- 1 Uncommon, Predictable, Potentially Serious
- 2 Tardive Psychopathology
- 3 Neuroleptic Malignant Syndrome
- 4 Anticholinergic Side Effects
- 5 Hematological Side Effects
- 6 Hepatic Side Effects
- 7 Related Posts
Uncommon, Predictable, Potentially Serious
Correll, Leutch, and Kane (2004) conducted a meta-analytic review of 11 long-term studies of second generation antipsychotics; their study supports the expectation that atypical antipsychotics have a reduced risk for tardive dyskinesia compared to first generation antipsychotics. This finding was true for children, adults, and particularly, for the vulnerable population of the elderly. In this review no aripiprazole data was included in the analysis.
Based on pooled data from 12 open-label studies and 15 double-blind studies with risperidone (9 lasting 3 months or more, and 7 lasting one year or more), the incidence of tardive dyskinesia was observed to be 0.2% in 878 adults who completed at least three months of treatment, and was only slightly higher (0.3%) when the study was restricted to the seven one-year studies. A shortcoming of this conclusion is that the incidence was extrapolated only from spontaneous reports of adverse events; this most likely represents significant underreporting.
According to Jibson and Tandon (2003), the prevalence of tardive dyskinesia is 0.5% to 1% per year of treatment, for the first line antipsychotic medications, excluding clozapine. That means that the risk for the development of this serious side effect increases with the duration of treatment (increased exposure) to atypicals. To complicate matters, there is not a standard definition of Tourette’s disorder and it has not been studied systematically. There are no systematic studies of Tourette’s disorder in children. Moreover, the incidence of Tourette’s disorder varies according to the nature of the cohort; the incidence is smaller in an antipsychotic naive cohort than in a cohort involving resistant schizophrenics; it is likely that the incidence is less in homogeneous populations by age and diagnostic categories than in heterogeneous populations for diagnoses and age.
In many studies the impact of withdrawal dyskinesia is not discriminated from the unfolding true dyskinesias. This explains why some studies report up to 35.8% of dyskinesia incidence in the placebo group. When olanzapine and clozapine were compared (90 patients in each group), olanzapine had an incidence of Tourette’s disorder of 2.2%, which was significantly higher than clozapine in which no cases were ascertained (p < 0.03). The second generation antipsychotics’ benefits of lower Tourette’s disorder risk are decreased when the doses are increased. This is consistent with the observation that higher doses of second generation antipsychotics are associated with higher incidence of extrapyramidal side effects. Furthermore, acute extrapyramidal side effects and a higher utilization of anticholinergic medications have been associated with an increase risk for Tourette’s disorder.
In adult and elderly patients the incidence of second generation antipsychotics appears to be about one fifth of the risk observed for first generation antipsychotics. It is likely that children and adolescents, who have a higher susceptibility for extrapyramidal side effects, and who potentially have a longer time exposure to these medications, may reveal a higher incidence of Tourette’s disorder. Although the above study indicates that second generation antipsychotics have a lower risk for Tourette’s disorder than first generation antipsychotics, the case is mostly made for risperidone; the data for olanzapine is limited and for the other atypicals is either limited or nonexistent. There is limited data on the long-term quetiapine Tourette’s disorder risk and, of course, it is unknown what will be the impact of the newest atypicals (ziprasidone and aripiprazole) in this regard.
The following vignette illustrates the vicissitudes of a very severe withdrawal dyskinesia that seemed to continue into a tardive dyskinesia syndrome:
Jittery was an 11-year-old Hispanic male with a long history of psychiatric disturbance. He had multiple psychiatric admissions to local psychiatric hospitals. The author first saw him when he was 9 years old. The hospital psychiatric admissions had been precipitated by suicidal and aggressive behaviors. He frequently talked about killing himself, and frequently got involved in fights with his brother. He also had held a knife to his sister’s neck. He used to argue with mother a great deal and had problems minding her. He had a history of multiple suicidal attempts and self-abusive behaviors. There was a long history of impulsivity and hyperactivity. There was an allegation of sexual abuse by a 13-year-old cousin in the past; when Jittery was 9 he reportedly fondled his 5-year-old sister. There was no history of seizures, and a prior EEG had been unremarkable.
Jittery had severe behavioral difficulties at school; he was severely learning impaired and had an obvious speech disorder. Actually, he suffered from a severe mixed language disorder. The presence of aphasia was inferred.
