Dysphoria Associated with Neuroleptic Withdrawal in an Adolescent with Tourette's Disorder

Chief Complaint and Presenting Problem

B. is a 13-year-old adolescent boy with Tourette's disorder (TD) referred by his university hospital-based developmental pediatrician for consultation regarding difficult-to-treat tics.

History of Present Illness

Parents report that B. had a long history of motoric hyperactivity, inattention and inability to sit still in class since early in the primary grades. At school, parents report B. was forgetful, disorganized and uncooperative. Parents report that B. became angry, shouted and cried easily when asked to do things. In the past, B. was described as having tantrums occurring nearly daily when he was frustrated. B. was diagnosed with attention-deficit/hyperactivity disorder (ADHD) in first grade; he was subsequently referred for a special education assessment and placed in a special education setting. Parents denied that B. had a previous history of mood, anxiety or obsessive-compulsive symptoms.

B. developed the onset of tics at around age 6 or 7 years; the first symptoms were shoulder-shrugging movements, followed by lateral lip movements and facial grimaces. The symptoms had a waxing and waning course. B. subsequently developed loud shouting sounds, and mother sought treatment at a hospital center where he was diagnosed with TD. Brief trials of atomoxetine followed by haloperidol were reported to be ineffective.

Parents report that they brought B. to another hospital center at age 8 for a second opinion. At this point, B.'s shouting had become louder and he had developed coprolalia that became more apparent both at home and at school. B. was treated by a neurologist for two years; medication trials included clonidine for one month, and risperidone, guanfacine and pimozide (up to 3 mg twice per day (b.i.d.)). Parents reported that only guanfacine had been somewhat helpful, but over time it seemed to lose effectiveness, and it also caused sedation. At one point, mixed dextroamphetamine salts was added for ADHD symptoms, but was discontinued after his tics increased.

B. was hospitalized at age 10 years for self-injurious behavior including banging his head against the wall, and forcing objects including pencils and forks down his throat in attempt to suppress his frequent vocal tics. It was reported by the school that B. had been growing increasingly upset regarding his inability to control his tics, and he was subject to teasing by his peers. Parents indicated that these behaviors were triggered in school after the teacher asked him to do something he did not want to do. During his hospital evaluation, clonidine was initiated, and increased to 0.1 mg orally (po) four times per day (q.i.d.) before discharge.

At age 10, B. and his parents were subsequently referred for participation in an open-label aripiprazole study for children with TD. Tics observed at baseline for this study included 4+ intensity, 2–3+ frequency shouting and snorting vocalizations and coprolalia of the “f” word, 1–2+ motor tics of shoulder shrugs and facial grimaces. Full Kiddie-Schedule for Affective Disorders and Schizophrenia (KSADS) diagnostic interview confirmed the diagnoses of moderately severe TD, and ADHD. Clonidine was tapered with full discontinuation which was associated with an increase in the frequency of tics. Aripiprazole was started and titrated to the final dose of 1.25 mg po b.i.d during the study period with a significant improvement in tic severity.

B. continued at this dose under the care of a pediatric neurologist. The developmental pediatrician assumed his care when he was age 11 years. Aripiprazole had been discontinued after about a year because of reported loss of efficacy, and haloperidol had been started. Under the care of the developmental pediatrician, B. had been treated with haloperidol 2.5 mg po b.i.d. and benztropine 1 mg po b.i.d. for at least a year.

Nevertheless, parents reported that B. continued to have loud vocal tics, including cursing, shouting out, spitting, and motor tics of upper arm jerks, stomping, and truncal movements. B. reported that he felt that the haloperidol made his tics “worse;” parents indicated that he was not always taking the medication for this reason. Parents also reported that B.'s grades at school declined over the last trimester, which his teachers reportedly related to the increase in vocal tics. B. reported being teased by his peers at school for his tics.

