1. Dr. Peter Chan, MD, FRCPC Geriatric and Consult-Liaison Psychiatrist and Head of ECT Program, Vancouver General Hospital. Clinical Associate Professor, Dept. of Psychiatry, University of British Columbia.

2. Learning Objectives  To review symptoms and signs of catatonia including lethal catatonia.  To know the overlap between catatonia and neuroleptic malignant syndrome.  To understand the role of ECT in both catatonia and neuroleptic malignant syndrome

3. Case Presentation-1: Ms. A  68 y.o. Italian independent woman, some command of English, on Thioridazine (Mellaril) for 49 years, since last institutional admission.  History of Psychosis, postpartum.  No family psychiatric history  Brief hosp. In 1990’s at SVH after Thioridazine briefly D/C’d...hysterectomy  Widow in 2002, lives alone in house, Gr. 5 education, restaurant worker, supportive 2 sons,1 dtr., brother and sister

4. Case Presentation-2: Ms. A  June 2007 Loxapine 25 mg bid after stop Mellaril in May 2007 Labile, energetic, little sleep, racing thoughts Smelling bad odours in home Paranoid, carrying knife, throwing items in frustration “Confused”, disorganized, suicidal VGH Inpt Unit via emergency (June 10-July 18) ○ Dx: Bipolar Disorder ○ Olanzapine 15 mg qhs ○ Trazadone 100 mg qhs ○ Clonazepam 0.25 mg/d

5. Case Presentation-3: Ms. A  Short-term Assessment and Treatment (STAT) Geriatric In Unit (Aug 23, 2007) Had been seen at STAT Dayprogram Incontinent with urinary retention Switched from Olanzapine to CPZ 250 mg/d by community psych. Dependent on IADL’s 3MS=72/100; FMMSE=24/29

6. Case Presentation-4: Ms. A  STAT In-Unit (Aug 23-Sept 14) Mood labile, insomnia Alternates between singing at night and weeping in daytime, playing opera Some pressure of speech ○ Dx: Bipolar, mixed state ○ Epival 750 mg/d ○ Quetiapine 100 mg qhs

7. Case Presentation-5: Ms. A  Sept 15-28, 2007: Home Hypomanic in Dayprogram Increased home support Compliant with Epival (level=498), mixing up blister packed meds? Son called emergency mental health services on Sept 25: threaten him with a knife “leave me alone”, crying continually, plays loud opera music in the phone, looking for a new partner, hostile and throwing things, isolate from family Quetiapine up to 175 mg/d

8. Case Presentation-6: Ms. A  VGH Psych Emerg. and STAT (Sept 28-Nov 5) Seroquel increased to 350 mg/d, multiple IM doses in Psych Emerg. Seclusion room. Oct 3: ○ Mood labile ○ Demanded to see her husband, anniversary party ○ Sad...join husband, tearful, tangential, speak loud ○ Physically aggressive ○ Grandiose “I’m God. Don’t touch me...kill you” ○ Sleeping 2 hrs. ○ 3MS=49/100; FMMSE=18/30 ○ Clonazepam 2 mg/d, Seroquel, Epival (level = 571)

9. Case Presentation-7: Ms. A  Oct 31: Feel dizzy, speech different, tremor, headache CPK=37, WBC=8000, Valproic level=660  Nov 2: 3 hrs/nt sleep past 2 nts Paranoid, hypervigilant Fine resting tremor (no cogwheeling) “Nothing inside”, Perseverate: “blood, blood, blood” Resistance to food, labile mood

10. Case Presentation-8: Ms. A  Nov 2-5: Meds: ○ Epival 875 mg/d, Seroquel 350 mg/d, Clonazepam 2 mg/d “Can’t see”, “Can’t swallow”, more tremor, disorganized Antipsychotic prn’s LoxapineSeroquel Nov 2525 Nov 317.525 Nov 41025