Prior to the first hospitalization and first contact with the author, he was receiving risperidone 8 mg/day and methylphenidate 40 mg q AM, and 20 mg q Noon & q 4 PM. He had been on the high risperidone dose for close to six months. He had also been receiving Neurontin 400 mg BID. At the time of the first psychiatric admission, a history of occasional involuntary movements of the limbs and the tongue was reported.
Risperidone was progressively withdrawn; at about 4 mg/day Jittery displayed conspicuous sniffing and throat clearing, and his hyperactivity and involuntary movements progressively increased. Further tapering of risperidone continued; the hyperactivity remained unchanged, however.
Prior to a subsequent admission he was on Tenex lmg q AM and Noon and 2 mg q HS, risperdal 2mg q HS, and dexedrine 15 mg q AM and Noon. After the readmission, risperidone was discontinued. Involuntary movements became conspicuously worse, then; Jittery displayed severe oral (buccolingual) dyskinetic movements as well as observable facial muscle contractions (blinking, facial gesturing), and gross choreathetotic movements in the upper limbs with associated involuntary movements of the feet. Furthermore, frequent neck and trunk contractions were noticed. The buccolingual movements consisted of frequent tongue darting and licking, and an ongoing movement of the lips and jaw.
This dramatic picture began to fade by the second week; by the third week most of the buccolingual aspects had receded. The choreathetotic movements took a number of months to dissipate. By the sixth month, evidence of an involuntary movement disorder was no longer present. By that time the patient was on high doses of quetiapine, and it was considered that this neuroleptic was camouflaging or silencing the involuntary movement syndrome. It is important to point out that the stimulants tended to increase or make the involuntary movements more noticeable. However, atomaxetine was more benign in this particular regard.
The diagnosis ofwithdrawal dyskinesia had been initially made, butlaterthe diagnosis of Tourette’s disorder was entertained. Since the involuntary movements reappeared every time attempts were made to decrease the neuroleptic (even quetiapine) we considered that the most correct diagnosis was chronic dyskinesia, most likely tardive dyskinesia.
On 600 mg of quetiapine/day, Jittery did not display evidence oforo-buccolingual movements; he was quite fidgety, however. On quetiapine, there was no observable choreathetotic movement of the hands, and no involuntary movement of the feet. Limited trunk and neck movements were still present. His mood was pleasant but continued displaying difficulties with impulsivity and hyperactivity. As stated, stimulant medications were somewhat helpful for the hyperactivity and impulsivity, but tended to increase the involuntary movements. Jittery continued displaying serious impairments in language and in learning, and impulsivity remained particularly problematic.
Further medication changes were implemented: Jittery began to receive atomaxetin 25 mg q AM and aripiprazole 10 mg q AM. On these medications, the child developed a maculo-papular eruption, mainly in the face and in the trunk, with a limited rash in the limbs. Because of the rash all the medications were discontinued for about five days. Since there was a major behavioral deterioration after the medications were discontinued, he was restarted on atomaxetin, 25 mg, for his severe impulsivity and hyperactivity, and ziprasidone 40 mg BID for aggressive behavior and agitation. Due to sedation, ziprasidone was changed to aripiprazole 10 mg BID, later adjusted to 7.5 mg BID. On these medications the impulsivity and hyperactivity came under satisfactory control and Jittery displayed no orobuccal movements, choreathetosis, or any other evidence of a movement disorder. No evidence of involuntary movement disorder was detectable in this child in subsequent follow-ups. After another inpatient admission for violence toward the family, he was involuntarily committed and observed without psycho-tropic medication for about a month; he did not show any evidence of extrapyramidal side effects then. This clinical example puts into question either the concept of irreversibility of Tourette’s disorder in children, or the timetable of reversibility of the withdrawal dyskinesia.
It is likely that the child’s neurodevelopmental background and the prolonged exposure to high doses of risperidone may have contributed to this complication. At a later time, when neuroleptics were discontinued for more than two moths, Jittery showed no evidence of orobuccal dyskinesia or other movement disorders. Unexpectedly, one day, he began to show some involuntary movements again. The psychiatrist was puzzled because Jittery was only supposed to be on atomaxetine, 80 mg/day The psychiatrist reviewed the record carefully and learned that the child was also receiving propanolol 10 mg BID. This medication was discontinued and the movement disorders subsided. In other words, the metabolic interference of atomaxetine brought on by propanolol induced a movement disorder in this child with a diathesis for involuntary movements. Two years later, Jittery remained free from involuntary movement disorders.