Upon initial referral for consultation, B.'s haloperidol had been increased to 3 mg po b.i.d.; benztropine 1 mg po b.i.d. was continued, and clonidine 0.1 mg po b.i.d. had been added several months earlier to address a spitting tic and hyperactivity. Parents reported that the tics had generally decreased somewhat in frequency on this medication regimen. B. continued to demonstrate vocalizations of high-pitched sounds and coprolalia, and motor tics of right shoulder movements. In a subsequent visit, B. and his parents agreed to participate in a study which required washout of haloperidol, and his developmental pediatrician began to taper the dose of haloperidol in preparation.

Benztropine 1 mg po b.i.d was continued while haloperidol was reduced to 2 mg po b.i.d., and clonidine increased to 0.1 mg three times per day (t.i.d.) (to address breakthrough tics on haloperidol taper). As haloperidol was gradually tapered, B. demonstrated an increase in the frequency of his tics, including coprolalia and spitting. The worsening of his tic symptoms was also associated with anxiety symptoms, which intensified around being teased by his peers and feeling embarrassed.

On the Yale Global Tic Severity Scale (YGTSS) upon presentation, B.'s total tic score was 41, with tic-related impairment 40, and global severity score 81, indicating moderate to severe tics and tic related impairment. The medication taper and washout, which included haloperidol, clonidine, lorazepam and benztropine, took place over several weeks. During the taper, B. demonstrated worsening of his motor and vocal tics.

In addition, parents reported worsening mood and anxiety symptoms; B. was described as having frequent crying spells and feelings of sadness during the medication taper. His mood was reported to be rather labile, and his teachers described him as being in “anguish.” Parents expressed concern that the situation would become worse over the ensuing two weeks prior to treatment with the study drug. Given the clinically significant distress that B. experienced during the washout period and off his medications, he was withdrawn from the study.

Past Psychiatric History

There is no other past psychiatric history, and B. did not receive behavioral treatment for tics. There is no history of suicidal ideation or self-injurious behavior prior to his inpatient hospitalization. B. began individual therapy with a social worker through the Tourette Syndrome Association at age 13.

Developmental History, Including Pregnancy, Birth and Infancy

B. is the product of an 8 month pregnancy, complicated by emotional problems and gestational diabetes. B. was born weighing almost 11 lbs. B.'s mother was diagnosed with diabetes during the pregnancy. B.'s developmental milestones were described as within normal limits for language and motor, except for delay in tying his shoes.

Educational History

B. attended public school throughout his life and currently is in seventh grade. He has been in a special education placement since the first grade for his diagnosis of ADHD.

Social History

B. is described as having friends, and enjoys video games, karate and basketball.

Family History

B. currently lives with his parents and his two siblings. B. has two other siblings who reside outside the country. Parents denied a history of physical or sexual abuse.

There is no known family history of tics, TD, obsessive-compulsive disorder (OCD), or mood and anxiety disorders.

Medical History

B. is receiving medical care through a pediatrics clinic. He is followed by both pediatrics and endocrine clinics for nutritional counseling given that he has gained weight, but has not been able to adhere to a diet.

There is no history of head trauma, accidents or seizure disorder. There is no history of cardiac, pulmonary, gastrointestinal, or endocrinologic illness. As a young child, B. had an appendectomy without complications. B. experienced frequent ear infections in early childhood with right ear conductive hearing loss as a sequela.

B. was evaluated by a geneticist at age 7 without findings of a genetic syndrome. B. has had mild elevations in liver function tests dating back to age 9, possibly related to medication exposure.

B. had experienced one episode of streptococcal pharygnitis at age 10, without significant increase in tics or anxiety, and was treated with cephalexin.

He started wearing dental braces at age 12, but was not always compliant with proper diet or dental care.

An ECG, echocardiogram and MRI of the head done in the past were described as within normal limits.

