Catatonia is a severe but treatable neuropsychiatric syndrome known since the middle of the nineteenth century. It has beenconsidered for a long time as a subtype of schizophrenia, even though this association occurs only in 10% of cases. Incontrast, it is frequently observed in bipolar patients. First-line treatment consists of benzodiazepines, while in case of resistanceelectroconvulsive therapy (ECT) and clozapine have shown positive results. In addition, recent studies reported the efficacy of someatypical antipsychotics. The present case shows the clinical response to augmentative asenapine in a catatonic manic patient with apartial response to clozapine.
1. Introduction
The term Catatonia, coined in 1874 by Karl Kahlbaum, is asevere psychomotor syndrome characterized by the presencefor more than 24 hours of at least two among a list of symp-toms including stupor/immobility, rigidity, excessive motoractivity (purposeless), staring, posturing, and autonomicalterations. Even though catatonia has been considered fora long time a subtype of schizophrenia, this syndrome fre-quently occurs over other conditions including mood disor-ders [1, 2].
According to international guidelines, high dosages ofbenzodiazepines are the first-line treatment for catatonia;Electroconvulsive Therapy (ECT) is to be taken into consid-eration when patients do not respond to benzodiazepines orrapid resolution is necessary [3]. In recent studies, some atyp-ical antipsychotics such as risperidone and olanzapine havebeen successfully used, while clozapine should be reserved toresistant cases [4, 5].
In this paper we report the case of a bipolar catatonicpatientwho showed response to augmentative asenapine afterpartial response to clozapine.
2. Case Presentation
R. was a 46-year-old man, with a 24-year history of bipolardisorder and manic psychotic episodes requiring hospital-ization. The first catatonic episode occurred in 2001 andresponded to high dosages of clozapine (600mg/day) after 6weeks of hospitalization. During the following ten years, thepatient maintained an adequate level of functioning, attend-ing most of daily activities despite of his limited social rela-tionships. Given that the subjective well-being had been con-tinuing for many years, the patient decided to stop assumingclozapine in May 2012. As a consequence, a recurrence of theprevious symptoms occurred, reaching its peak in September2012, when he was admitted to our inpatients service. At theadmission, R. showed euphoric mood, purposeless excessivemotor activation, stereotypedmovements, delusions, and vis-ual/auditory hallucinations that required restraint and urgenthospitalization. The physical examination and routine bloodtests were normal with the exception of a thalassemia trait.
At baseline, the Bush-Francis Catatonia Rating Scale [6]was administered with a total score of 33. Young-Mania Rat-ing Scale (MRS) score was 37 [7]. His first psychopharmaco-logical treatment included risperidone 12mg/day combined
2 Case Reports in Psychiatry
with clonazepam 12mg/day; it continued for five days, andthen the dose of risperidone was decreased to 7mg/day. Inthose days he was considerably sedated and he was not able tospeak clearly, so clonazepam was stopped.
Ten days after admission no improvement in mental statewas noted; R. required continuous restraint to avoid droppingdown. He continued to show psychotic symptoms and psy-chomotor agitation.
Therefore, on the 14th day, risperidone was replaced withzuclopenthixol (45mg/day) and gabapentin was introducedat a dose of 600mg/day in addition to clonazepam 3mg/day;after three days clonazepam was stopped and gabapentin wasincreased to 900mg/day.
During the three weeks of hospitalization, the patientspent his days in bed, often restrained for self-harm risk; thespeech was not spontaneous and he frequently shouted torespond to his hallucinations and presentedmystic delusions.Vitamins B and glucosate were introduced as he did not feedhimself adequately; moreover, in order to prevent throm-bosis, anticoagulant therapy with heparin was administereduntil the 53th day.
In order to improve agitation, impulsivity, and frequenthallucinations presented by the patient, it was planned toadminister olanzapine IM 10mg three times a day sincethe 19th day in combination with valproate (1000mg daily)and zuclopenthixol (45mg daily). After one week olanzapineinjections were substituted with tablets at the same dosage(30mg/day).
None of these treatments were effective. After one monthof hospitalization, the patient was still restrained most ofthe time. Auditory hallucinations and impulsive behaviourpersisted, R. frequently prayed shouting and often hurthimself by falling and hitting the head suddenly with greatconcerns for his health: in order to rule out any cerebral dam-age, a Cerebral Computerized Tomography had been per-formed at every serious downfall of the patient. Fortunately,no brain damage was detected. The interpersonal contactswere reduced and his severe symptoms showed no improve-ment. The Bush-Francis Catatonia Rating Scale [6] score stillremained at 28, while MRS remained at 32.
