References

1. Biederman J. The evolving face of pediatric mania. Biological Psychiatry 2006; 60 901–22. Baumer FM, Howe M, Gallelli K et al. A pilot study of antidepressant-induced mania in pediatric bipolar disorder: characteristics, risk factors, and the serotonin transporter gene. Biol Psychiatry 2006; 60: 1005–123. Dickstein DP, Milham MP, Nugent AC et al. Frontotemporal alterations in pediatric bipolar disorder. Arch Gen Psychiatry 2005; 62: 734–414. Stahl SM, Mood Disorders, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 453–5105. Stahl SM, Antidepressants, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 511–6666. Stahl SM, Aripiprazole, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 45–50

Patient FileThe Case: The young man whose dyskinesia was prompt and not tardive

The Question: What is the cause of a profound and early onset movement disorder in a young man who just started a second generation atypical antipsychotic?

The Dilemma: How can you treat the psychotic illness without making the movement disorder worse?

Pretest Self Assessment Question(answer at the end of the case) Which of the following has the least risk of causing movement disorders?

A. Clozapine (Clozanil)

B. Olanzapine (Zyprexa)

C. Paliperidone (Invega)

D. Quetiapine (Seroquel)

Patient Intake 21-year-old male with a three-year history of psychotic illness arrives with his mother and sister

Chief complaint: “I’ve been misdiagnosed as schizophrenia”

He believes that medications do not help and that they cause movement disorders

Psychiatric HistoryPremorbid and Prodrome According to his mother and sister, premorbidly he was shy, introverted, and bright

He began behaving strangely at age 17 or so

He thought that the cable installation man was spying on him

He would say tangential things in the middle of a conversation and would inappropriately smile

He began to complain of the inability to sleep yet felt sleep deprived

Eventually he stopped going to classes and dropped out of school

He came to believe that his mother and father were evil, and that:– His mother commits voodoo with Hillary Clinton, who communicates with her through a voice chip in the mother’s brain– His mother eats good food with Hillary Clinton and cooks bad food for him and for others– His father molested him as a child and communicates with Robert DeNiro via a voice chip in his father’s brain

The patient was told these things via a voice chip in his own head, through which his favorite professor speaks to him

First Psychotic Break When he was nearly 19 he had an outburst in which he became violent and was yelling, shoving, pushing, and slapping

His parents called the police and he was hospitalized for three days, diagnosed with schizophrenia, and prescribed olanzapine (Zyprexa) 12 mg/day, to which he responded

He attended one semester of college, with good grades and good behavior, while gradually tapering his medication over several months

Second Hospitalization Two months after discontinuing medication he relapsed and was rehospitalized after an episode during which he shoved, pushed, and screamed that his food was poisoned

He initially refused medications but was then court-ordered to take medication for one week, after which he was released but not stabilized

He immediately stopped his medications upon returning home and became violent with screaming and threatening behavior

Third Hospitaliztion and Onset of Movement Disorder He was rehospitalized and initially treated with olanzapine, but seemed not to respond and so was switched to aripiprazole (Abilify) and then to paliperidone (Invega) 12 mg/day

Over the following several months he did not have overt symptoms of psychosis and was not talking about his delusions or hallucinations, but did have an increasing number of anxiety attacks

During that time his paliperidone dose was gradually decreased, with the ultimate dose being 3 mg/day

Despite reduction of paliperidone dose, he experienced noticeable muscle spasms, tremor, leg twitching, abnormal arm posture, neck spasms, and torticollis

After three months on paliperidone 3 mg/day he stopped his medications, thinking he was fine

What do you think about his movement disorder?

So far, sounds like drug induced extrapyramidal symptoms (EPS)

This is already tardive dyskinesia

Seems like a reaction to high dose paliperidone that has not yet resolved with dosage reduction

Hysteria

Bizarre postures of schizophrenia, not caused by antipsychotics

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation Too early for tardive dyskinesia,

Very unlikely to be due to hysteria or to bizarre postures of a psychotic illness

Seems likely to be an EPS in a patient who is very sensitive to high doses of paliperidone, and has not yet resolved with dosage reduction, which can take weeks or months in the vulnerable

Psychiatric History, ContinuedFourth Hospitalization and Worsening of Movements Two days after discontinuing his medication he was fully delusional with his usual symptoms, and called the police several times claiming he was being abused

He also called an ambulance several times because he believed he was having panic attacks, but was not hospitalized

He reported rush of thoughts, his eyes freezing and moving backwards into his head to stare at the back of his brain, tremor, and feeling that his heart would stop when he breathed

At this point he was hospitalized, voluntarily, for the fourth time

He took medication but refused all laboratory testing

He was discharged on paliperidone 12 mg during the day and quetiapine (Seroquel) 400 mg at night

Switched as an outpatient to olanzapine 10 mg at night, plus paliperidone 12 mg during the day to reduce psychotic symptoms, but many positive symptoms persist

Added benztropine (Cogentin) 0.5 mg for movement disorder without any response

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation, Continued Sounds like he had an old-fashioned oculogyric crisis

These were described with conventional antipsychotics but rarely if ever with second generation atypical antipsychotics

Very few EPS likely with quetiapine; also few on this dose of olanzapine, so probably caused by paliperidone

Why is he so sensitive to paliperidone?