B. has had seasonal allergies for which he has been treated with intranasal steroids, but has no allergies to food or medications

Medication History

B. has an extensive medication history, but unfortunately there is little information available regarding dosage and duration. He was initially started on atomoxetine for ADHD symptoms at age 6 which was reported to be ineffective. He was later then switched to haloperidol for tics, which was also felt to be ineffective. Other brief trials in the past included clonidine, risperidone, and pimozide (up to 3 mg b.i.d.). Guanfacine was introduced at age 7 and dextroamphetamine salts were added to address ADHD symptoms. Apparently, the stimulant was discontinued due to exacerbation of tics, and guanfacine maximized to 4 mg per day. Per mother's report, both clonidine and guanfacine were very sedating.

Most recently, B. had been taking haloperidol 2.5 mg po b.i.d. and benztropine 1 mg po b.i.d. for several months prior to referral for consultation.

Mental Status Examination on Presentation to the Clinic

B. was evaluated with his mother in the room. He was a neatly dressed and overweight boy who looked a bit younger than his age of 13. He was pleasant and cooperative. His gait was normal. No abnormal facies were noted. Vocal tics were noted to be of 4+ (0–4 scale) intensity and 2+ frequency and characterized by shouting. Truncal movements, including leg stretching and occasional 1+ frequency, 1+ intensity stomping were also noted. Spitting with 1+ frequency, 1+ intensity was notable toward the end of the interview. B. was not able to identify a premonitory urge prior to the motor or vocal symptoms. He offered little spontaneous speech, but did indicate he understood the conversation. He often covered his mouth when shouting or spitting, and seemed embarrassed and upset about the tics. His thought process was linear, concrete and goal directed. He denied depressed mood and his affect was full and reactive. He denied suicidal and homicidal ideation, and further denied perceptual disturbances including auditory and visual hallucinations. There were no obsessions or compulsions. Insight was good; judgment was fair but impulse control was poor.

Severity Ratings (Instruments)

The YGTSS was notable for total tic score of 41, tic-related impairment of 40 and a global severity score of 81 (Leckman et al. 1989). The Children's Yale-Brown Obsessive Compulsive Scale (CYBOCS) was 0 (Scahill 1997). Review of past K-SADS indicated diagnoses of Tourette's disorder and sub-threshold ADHD (Kaufman et al. 1996).

Brief Formulation

In summary, B. is a 13-year-old adolescent boy referred by the pediatric service for a history of moderate to severe TD requiring one hospitalization to manage his tics. By history, he also appears to display symptoms of ADHD, but does not meet full diagnostic criteria currently.

There is no known family history of tics, TD, or OCD. Medical history contributes seasonal allergies, frequent past serous otitis media with mild right conductive hearing loss, streptococcal pharyngitis without association with onset or exacerbation of tics or anxiety, overweight, and an appendectomy in early childhood.

From a developmental perspective, B. was on a healthy trajectory until the onset of tics, which resulted in a decline in academic and social functioning, and complications associated with medication, including increased appetite and weight gain.

On the positive side, B. has a strong support network including teachers at school and his family who are seeking to optimize his care.

Multi-Axial Diagnoses

Discussion

This is an interesting case report of an adolescent who experienced de novo onset of clinically significant dysphoria and anxiety during a systematic taper and discontinuation of haloperidol. B. became acutely more anxious and dysphoric during the taper. The dysphoria was specifically characterized by anxiety, sadness, and crying spells that were not associated with a specific other precipitant.