On the 32nd day, the treatment was changed: olanzapineand zuclopenthixol were stopped and clozapine was intro-duced in combination with valproate. Clozapine was rapidlyincreased from 100 to 800mg/day with a gradual improve-ment of symptoms and restraint was gradually reduced.
Ten days after the introduction of clozapine, valproatewasstopped for its plausible pharmacokinetic interaction withclozapine (an increase in total clozapine metabolites) [8].A reduction of hallucinations and mood improvement wereobserved. The speaking was more fluid and associative linkswere more frequently maintained. In contrast delusions andimpulsivity still remained (MRS = 20).
On the 53rd day, augmentative asenapine was introducedat the dosage of 10mg/day,withMRS scores being unchanged.The clozapine dosage was kept stable. R. showed furtherimprovement in mood, sleep, impulsivity, psychomotor agi-tation, and speech. Delusion and hallucination disappeared.The patient was discharged after ten days with a Bush-Francis Catatonia Scale score of 8 and an MRS score of 9.
+ asenapine 10 mg/day
YMRS = 9
BFCRS = 8
Clozapine 800mg/day
Discharge day 63
+ gabapentin up to 900 mg/day
+ zuclopenthixol 45 mg/day
+ valproate 1000 mg/day
+ clozapine up to 800 mg/day
T0 (baseline)
Clonazepam 12mg/day
Day 14
Stop risperidone
Stop clonazepam
Zuclopenthixol 45mg/day
Day 19
Stop gabapentin
Olanzapine 30mg/day
T1 (day 32)
Stop zuclopenthixol
Stop olanzapine
Valproate 1000mg/day
Stop valproate
YMRS = 32
BFCRS = 28
YMRS = 37
BFCRS = 33
Risperidone 12 mg−→ 7 mg/day
T3 (day 53) −→ YMRS = 20
T2 (day 42)−→ YMRS = 20
Figure 1: Treatment flow chart with related YMRS and BFCRS totalscores.
During the subsequent 3 months, follow-up visits confirmedclinical stabilisation with clozapine 800mg/day and ase-napine 10mg/day. The patient did not develop side effects
Case Reports in Psychiatry 3
nor during hospitalization neither during follow-up period(Figure 1).
3. Discussion
Catatonia is a challenging clinical condition whose etiologyhas not been totally clarified but it involves alteration of sev-eral neurotransmitters (GABA, glutamate, and dopamine) indifferent brain areas [9].
Clozapine appears efficacious in treating catatonic casesfor its broad spectrumof action and lowpotency onD2 recep-tors [10]. In addition, it has been hypothesized that high dosesof clozapine can modulate glutamate neurotransmission [11].In our case clozapine improved catatonic symptoms but itresulted to be less effective in improving rapidly mania and inachieving clinical stabilization. Of note, clozapine is not actu-ally recommended for treatingmanic episodes for lack of evi-dence [12] and this molecule can perhaps worse impulsivityand executive functioning of bipolar patients in light of itsanticholinergic effects [13].
Augmentative asenapine probably was proved to be effec-tive in improving impulsivity and clinical stabilization forabsence of anticholinergic effects and its marked antagonismon D3 and 5-HT7 receptors [14]. Of note, D3 antagonism isthought to be responsible for rapid solution of manic symp-toms,while 5-HT7 antagonism should prevent the switch intoa major depressive episode. In light of these considerations,clozapine plus asenapine combined treatment can be thoughtas a treatment option in case of manic catatonia [15]. How-ever, even though our patient did not develop side effects, anincreased risk for dangerous conditions such as myocarditisor agranulocytosis has to be taken into account [16].
As a delayed efficacy of clozapine independently fromasenapine augmentation has to be taken into account, furtherstudies are needed to support this preliminary evidence aboutthe effectiveness and tolerability of this pharmacologicalcombination.
Disclosure
A.CarloAltamura has served as aConsultant or served on theadvisory boards of Roche,Merck, Astra Zeneca, BristolMyersSquibb, Janssen-Cilag, andLundbeck.M. Buoli is RocheCon-sultant.
References
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