Is the combination of paliperidone plus quetiapine causing too much dopamine D2 receptor blockade for him?

Is he a poor metabolizer or does he for some reason have disproportionately high blood levels of his antipsychotics even though paliperidone is not metabolized by CYP450 2D6?

Seems like a motor reaction well out of proportion to what would be expected for these drugs at these doses

Does he have an underlying extrapyramidal disorder as well as schizophrenia, or early onset Huntington’s disease or similar condition?

Social and Personal History Attended one semester of college between his first and second hospitalizations

Non smoker, denies drug and alcohol abuse including no marijuana

Lives at home, few friends, no dating

No notable activities outside the home since dropping out of college before his second hospitalization

No competitive employment

Medical history Thin, low normal BMI

BP, routine labs including fasting glucose and trigylcerides normal

Has been refusing venepuncture for over a year

Family history Maternal uncle: schizophrenia

Patient Intake Patient states, “I have a chip in my brain. It tells me I was starved in Romania before I was age 2 and came to the United States”

He admits to a three-year history of delusions and hallucinations but believes that medications do not help, yet cause horrible movement disorders

He has no insight into his illness and is adamant that he does not have schizophrenia; he believes that his current treating doctor is evil because he medicates him

He wants to live independently but is on social security disability and Medicare

He is not currently suicidalMovement DisorderHe displays torticollis to the right with an abnormal stooped posture with dystonic axial toneHe also has abnormal bizarre dystonic arm postures and frequent playing finger movements, like playing a piano keyboard constantlyThere are no oral, buccal, lingual, masticatory, or facial dyskinesias noted

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation, Continued Clearly a psychotic illness, probably schizophrenia as this runs in the family

However, now his movement disorder presents with signs both of acute EPS (stooped posture), dystonias, and finger dyskinesias more characteristic of long-term treatment and tardive dyskinesia

Could be due to another illness, but treatment emergent with paliperidone, so most likely drug-induced

Which of the following strategies would be your top priority?

Send him to a neurologist for a movement disorder evaluation

Send him for a genetic test for Huntington’s Disease

Do a brain MRI and EEG and lumbar puncture

Maintain his medications unchanged in order not to jeopardize what response he is having nor worsen his movement disorder

Adjust his medications in order to try to achieve a greater antipsychotic response as the top priority

Adjust his medications in order to try to reduce motor side effects even if this jeopardizes his antipsychotic response and risks rehospitalization

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation, Continued This situation feels like being between a rock and a hard place (i.e., whatever you do for his psychosis may be bad for his movement disorder and vice versa)

His current medication regimen seems to be causing an unusually disproportionate set of movement disorders; this is most likely attributable to paliperidone as they originated during paliperidone treatment

Over the long-term he is at risk for tardive dyskinesia or tardive dystonia if he does not have one of these already

It is therefore best to switch him to a different medication regimen soon or else he risks permanent disfigurement

So now, how do we have our cake and eat it, too (i.e., improve psychosis as well as current movement disorder while reducing risk for long-term complications of tardive dyskinesia)?

Which of the following would you do?

Convert him to intramuscular depot paliperidone every 4 weeks

Discontinue current medications and switch him to risperidone (Risperdal)

Discontinue paliperidone and maintain olanzapine but at a higher dose

Discontinue current medications and switch him to another second generation atypical antipsychotic, either quetiapine (Seroquel), ziprasidone (Geodon, Zeldox), aripiprazole (Abilify), asenapine (Saphris), iloperidone (Fanapt), or lurasidone (Latuda)

Discontinue current medications and switch him to clozapine (Clozaril)

Discontinue current medications and switch him to a conventional antipsychotic

Attending Physician’s Mental Notes: Initial Psychiatric Evaluation, Continued Because of the patient’s movement disorder, it may not be best to switch him to either a conventional antipsychotic or risperidone (paliperidone, which is causing his movement symptoms, is the active metabolite of risperidone)

High-dose monotherapy with an agent associated with less risk of movement disorders may be the best option for this patient

