Attending physician’s mental notes: 48-month follow-ups

This patient now has failed three atypical antipsychotics (risperidone, olanzapine, quetiapine), two typical augmentations (thiothixene, perphenazine), one typical antipsychotic monotherapy (perphenazine) at therapeutic doses, and yet his psychosis continues

His prognosis now seems guarded as he is in another psychotic episode, and despite more aggressive treatment, his psychosis continues

He has developed EPS, TD, and anticholinergic side effects, thus tolerability is becoming problematic

He was taken out of work as his symptoms could cause a danger to self or others on the assembly line, which has put more stress on the family financially

This is now a risky, complicated, and treatment-resistant case

Question

What would you do next?

Continue to try a new monotherapy every one to two years as new atypical antipsychotics are approved and released to the market

Use typical antipsychotics from different chemical families. Thus far, a thioxanthene (thiothixene) and a phenothiazine (perphenazine) have been tried. Consider a butyrophenone (haloperidol), dibenzoxazepine (Loxitane), or other chemical family

Clozapine (Clozaril) is often more effective than other antipsychotics and can be used in more refractory cases or those with problematic movement disorders complicating treatment

Case outcome and multiple interim follow-ups to 48 months

The patient elects to take clozapine (Clozaril)

This trial escalates to 400 mg/d where side effects become problematic

• – Sedation ruins his quality of life

• – He developes enuresis

• – He begins drooling. At night, he chokes and aspirates

This agent is lowered to a better tolerated 300 mg/d, albeit with subtheraputic levels (<0.3 mg/L)

This prescriber obtained an informal consultation via email at this point to discuss refractory schizophrenia treatment options with two well-published colleagues in order to better delineate future treatment options for this patient

Clozapine is now augmented with the typical antipsychotic loxapine (Loxitane) from the dibenzoxazepine chemical family up to 200 mg/d for a few months

• – Psychosis is less but still fluctuates

• – EPS continues but is treated with benztropine (Cogentin) 1–3 mg/d

• – TD is not apparent

• – EKG is obtained and shows some nonspecific changes and a slightly increased QTc that is not alarming but must be monitored

A newer version of clozapine (Fazaclo) is released

• – It utilizes a dissolving oral preparation tablet with some preliminary evidence of less sedation and drooling effects

• – It replaces the patient’s usual clozapine tablets but without a clinical or side-effect difference

• – Psychosis continues

Weight gain now becomes problematic

• – 30 lbs of AAWG occurs gradually

• – Laboratory results are monitored and now suggest increased blood glucose levels (100–120 mg/dL), which is consistent with DM2

• – Prophylactically takes metformin (Glucophage) 1000 mg twice a day to lower his weight and keep blood glucose levels down

• – Lipid triglyceride levels later increase (200–250 mg/dL) and are controlled with omega-3-acid ethyl esters (Lovaza) 4 gm/d

Clozapine is discontinued as ineffective and unable to be tolerated much past the therapeutic 300 mg/d dose

Loxapine (Loxitane) is tapered off as ineffective

Ziprasidone (Geodon) is started and ultimately dosed above approved levels to 200 mg/d

• – Is not effective

• – EKG shows cardiac changes (QTc prolongation above 450 ms) and he has clinical palpitations and dyspnea

• – It is stopped

Paliperidone (Invega) is approved and tried next

• – Approved dose of 12 mg/d is not effective

• – Blood levels are measured now and are low despite excellent compliance

• – It is super-dosed to 18 mg/d

  • Plasma levels are obtained and found to be comparable to 12 mg risperidone

  • There is no antipsychotic response

• – EPS continues and requires ongoing benztropine (Cogentin), which at 3 mg/d is moderately effective but dry mouth and constipation are problematic

Asenapine (Saphris) is approved and the patient is switched to this agent and titrated to approved 10 mg twice a day sublingual dose, to no avail

• – 30 mg/d super-dosing is tried, also without psychosis relief

Iloperidone (Fanapt) is approved and is administered next as monotherapy

• – Half-way through usual titration there is marked fatigue and orthostasis, thus it is discontinued

• – QTc was elevated, which would have limited further titration

• – Interestingly, his weight began to decrease with use of the last three atypical antipsychotics as clozapine was no longer being utilized

Most recently, patient was placed on the latest atypical antipsychotic approved, lurasidone (Latuda) 40 mg/d

• – This was titrated to 120 mg/d, which was the highest approved dosing at the time, but without effect

• – It was next dosed to 160 mg/d without result

• – He continued on low-dose benztropine (Cogentin) for mild EPS

• – Since switching off olanzapine (Zyprexa), quetiapine (Seroquel), and clozapine (Clozaril), his weight, blood glucose, and lipids normalized

  • He lost his 30 lbs of AAWG

  • He does not require metformin

  • His EKG is normal

  • He does not have TD