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COMBINED PHARMACOTHERAPY FOR TS AND OCD
LETTERS TO THE EDITOR
COMBINED PHARMACOTHERAPY FOR TS AND OCD To the Editor: Although neuroleptics are frequently used in the treatment of Tourette's syndrome (TS) , these medications are not always effective or well tolerated. The frequent comorbidity ofTS and obsessive-compulsive disorder (OCD), and the possibility that the two disorders are in fact different behavioral manifestations of the same underlying disorder (Pauls and Leckman, 1986), suggests that serotonin reuptake inhibitors (SRIs), which are effective in OCD, may also be useful for the treatment ofTS. Indeed, Riddle et al. (1990) found that Buoxetine was effective for OCD symptoms in three of six children with TS and OCD. Como and Kurlan (1991) found that 81 % of children and adults with TS and OCD reported a subjective improvement in OCD symptoms while taking Buoxetine. A number of other reports suggest that SRIs may be useful for tics in TS patients (Kurlan et al., 1993), although these agents have also been reported to increase tics. Given the complex interactions of dopamine and serotonin in the brain, it would not be surprising if both systems played a role in both TS and OCD. In preclinical paradigms, SRIs decrease dopamine agonist-induced stereotyped behaviors. Furthermore, in clinical trials, obsessions and compulsions in OCD patients with comorbid chronic tic disorders such as TS have been found to respond to neuroleptic augmentation of SRI treatment (McDougle et al., 1994). The question arises as to whether the combination of neuroleptics and SRIs would not be a useful treatment strategy in TS, particularly in patients with comorbid OCD. It might be hypothesized that neuroleptics would be helpful for tics, while SRIs would be helpful for obsessive-compulsive symptoms. On the other hand, concerns have been raised about the safety of this combination of agents. We report on the use of this treatment combination in a series ofTS patients seen in (predominantly pediatric) clinical practice. We undertook a retrospective chart review ofTS patients treated in our (predominantly pediatric) clinic with a combination of neuroleptics and SRIs. Five patients (four males, one female; mean age 15.4 :::'::: 5.7) who met DSM-IV diagnostic criteria forTS had been treated with this combination of agents. Symptoms were rated by the treating clinician using a clinical global impression change score (1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = unchanged,S = minimally worse, 6 = much worse, 7 = velY much worse). Four of the 5 patients had comorbid OCD. Other comorbid DSM-IV diagnoses were attention deficit disorder (two cases), major depressive episode (one case), conduct disorder
J. AM. ACAD. CHIl.D ADOl.ESC. PSYCHIATRY, }":G, JUNE I
(one case), and generalized anxiety disorder (one case). Family history in first-degree relatives was positive for chronic motor tic disorder (three cases), generalized anxiety disorder (two cases), OCD (one case), and alcohol dependence (one case). All four of the patients with TS and OCD had improvement of tics while taking neuroleptic only, but no improvement (three cases) or exacerbation (one case) of OCD symptoms. In all these patients the use of a neuroleptic together with an SRI led to improvement in OCD symptoms. In one case, there was also further improvement in tics. A fifth patient with TS including complex tics, but without classic OCD symptoms, had some improvement of simple tics while taking a neuroleptic only, and exacerbation of tics while taking an SRI only. The combination of a neuroleptic with an SRI was clinically effective, with decrease in a distressing complex tic also. Thus, in our small sample of predominantly pediatric patients, neuroleptics were moderately helpful for tics but not for OCD symptoms. Combined use of a neuroleptic together with an SRI also resulted, however, in improvement in the OCD symptoms (four cases). In some patients, the combination of a neuroleptic and SRI also resulted in further improvement in tics (two cases). Four of the five patients tolerated the combination of neuroleptic and SRI without undue side effects at the doses used. One patient developed urinary retention in her medication regimen. It may be argued that tics are a form of compulsion and would, therefore, respond to an SRI alone. Only one of our patients received an SRI without a neuroleptic. In this particular patient, the SRI resulted in an exacerbation of tics. Such a finding is consistent with previous case reports. However, there are contrasting case reports of SRIs being effective for tics in patients with TS. Nevertheless, the growing evidence that SRIs are useful for OCD symptoms in patients with comorbid TS and OCD suggests that SRIs are primarily effective for OCD symptoms in these patients (Como and Kurlan, 1991; Riddle et al., 1990). Some authors have argued that OCD symptoms in TS patients are really complex tics. However, in our patients, neuroleptics alone were not helpful for OCD symptoms. Indeed in one patient, neuroleptic alone (clozapine) resulted in an exacerbation of OCD symptoms. Exacerbation of OCD symptoms by clozapine has also been noted in previous case reports of OCD patients. It may be postulated that the neurobiological basis for this phenomenon lies in the serotonergic effects of this atypical neuroleptic. A synthesizing hypothesis would argue that TS patients may have comorbid OCD, and OeD patients may have comorbid tics, reBecting a common genetic diathesis (Pauls and Leckman, 1986) and perhaps involvement of both