Increasing the dose of olanzapine to as much as 40 mg/day may be efficacious if tolerated

High-dose quetiapine (800–1000 mg/day) may be efficacious if tolerated

High-dose aripiprazole (20–30 mg/day) may be efficacious (but previous trials of lower doses of aripiprazole have not been deemed successful for this patient and aripiprazole can be associated with akathisia)

High doses of asenapine (>20 mg/day) have not been studied and may not be well absorbed due to the need for sublingual administration. Note this agent can cause some EPS

High doses of iloperidone (>24 mg/day) have been studied somewhat and this agent reportedly has low incidence of EPS and thus might be a consideration if olanzapine fails

Lurasidone is a new agent just released but has controlled date up to 160 mg/day

Because he has a history of nonadherence and a somewhat irregular diet, ziprasidone may not be a good choice as a monotherapy (it must be taken twice per day with food and can have erratic absorption), but could be used to augment his current olanzapine dose

In theory, clozapine may be an excellent choice for this patient as it may help his psychosis more than the other medications and has least risk of movement disorder; however, this is not a feasible choice unless he becomes compliant with laboratory testing

Supplementary doses of benzodiazepines for sleep and/or during the day for agitation may be helpful in keeping the doses of any psychotic lower

Case Outcome: First Interim Followup, Week 12 Family returns for reevaluation

Patient’s doctor angry that family came for the initial evaluation here, and thus refuses to change medications other than to raise olanzapine dose to 20 mg

Movements persist, and patient is slightly sedated without robust improvement in residual psychotic symptoms

Family told by treating doctor that changing paliperidone will mean rehospitalization and that the movements cannot be avoided

Also, treating doctor does not think neurological evaluation or other tests are necessary

Family told by him that treating the psychosis and avoiding hospitalization is the priority

Family then asked at the current visit whether this was an acceptable treatment plan for them, or if they wanted to change treating doctors and pursue a plan to treat the movement disorder as well as the psychosis

Family agrees to change medications and referred to another psychiatrist in their town

Patient remains without insight, denying psychosis, refusing blood tests, having continued delusions about poisoning but not having aggressive behavior

Movements continue unabated and unchanged from before

Recommended trial of high dose olanzapine (if necessary), while discontinuing paliperidone, or high dose quetiapine

Case Outcome: Second Interim Followup, Week 24 Family returns for another reevaluation

New physician tried up to 40 mg/day of olanzapine, with improvement in delusions, but worsening of motor restlessness plus new onset of sedation, little or no weight gain

Did not monitor fasting triglycerides

Paliperidone reduced to 3 mg/day but lower doses trigger recurrent agitation and acting out

Now on 600 mg quetiapine XR plus 3 mg paliperidone with benztropine 0.5 mg daily

Not as well controlled in terms of delusions and occasional aggressive behavior now, compared to high dose paliperidone

Movements appear slightly better but are still dramatically abnormal, especially the torticollis

What would you do?

Leave well enough alone

Increase quetiapine further

Try to get him to take clozapine

Trial of iloperidone

Neuropsychological testing for early dementia, or Huntington’s or other disorder

Neurological evaluation

Attending Physician’s Mental Notes: Second Interim Followup, Week 24 Clozapine, potentially the best option, is not feasible due to lack of patient cooperation with venepuncture

Although the dose of the possible offending agent paliperidone has been reduced from 12 mg/day to 3 mg/day, it does not seem further dose reduction of this agent can be accomplished unless another agent is added or current dose of quetiapine is increased

Recommended to slowly increase quetiapine without dose reduction of paliperidone over 4 to 12 weeks, up to 1000 mg/day, and then slowly decrease paliperidone by 0.5 mg per week over 6 weeks

For now, discontinue benztropine as the dose is too low to be effective and an adequate trial of this agent should await discontinuation of paliperidone

Neuropsychological evaluation seems prudent for many reasons, both to assess psychosis and cognition, and to get a baseline for the future; family agrees

Monitor weight and also fasting triglycerides in 8 weeks

Case Outcome: Third Interim Followup, Week 36 Now off paliperidone, on quetiapine XR 900 mg qhs

Some sedation but psychosis better now despite discontinuing paliperidone

However, no improvement in movements

Case Debrief Movement disorders can become permanent and are disfiguring; patients with movement disorders should have their medication regimens adjusted to minimize such side effects if possible

Long term, movements will impair adherence

This patient must be extraordinarily sensitive to EPS even from second generation atypical antipsychotics

Quetiapine is probably the best option other than clozapine, for an antipsychotic that should not exacerbate his movement disorder, assuming that it is a powerful enough antipsychotic for him

