risperidone and also the stress disorders but not to risperidone as a treatment for the stress disorders.
Friedman,
M J. (1998) (19) Overview
of pharmacological intervention in PTSD. Refers to anecdotes of encouraging results
for the use of atypical antipsychotics, including risperidone, but contains no details.
Gupta S, Popli A,
Bathurst E, Hennig L,
Droney T, Keller P. (1998) (20) Intervention
not risperidone.
Marshall R D, Pierce D. (2000)
(21) Review
of a range of pharmacological interventions in PTSD, including risperidone, but only includes studies already identified
in this review.
Stein, D J, Zungu-Dirwayi, N, van der Linden, Systematic review of a range of pharmacological
G J H, Seedat S. (2000) (1) interventions for PTSD but no trials of risperidone though one trial is noted as pending (Hamner et al 1999).
Torem, M S. (1995) (22) A book chapter
about pharmacological interventions for dissociative
identity disorders. The
author does include risperidone and states that in
his own and colleagues’ experiences risperidone has
been effective for symptomology also found in stress
disorders, which he describes as “severe flashbacks, and other PTSD intrusive
symptoms, such as severe anxiety, panic and agitation.” Had this professional
opinion been supported by case descriptions it might well have merited
inclusion in this review.
Verhoeven W M A, Marijnissen
G, Van Ooy J M, Participants
not suffering from stress or dissociative
Tuinier S, Van Den Berg Y W M M,
disorders.
Pepplinkhuizen L, Fekkes D.
(1999) (23)