11. Case Presentation-9: Ms. A  Nov 5: Perseverate: “blood, blood, blood” Thinks food is poisoned Pacing, Didn’t sleep ○ CPK= 18,245 (normal < 230) ○ WBC= 12,400 (normal < 11,000) ○ T= 37.4 ○ BP = 170/90 (not labile) ○ PR = 120

12. Case Presentation-10  What is your diagnosis?  What is the differential diagnosis?  What is your next step?

13. Case Presentation-11 : Ms. A  Nov 5-7: Nov 5: ○ Transfer to Acute Medicine Step Down: NMS? ○ Antipsychotics stopped Nov 6: “lead pipe rigidity”, Dantrolene Nov 7: Bromocryptine added, Desat 80% O 2 Transfer to ICU after code blue (aspiration LLL) ○ EEG: Mild slowing left side ○ Troponin 0.53 (normal < 0.10) TemperatureCPKWBC Nov 537.418,24512,900 Nov 636-38.212,21013,900 Nov 737. 2335415,800 Nov 838.36668100-14,600 Nov 937.34718800

14. Case Presentation-12: Ms. A  Nov 8-12 (ICU): Nov 8: Midazolam drip, no clonazepam, stop Epival. Nov 9: ○ Repeat EEG Mild diffuse encephalopathy, intermittent slowing ( 1-3 Hz delta) ○ CT head Nil acute changes Nov 12: ○ Rigidity, voluntary component, Rabbit-like jaw tremor

15. Case Presentation-13  What is the next step?

16. Case Presentation-14: Ms. A  Nov 12: BT ECT initiated in ICU (rocuronium used) Hypotension, bolus helped  Nov 13-Dec 6 (ICU then Acute Medicine Unit) BT ECT’s times 9, 50% energy dosing Slow improvement in alertness, rigidity, speech Tremor and “rabbit” jaw movements gone Smiling, recognizing family Feeding tube but eating some Transferred to Provincial Institution from STAT on Dec 10 for further treatment…

17. Catatonia: DSM-IV criteria  Motor immobility as evidenced by catalepsy (including waxy flexibility) or stupor;catalepsy  Excessive motor activity (purposeless, not influenced by external stimuli);  Extreme negativism (motiveless resistance to all instructions or maintenance of a rigid posture against attempts to be moved) or Mutism;  Peculiarities of voluntary movement as evidenced by posturing, stereotyped movements, prominent mannerisms, or prominent grimacing  Echolalia or Echopraxia. EcholaliaEchopraxia A. At least 2 of the above features B. Due to mental (eg: Schizophrenia or Mood Disorders) or medical disorder C. Does not occur exclusively during the course of a Delirium *Gegenhalten, Mitgehen, Automatic Obedience, Ambitendency Fink Catatonia Scale (1996): www.ukppg.org.uk/catatonia.html

18. Catatonia: Phenomenology-1  Posturing Spontaneous maintenance of posture (s), including mundane (e.g. sitting or standing for long periods without reacting). ○ Limb posturing ○ “Psychic pillow” ○ Staring

19. Catatonia: Phenomenology-2  Rigidity Maintenance of a rigid position despite efforts to be moved, exclude if cog-wheeling or tremor present  Negativism Apparently motiveless resistance to instructions or attempts to move/examine patients. Contrary behaviour, does exact opposite of instruction.  Waxy Flexability During reposturing of patient, patient offers initial resistance before allowing himself to be repositioned, similar to that of a bending candle.

20. Catatonia: Phenomenology-3  Gegenhalten Continuous involuntary sustained muscle contraction When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched.  Mitgehen "Anglepoise lamp" arm raising in response to light pressure of finger, despite instructions to the contrary.

21. Catatonia: Phenomenology-4  Ambitendency Patient appears "motorically stuck" in indecisive, hesitant movement.  Automatic Obedience Exaggerated cooperation with examiner's request or spontaneous continuation of movement requested.