Caine and Polinsky first reported in 1979 emergence of sudden, pronounced dysphoric states in association with haloperidol treatment in patients with TD, despite significant reduction of tics (Caine and Polinsky 1979). Symptoms observed in 3 of 72 individuals on haloperidol included sadness, crying, and loss of energy. The authors report that the notable change in mood was not related to the presence of extrapyramidal side effects, and appeared to be dose-related. None of these patients had a history suggestive of affective disorder prior to treatment with haloperidol. The dysphoria improved with dose reduction. In 1981, Mikkelsen and colleagues described 15 patients with TD who developed school and work avoidance syndromes when treated with low dose haloperidol (mean 2.5 mg/day); the phobic syndromes disappeared with discontinuation or dose reduction (Mikkelsen et al. 1981). Linet coined the term “neuroleptic separation anxiety syndrome” in 1985 to characterize patients who developed refusal to attend school (school phobia) during treatment with pimozide, a neuroleptic similar to haloperidol in its D2 dopamine blocking properties (Linet 1985). Bruun (1988) reported that in a sample of 208 children with TD treated with neuroleptic medication (haloperidol is the most commonly used), 34 manifested dose-related symptoms of dysphoria or depression, 9 experienced worsening of TD symptoms attributed to akathisia, and 5 became hostile and aggressive (Bruun 1988). Symptoms reported included crying spells, irritability, social withdrawal, anxiety and fearfulness. Bruun found that a “threshold” dose could be identified, below which, symptoms of dysphoria disappeared. Silva and colleagues reported in patients with TD treated with haloperidol, the principal adverse effects that led to discontinuation included dysphoric reactions, akathisia, nervousness, sedation, dystonic reactions, and cognitive dulling (Silva et al. 1996). More recently, in 2002, Margolese and colleagues reported that 17 of 58 patients (29.3%) with TD developed major depressive disorder (MDD), and 13 patients (22.4%) became dysphoric while taking risperidone. Nine of the 17 patients who developed MDD had relapses, ie, patients with a history of depression prior to taking risperidone became depressed, while the remainder were new cases. Depression and dysphoria were also frequent reasons for risperidone discontinuation in TD patients (Margolese et al. 2002).

In addition, dysphoric responses have also been observed in schizophrenic patients on chronic neuroleptic treatment, and have been implicated as the cause for treatment non-adherence, poor clinical outcome, increased suicidality and compromised quality of life (Emerich and Sanberg 1991; Gilbert et al. 1995; Voruganti and Awad 2004b). It has been suggested that changes in mood state on neuroleptic medication is due to alteration of dopamine-mediated neurotransmission through D2 receptor blockade in the mesolimbic dopaminergic (DA) pathway. Impaired dopamine function, specifically in the nucleus acumbens and prefrontal cortex, is believed to give rise to dysphoria (Voruganti and Awad 2004; Voruganti and Awad 2004b); adverse subjective experience with neuroleptics may be related to higher D2 receptor occupancy in striatal areas (Mizrahi et al. 2007).

Our case of an adolescent with TD demonstrates an acute onset of dysphoria following discontinuation of haloperidol, which has not been previously reported in the literature, and is in contrast to these earlier case reports and studies of both TD and schizophrenic patients. It is possible that dysphoria syndromes upon neuroleptic withdrawal, related to blockade of D2 DA antagonists in the mesolimbic pathways, might be a component of the well-known phenomenology of tardive or withdrawal emergent syndromes reported in youth on neuroleptics related to blockade of these receptors in the nigrostriatal pathways, such as withdrawal emergent dyskinesias, dystonias, and choreoathetosis (Mejia and Jankovic 2010).

It is also possible that these dysphoria symptoms in B., as a young adolescent, may represent a prodrome of a future mood or anxiety disorder which has yet to declare itself. In addition to OCD, ADHD and explosive outbursts, it is known that major depressive and bipolar symptoms are common in TD patients (Comings and Comings 1987). In a recent study of outcome of a clinical sample of older adolescents with TD, Gorman and colleagues (2010) reported that nearly two third of older adolescents had a lifetime diagnosis of MDD, independent of comorbidity with ADHD or OCD, which might be expected to render these patients more vulnerable to depression. The authors suggested that depression could be inherently linked to TD, independent of the burden of chronic illness (Gorman et al. 2010). Our case may suggest a biological link of dysphoria and depression in TD patients that extends beyond the dysphoric effects of neuroleptic treatment.