703
LETTERS TO THE j'D!TOR
the dopamine and the serotonin system in these disorders. Certainly, there is some evidence for dopaminergic involvement in OCD and for serotonergic involvement in TS. Furthermore, addition of neuroleptic to an SRI appears effective in adult OCD patients with comorbid tics (McDougle et aI., 1994). Our findings are consistent with this earlier research. Significant limitations of this study include the lack of adequate controls, the absence of standardized ratings, and the small sample size. The retrospective design further limits the reliability of the clinical ratings. Nevertheless, our results suggest that controlled trials are warranted to assess the efficacy and safety of combining a neuroleptic with an SRI in TS patients, particularly when OCD is also present. Susan Hawkridge, M.B. Dan J. Stein, M.B. Colin Bouwer, M.B. University of Stellenbosch Tygerberg, South Africa Como pG, Kurian R (1991), An open-label trial of f1uoxetinc for obsessivecompulsive disorder in Gilles de laTourette's syndrome. Neurology 41 :872-874 Kurian R, Como pG, Deeley C, McDermott M, McDermott Mp (I993), Apilot controlled study offluoxetine ttlr obsessive-compulsive symptoms in children witb "'ourette's syndrome. elin Neul'Ophrlrmacol16: 167-172 McDougle q, Goodman WK, Leckman JF et al. (I 994), Haloperidol addition in Huvoxaminc-rcfracrory obsessive-compulsive disorder: a dou-
ble-blind placebo-controlled study in patients witb and without tics. Arch C;m Ps)'chiatr)' 51 :302-308
Pauls DL, Leck;nan Ji' (I986), The inheritance of Gilles de la Tourette syndrome and associated behaviors: evidence for
transmission. N Fngl J Med 315:993-996
JI. (1 <)<)()) , Fluoxetine treatment of children and adolescents with Tourette's and
Riddk MA, IIa ..din MT, King Ie Scahill I.S, Woolston
obsessive compulsive disorders: preliminary clinical experience.
J Am
Amd Chi/tl Adolesc Psychiatry 29:45-48
We thought melatonin might benefit children with psychiatt'ic disorders and sleep problems, because it appears to affect the child's biological circadian clock and not stages of sleep. We have successfully treated 20 children with multiple diagnoses on multiple medications, whose disorders preceded their medication use. The length of use of melatonin by these children ranged from 7 to 90 days and in no case was there any breakthrough in which melatonin ceased to be effective. Melatonin was given 12 hours prior to the time the child was supposed to wake up. The standard dose was 3 mg and if it failed, as in one case, it was increased to 6 mg. The concerns about using melatonin with children are the following: Although melatonin is not a prescription drug and is usually found in health food stores, it is not currently FDA-approved as a sleep medication for either adults or children. The purity of melatonin as a compound is important, particularly in view of the fact that I.-tryptophan, an effective sleep aid, had contaminants causing eosinophilia myalgia syndrome. Recent samples of melatonin have shown 95% purity (Dennis Hill, M.D., personal communication). Melatonin could reset the sleep cycle of a child with cyclic mood disorder and so precipitate mania. This did not happen in either of our two cases. It is unclear whether melatonin can be discontinued after several weeks' or months' use. Theoretically, once the biological clock is reset, melatonin supplementation should no longer be necessary. Thus shortterm use of melatonin should restore normal sleep/wake cycles. Finally, it is unknown if there are long-term negative effects from melatonin use. All of these concerns notwithstanding, our clinical experience suggests that perhaps melatonin may be worth studying further as a potential sleep aid for children with psychiatric illnesses. Kim
MELATONIN FOR SLEEP PROBLEMS
10 the Editor: Melatonin, a compound derived from serotonin and made in the pineal gland, is thought to be involved in the organization of the sleep/wake cycles in human beings (Lewy, 1994). People traveling across time zones have used melatonin to reset their biological clocks and diminish jet lag. There has been recent public interest in melatonin's use as a sleep agent in adults (Cowley, 1995). Sleep problems, including difficulty going to sleep and early morning wakening, are common in children with psychiatric disorders. A variety of agents have been used, including clonidine, diphenhydramine, chloral hydrate, and clonazepam. However, they all alter sleep architecture and REM and non-REM sleep.