A related but different movement disorder is represented by Superman:
This 8-year-old white boy had a long history of aggressive behavior at home and at school. As a result of his violent and psychotic behavior he had undergone multiple psychiatric admissions in the past. His mother reported that he had severe neurodevelopmental difficulties since birth. Actually, the child was “blue and unresponsive at birth.” Superman had delays in the development of milestones and a history of severe expressive language difficulties. He also had difficulties progressing in learning, and from the very beginning of elementary school, he had been provided with special education services. He had received speech therapy and occupational therapy for gross and fine motor deficits. There was no history of seizures. Mother began to notice involuntary movements of the mouth and face other son by the second year of age, long before he started receiving psychotropic medications.
Superman was an engaging and at times endearing blond child who was markedly hyperactive and impulsive. During one of his hospitalizations, he hit peers indiscriminately and even elbowed his psychiatrist in the genital area; he also hit a number of peers in the “privates” (no history of physical or sexual abuse was ever elicited).
One aspect of his behavior was somewhat perplexing: with some frequency, he would go to his room and stay there for long periods of time, and even though he was encouraged to participate in group or other therapeutic activities, he kept to himself. In his room, he stayed quiet, appeared rather placid, and remained isolated and calmed for extendedperiods of time. At those times, he would respond and would engage when prompted.
On one occasion, during a psychiatric hospitalization, when a physician was nearby, Superman displayed seizure activity: he rolled his eyes backward and became unresponsive for a short while. After a number of EEGs, one tracing was conclusive for the presence of bilateral spiking in the temporal and frontal areas. In retrospect, the very short-lived episodes of eye rolling lasting for a few seconds were most likely seizure episodes, with a frontal lobe focus. The described behaviors, however, remained unabated in spite of treatment with valproate, carbamazepine, and oxicarbamazepine.
The mental status revealed an exuberant hyperactive and impulsive child who required ongoing structuring; he was very oppositional and rarely sat down on the designated chair. He displayed overt expressive language and articulation deficits; he had limited vocabulary, and displayed disturbance in the melodic aspects of language, dysprosody
The child was very psychotic: he believed he was Superman and felt he could “burn things with the lava that come from my eyes.” He had tried to fly from high places before. The child adhered to the conviction that he was Superman even when challenged. Every time the examiner expressed disbelief that he was Superman, he would start enacting contortions in the air, and would throw himself to the ground enacting fights, all this to prove to the examiner he was Superman. The child never lost his delusion that he was the man of steel. Not surprisingly, he used a Superman costume for Halloween.
Superman revealed that he heard voices telling him to kill people; he claimed that the voices told him “to hit people in the nuts.” He reported that the voices told him to kill his mother, too. Although, the child was somewhat engaging, his affect was frequently bland and inappropriate. His affect brightened every time he enacted his Superman beliefs. On close observation, he displayed involuntary movements of the mouth, lips, and jaw, and his tongue was very restless. These movements extended to the face, mainly to the lower eyelids and nose. When he was asked to extend the hands with the fingers spread, obvious choreathetotic movements were observed. The examiner also noticed involuntary movements of the neck and trunk. All along, the child displayed generalized fidgeting.
When the psychiatrist called mother’s attention to the involuntary movements, she indicated that the child had problems with these movements from a very early age, and reiterated that the movements had been present before he started receiving psychiatric medications.
Treatment of this child posed challenges on many fronts. Psychopharma-cologically, the child needed stimulant medications, but these worsened the movement disorder (even atomaxetine made the movement disorder worse). This child also needed antipsychotic medications, but those medications also worsened the movement disorder. The seizure disorder did not respond to three antiepileptic medications.
The history indicated that the oro-buccal-lingual and facial movements preceded the exposure to antipsychotic medications. Technically, this child suffered from a chronic dyskinesia, secondary to cerebral palsy. This was not a case of neuroleptic induced tardive dyskinesia.
Rare, Unpredictable, Potentially Serious
Tardive psychopathology is postulated to be more frequent than tardive dys-kinesia. Tardive psychopathology includes psychosis, obsessive-compulsive disorders, or depression. It has been proposed that clozapine’s ability to treat neuroleptic-resistant schizophrenia is due to this medications purported ability to specifically treat tardive psychopathology, in a fashion similar to lithium.