Some patients may require doses above 900 mg/day of quetiapine for adequate control of psychosis although these doses are poorly studied

Although this patient has been off high doses of paliperidone for several months and off all paliperidone for several weeks, his movements are not improving

However, this is still a relatively short period of time since it can take many months for the effects of antipsychotics on motor symptoms to wash out and thus there is every possibility that he will improve in the coming months if he can remain off paliperidone

His dystonias, including his torticollis, are the most worrisome because they may represent tardive dystonia

Tardive dystonia can be very difficult to treat and can become permanent

If medication washout of the paliperidone in the next months does not lead to improvement of dystonias, high dose benztropine can be considered

Local injections of botulinum toxin, especially for neck muscles in torticollis, can be effective in improving this problem as well

Reconsideration of a neurological condition such as Huntington’s disease may be necessary

Take-Home Points Although EPS and tardive dyskinesia have remarkably diminished since the introduction of second generation atypical antipsychotics, these conditions have not entirely been eliminated, especially in vulnerable individuals and with certain drugs

Paliperidone and risperidone may be more likely to cause EPS than some other agents in the class

No pharmacogenetic test yet exists to predict who is most vulnerable to these complications

This patient had the rapid onset of movement disorders, including both a probably reversible form of EPS (rigidity and restlessness/akathisia) and also a possibly irreversible form of tardive dyskinesia/tardive dystonia (finger movements, torticollis, arm postures) despite being given second generation atypical antipsychotic agents

It is nevertheless the duty of the treating psychopharmacologist to attempt to control psychosis while not inducing movement disorders such as this, even though that can be a considerable therapeutic challenge

Performance in Practice: Confessions of a Psychopharmacologist What could have been done better here?– Would better liaison with the original treating psychiatrist other than just an exchange of a written consultation have led to more rapid implementation of this plan without the delay and disruption of finding another treating psychiatrist?– Would more rapid conversion to an antipsychotic other than paliperidone have improved movement disorders?

Possible action item for improvement in practice– Early involvement of movement disorder experts– Early neuropsychological evaluation– Better support of the family in their heroic efforts to help this patient throughout multiple hospitalizations, medication complications and disruptive changing of physicians

Tips and Pearls Movement disorders can still occur with second generation atypical antipsychotics and take a potentially malignant form, such as dystonias, early in treatment

Quetiapine or clozapine may be the treatments of choice in such patients

Not only is there evidence that clozapine may not cause EPS, but over long treatment periods, may actually improve tardive dyskinesia

It can take a long time for the maladaptive effects of an antipsychotic on the motor system to wear off, presumably via potentially reversible re-adaptations of dopamine D2 receptors in the nigrostriatal pathway

There are theoretical concerns and actual data to suggest that acute EPS may predict chronic tardive dyskinesia; therefore, abolishing acute EPS is a priority and may help reduce the onset of irreversible tardive dyskinesia/dystonia, especially in a patient as seemingly vulnerable as this one to the movement disorder complications of antipsychotics

Two-Minute Tute: A brief lesson and psychopharmacology tutorial (tute) with relevant background material for this case – Tardive dyskinesia and D₂ receptors

Figure 1: The nigrostriatal pathway is theoretically unaffected in untreated schizophrenia.

Figure 2: Blockade of D2 receptors in the nigrostriatal pathway by an antipsychotic agent can prevent binding of dopamine to its postsynaptic receptors and thereby cause motor side effects, called extrapyramidal symptoms or EPS. This can include acute dystonias such as torticollis and oculogyric crises, such as this patient experienced.

Figure 3: Tardive Dyskinesia and Tardive Dystonia. Long term blockade of D2 receptors in the nigrostriatal pathway(or even shorter term blockade of D2 receptors as in this case) theoretically causes upregulation of those receptors, which may lead to a hyperkinetic motor condition known as tardive dyskinesia, characterized by facial and tongue movements (e.g., tongue protrusions, facial grimaces, chewing) as well as quick, jerky limb movment and distal extremity movements, such as the finger movements this patient experienced. Although this patient did not have classical facial dyskinesias, his acute dystonias were converting into chronic dystonias, with the fear that these represented tardive dystonias and would become potentially irreversible. The upregulation of the D2 receptors may be the consequence of the neuron’s futile attempt to overcome drug-induced blockade of its dopamine D2 receptors. In some cases this may lead to classical oro-buccal-facial tardive dyskinesia, and in other cases tardive dystonia in vulnerable individuals.

Posttest Self Assessment Question: Answer Which of the following has the least risk of causing movement disorders?

A. Clozapine

B. Olanzapine

C. Paliperidone

D. Quetiapine

Answer: A