704
J.
Masters, M.D. Asheville, NC
Cowley G (I995), Melatonin. Newsweek Aug 7, PI' 47-49 Lewy AJ (I 994), Ordering sleep. Audio Digest Psychiatry 23(14):July 15, PI' 1-4 The Letters column is a corner of the journal which encourages opinion, controversy, and preliminary ideas. We especially invite reader comments on the articles we publish as well as issues or interests of concern to child and adolescent psychiatry. The Editor reserves the right to solicit responses and publish replies. All statements expressed in this column are those of the authors and do not reflect opinions of the journal. Letters should not exceed 750 words, including a maximum of 5 references. They must be signed, typed doublespaced, and submitted in duplicate. All letters are subject to editing and shortening. They will be considered for publication but may not necessarily be published nor will their receipt be acknowledged. Please direct your letters to John F. McDermott, Jr., M.D., Editor, journal o/the AACAP, University of Hawaii School of Medicine, Kapiolani Medical Center, 1319 Punahou Street #635, Honolulu, HI 968261032.
J. AM. ACAD. CHILD ADOl.ESC:. PSYCHIATRY, 35:6, JUNE 1996
COMBINED PHARMACOTHERAPY FOR TS AND OCD To the Editor: Although neuroleptics are frequently used in the treatment of Tourette's syndrome (TS) , these medications are not always effective or well tolerated. The frequent comorbidity ofTS and obsessive-compulsive disorder (OCD), and the possibility that the two disorders are in fact different behavioral manifestations of the same underlying disorder (Pauls and Leckman, 1986), suggests that serotonin reuptake inhibitors (SRIs), which are effective in OCD, may also be useful for the treatment ofTS. Indeed, Riddle et al. (1990) found that Buoxetine was effective for OCD symptoms in three of six children with TS and OCD. Como and Kurlan (1991) found that 81 % of children and adults with TS and OCD reported a subjective improvement in OCD symptoms while taking Buoxetine. A number of other reports suggest that SRIs may be useful for tics in TS patients (Kurlan et al., 1993), although these agents have also been reported to increase tics. Given the complex interactions of dopamine and serotonin in the brain, it would not be surprising if both systems played a role in both TS and OCD. In preclinical paradigms, SRIs decrease dopamine agonist-induced stereotyped behaviors. Furthermore, in clinical trials, obsessions and compulsions in OCD patients with comorbid chronic tic disorders such as TS have been found to respond to neuroleptic augmentation of SRI treatment (McDougle et al., 1994). The question arises as to whether the combination of neuroleptics and SRIs would not be a useful treatment strategy in TS, particularly in patients with comorbid OCD. It might be hypothesized that neuroleptics would be helpful for tics, while SRIs would be helpful for obsessive-compulsive symptoms. On the other hand, concerns have been raised about the safety of this combination of agents. We report on the use of this treatment combination in a series ofTS patients seen in (predominantly pediatric) clinical practice. We undertook a retrospective chart review ofTS patients treated in our (predominantly pediatric) clinic with a combination of neuroleptics and SRIs. Five patients (four males, one female; mean age 15.4 :::'::: 5.7) who met DSM-IV diagnostic criteria forTS had been treated with this combination of agents. Symptoms were rated by the treating clinician using a clinical global impression change score (1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = unchanged,S = minimally worse, 6 = much worse, 7 = velY much worse). Four of the 5 patients had comorbid OCD. Other comorbid DSM-IV diagnoses were attention deficit disorder (two cases), major depressive episode (one case), conduct disorder
J. AM. ACAD. CHIl.D ADOl.ESC. PSYCHIATRY, }":G, JUNE I