Anticholinergic Side Effects
Common, Unpredictable, Rarely Serious
Anticholinergic effects result from blockade of cholinergic receptors. Blurred vision, dry mouth, sweating, constipation, tachycardia, delayed micturition, exacerbation of narrow angle glaucoma, impaired memory and learning, and dental disease are common anticholinergic symptoms secondary to neurolep-tics, TCAs, and anti-Parkinson medications. More severe anticholinergic toxicity is manifested by seizures, hyperthermia, delirium, central nervous system depression, and coma. Impaired acquisition of new learning is the earliest detectable anticholinergic toxic CNS effect. Dosage increase or cumulative effects of several different anticholinergic medications cause more obvious impairments in attention and cognitive functioning. The proposed anticholinergic side effect ranking for second generation antipsychotics in adults is as follows: Clozapine > quetiapine > olanzapine > risperidone > ziprasidone = aripiprazole.
In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) report, quetiapine was associated with a higher rate of anticholinergic effects than the other medications (olanzapine, risperidone, ziprasidone, perphenazine).
An anticholinergic side effect that often progresses in silence is constipation; this adverse event may advance to fecal impaction and to paralytic ileus. It is easy to overlook monitoring bowel movements. It is not rare for children with unidentified constipation to require evaluation at the emergency room for abdominal pain or symptoms of abdominal obstruction.
Orthostatic hypotension often causes dizziness and rarely, fainting. Atypicals with higher anticholinergic activity cause this side effect more frequently. In children with a normal heart, this symptom maybe inconsequential and simple measures of avoiding rapid standing from a supine or a sitting to a standing position, such as a slow arising to full standing, are sufficient to control this adverse event.
Hematological Side Effects
Uncommon, Unpredictable, Potentially Serious
Agranulocytosis is a well-known and feared clozapine side effect. Changes in blood counts associated with clozapine treatment appear to occur at the same rate in youngsters as in adults. The same hematologic monitoring as in adults is recommended for children on clozapine treatment.
Less known, are the hematological effects of other atypical medications. For instance, olanzapine may induce a dose related leukopenia. Leukopenia has also been reported with risperidone. So far, no agranulocytosis has been reported with either quetiapine, or with ziprasidone. To this day, there is no indication that aripripazole has any untoward hematological side effects.
Leukopenia (WBC < 3,500) associated with conventional antipsychotics is usually transitory; it is rather common but not problematic. Agranulocytosis associated with classical antipsychotics occurs most often during the first three months of treatment with an incidence of 1 in 500,000.
Hepatic Side Effects
Rare, Unpredictable, Potentially Serious
Olanzapine produces an increase in the hepatic enzymes and is potentially more toxic than divalproex. It may also be associated with pancreatitis and with steatohepatitis. Fifty-nine percent of patients taking olanzapine alone, had elevations of alanine aminotransferase, AST, or LDH during the treatment period, whereas 26% of the divalproex alone group showed those elevations; 100% of subjects on a combination of olanzapine and divalproex had these elevations. For 42% of the children on combined olanzapine plus divalproex, the elevated peak hepatic enzymes did not return to normal during the observed course of treatment. For these patients, the mean period of time for which the levels of hepatic enzymes were observed after the peak level was 8 ± 6 months.
In the case of both peak and mean enzyme levels, the hepatic enzyme elevations were less than three times the upper limit of normal range, and did not meet the threshold for heightened concern. Two patients in olanzapine + divalproex experienced severe complications. One patient developed pancreatitis and was lost to follow-up, and the other developed esteatohepatitis which resolved after the discontinuation of olanzapine. The risk of hepatic failure has been estimated as 1/45,000 for divalproex and 1/12,000 for olanzapine. Olanzapine is, then, more hepatotoxic than divalproex. Olanzapine may cause pancreatitis and steatohepatitis. This risk is further increased when olanzapine is used concomitantly with divalproex.
The conclusion is unavoidable: the combination of olanzapine-divalproex increases the risk of hepatotoxicity and should only be used with caution.
When elucidating liver disease secondary to antipsychotics, the psychiatrist will keep in mind that nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), secondary to obesity, need to be ruled out. Currently hepatic disease obesity-related surpasses alcohol-related liver disease. Obese persons who drank more than two drinks a day, had close to a sixfold increase of liver damage risk compared to normal weight persons who did not drink alcohol.
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