(one case), and generalized anxiety disorder (one case). Family history in first-degree relatives was positive for chronic motor tic disorder (three cases), generalized anxiety disorder (two cases), OCD (one case), and alcohol dependence (one case). All four of the patients with TS and OCD had improvement of tics while taking neuroleptic only, but no improvement (three cases) or exacerbation (one case) of OCD symptoms. In all these patients the use of a neuroleptic together with an SRI led to improvement in OCD symptoms. In one case, there was also further improvement in tics. A fifth patient with TS including complex tics, but without classic OCD symptoms, had some improvement of simple tics while taking a neuroleptic only, and exacerbation of tics while taking an SRI only. The combination of a neuroleptic with an SRI was clinically effective, with decrease in a distressing complex tic also. Thus, in our small sample of predominantly pediatric patients, neuroleptics were moderately helpful for tics but not for OCD symptoms. Combined use of a neuroleptic together with an SRI also resulted, however, in improvement in the OCD symptoms (four cases). In some patients, the combination of a neuroleptic and SRI also resulted in further improvement in tics (two cases). Four of the five patients tolerated the combination of neuroleptic and SRI without undue side effects at the doses used. One patient developed urinary retention in her medication regimen. It may be argued that tics are a form of compulsion and would, therefore, respond to an SRI alone. Only one of our patients received an SRI without a neuroleptic. In this particular patient, the SRI resulted in an exacerbation of tics. Such a finding is consistent with previous case reports. However, there are contrasting case reports of SRIs being effective for tics in patients with TS. Nevertheless, the growing evidence that SRIs are useful for OCD symptoms in patients with comorbid TS and OCD suggests that SRIs are primarily effective for OCD symptoms in these patients (Como and Kurlan, 1991; Riddle et al., 1990). Some authors have argued that OCD symptoms in TS patients are really complex tics. However, in our patients, neuroleptics alone were not helpful for OCD symptoms. Indeed in one patient, neuroleptic alone (clozapine) resulted in an exacerbation of OCD symptoms. Exacerbation of OCD symptoms by clozapine has also been noted in previous case reports of OCD patients. It may be postulated that the neurobiological basis for this phenomenon lies in the serotonergic effects of this atypical neuroleptic. A synthesizing hypothesis would argue that TS patients may have comorbid OCD, and OeD patients may have comorbid tics, reBecting a common genetic diathesis (Pauls and Leckman, 1986) and perhaps involvement of both
703
LETTERS TO THE j'D!TOR
the dopamine and the serotonin system in these disorders. Certainly, there is some evidence for dopaminergic involvement in OCD and for serotonergic involvement in TS. Furthermore, addition of neuroleptic to an SRI appears effective in adult OCD patients with comorbid tics (McDougle et aI., 1994). Our findings are consistent with this earlier research. Significant limitations of this study include the lack of adequate controls, the absence of standardized ratings, and the small sample size. The retrospective design further limits the reliability of the clinical ratings. Nevertheless, our results suggest that controlled trials are warranted to assess the efficacy and safety of combining a neuroleptic with an SRI in TS patients, particularly when OCD is also present. Susan Hawkridge, M.B. Dan J. Stein, M.B. Colin Bouwer, M.B. University of Stellenbosch Tygerberg, South Africa Como pG, Kurian R (1991), An open-label trial of f1uoxetinc for obsessivecompulsive disorder in Gilles de laTourette's syndrome. Neurology 41 :872-874 Kurian R, Como pG, Deeley C, McDermott M, McDermott Mp (I993), Apilot controlled study offluoxetine ttlr obsessive-compulsive symptoms in children witb "'ourette's syndrome. elin Neul'Ophrlrmacol16: 167-172 McDougle q, Goodman WK, Leckman JF et al. (I 994), Haloperidol addition in Huvoxaminc-rcfracrory obsessive-compulsive disorder: a dou-
ble-blind placebo-controlled study in patients witb and without tics. Arch C;m Ps)'chiatr)' 51 :302-308
Pauls DL, Leck;nan Ji' (I986), The inheritance of Gilles de la Tourette syndrome and associated behaviors: evidence for
transmission. N Fngl J Med 315:993-996
JI. (1 <)<)()) , Fluoxetine treatment of children and adolescents with Tourette's and
Riddk MA, IIa ..din MT, King Ie Scahill I.S, Woolston
obsessive compulsive disorders: preliminary clinical experience.
J Am
Amd Chi/tl Adolesc Psychiatry 29:45-48
We thought melatonin might benefit children with psychiatt'ic disorders and sleep problems, because it appears to affect the child's biological circadian clock and not stages of sleep. We have successfully treated 20 children with multiple diagnoses on multiple medications, whose disorders preceded their medication use. The length of use of melatonin by these children ranged from 7 to 90 days and in no case was there any breakthrough in which melatonin ceased to be effective. Melatonin was given 12 hours prior to the time the child was supposed to wake up. The standard dose was 3 mg and if it failed, as in one case, it was increased to 6 mg. The concerns about using melatonin with children are the following: Although melatonin is not a prescription drug and is usually found in health food stores, it is not currently FDA-approved as a sleep medication for either adults or children. The purity of melatonin as a compound is important, particularly in view of the fact that I.-tryptophan, an effective sleep aid, had contaminants causing eosinophilia myalgia syndrome. Recent samples of melatonin have shown 95% purity (Dennis Hill, M.D., personal communication). Melatonin could reset the sleep cycle of a child with cyclic mood disorder and so precipitate mania. This did not happen in either of our two cases. It is unclear whether melatonin can be discontinued after several weeks' or months' use. Theoretically, once the biological clock is reset, melatonin supplementation should no longer be necessary. Thus shortterm use of melatonin should restore normal sleep/wake cycles. Finally, it is unknown if there are long-term negative effects from melatonin use. All of these concerns notwithstanding, our clinical experience suggests that perhaps melatonin may be worth studying further as a potential sleep aid for children with psychiatric illnesses. Kim
MELATONIN FOR SLEEP PROBLEMS
10 the Editor: Melatonin, a compound derived from serotonin and made in the pineal gland, is thought to be involved in the organization of the sleep/wake cycles in human beings (Lewy, 1994). People traveling across time zones have used melatonin to reset their biological clocks and diminish jet lag. There has been recent public interest in melatonin's use as a sleep agent in adults (Cowley, 1995). Sleep problems, including difficulty going to sleep and early morning wakening, are common in children with psychiatric disorders. A variety of agents have been used, including clonidine, diphenhydramine, chloral hydrate, and clonazepam. However, they all alter sleep architecture and REM and non-REM sleep.
704
J.
Masters, M.D. Asheville, NC
Cowley G (I995), Melatonin. Newsweek Aug 7, PI' 47-49 Lewy AJ (I 994), Ordering sleep. Audio Digest Psychiatry 23(14):July 15, PI' 1-4 The Letters column is a corner of the journal which encourages opinion, controversy, and preliminary ideas. We especially invite reader comments on the articles we publish as well as issues or interests of concern to child and adolescent psychiatry. The Editor reserves the right to solicit responses and publish replies. All statements expressed in this column are those of the authors and do not reflect opinions of the journal. Letters should not exceed 750 words, including a maximum of 5 references. They must be signed, typed doublespaced, and submitted in duplicate. All letters are subject to editing and shortening. They will be considered for publication but may not necessarily be published nor will their receipt be acknowledged. Please direct your letters to John F. McDermott, Jr., M.D., Editor, journal o/the AACAP, University of Hawaii School of Medicine, Kapiolani Medical Center, 1319 Punahou Street #635, Honolulu, HI 968261032.
J. AM. ACAD. CHILD ADOl.ESC:. PSYCHIATRY, 35:6, JUNE 1996