22. Lethal Catatonia (Kahlbaum 1874) Mann et al., Amer. J. Psych. 1986; 143:11, p. 1374-81  Classic description (Pre-neuroleptic era): Intense motor excitement followed by hyperthermia and exhaustion or stupor Often prodromal phase of insomnia, anorexia, labile mood May demontrate catatonic signs, and be delirious-like (disorganized thinking, psychosis, destructive) May have rigidity, or flaccidity, in terminal stages Presence of acrocyanosis in some Fatal in 75-100%

23. Lethal Catatonia  Post-neuroleptic era: Stupor may be predominant presentation Antipsychotics, benzo’s, etc. can decrease excitement Up to 10% inpatient psych. admission? Fatal in 60%?

24. Neuroleptic Malignant Syndrome: DSM-IV criteria A. Development of severe rigidity and elevated temperature associated with the use of neuroleptic medication B. 2 of the following: diaphoresis, dysphagia, tremor, incontinence, change LOC, mutism, tachycardia, elevated or labile BP, elevated WBC or CPK (may also observe myoclonus) C. Not due to another substance, or neurological disorder, or other general medical condition D. Not better accounted for by a mental disorder

25. NMS and Medications  Antipsychotic medications  Withdrawal of L-Dopa or dopamine agonists  Prochlorperazine (Stemetil)  Metoclopramide (Maxeran)  Tetrabenanzine (Nitoman)

26. NMS risk factors  Exhaustion and Dehydration  Agitation, Stress, Psychosis  Higher potency, rapid titration, multiple I.M.’s  Environmental heat a factor?  Previous history (trait vulnerability?) 17% hx. of NMS 30% will develop NMS again upon re-challenge

27. NMS: Pathogenic Mechanisms Figure 1. Simplified Pathophysiology of Neuroleptic Malignant Syndrome (NMS), and Elements of Sympathoadrenal Dysregulation From: Strawn J. Neuroleptic Malignant Syndrome (review). Am J Psychiatry 164:870-876, June 2007

28. ItemSachdev NMS Scale (2005): total=36SubtotalScore Oral temperature0123456____ Rigidity0123____ Dysphagia01____ Resting tremor012____ Systolic BP01____ Diastolic BP01____ Tachycardia01____ Diaphoresis01____ Incontinence01____ Tachypnea01____ Altered LOC0123456____ Posturing01____ Poverty of speech01____ Mutism012____ Choreiform01____ Dystonia01____ CK level (U/L)01234____ Leucocytosis012____

29. CK level (U/L):< 200rate “0” 200–400rate “1”(0 if i.m. injection in previous 24 h) 400–1000rate “2”(1 if i.m. injection in previous 24 h) 1000–10,000rate “3” > 10,000rate “4” Sachdev NMS Rating Scale: CK Levels (Psych Res. 2005)

30. NMS Course  0.2% of patients  16% develop within 24 hrs of exposure  66% develop within 1 week of exposure  Virtually all by 1 month of exposure  63% recover within 1 week of elimination  Virtually all recover by 1 month of elimination  Should wait 2 weeks at least after recovery before re-challenge with antipsychotics  10-20% mortality rate  Few have persistent catatonic and/or parkinsonian state (Caroff, S. J. Clin. Psychopharm. 2000)

31. NMS Treatment: Information  Neuroleptic Malignant Syndrome Information Service (NMSIS): 24 hr. Hotline for professionals: 1-888-667-8367 www.nmsis.org Information: 1-888-776-6747 Non-profit clinical and research group—Drs. Caroff, Mann, Campbell (U. Penn)

32. NMS: Catatonic and Non-Catatonic Lee JW, Aust NZ J. of Psych. 2000; 34(5): 877-8  Antecedent Catatonia may predispose to catatonic NMS  Non-catatonic NMS more likely preceded by severe EPS and delirium

33. NMS and Catatonia: Similarities  Appearance of catatonic symptoms in NMS  Appearance of rigidity and hyperthermia in (lethal) catatonia  Treatment with Lorazepam in NMS (Francis A. CNS Spectrum 2000) and Catatonia can improve  ECT effective in both  N=292 Lethal Catatonia patients from 1960 (Mann S. Am J Psychiatry 1986; 143:1374-1381) Unable to distinguish from NMS in 22%

34. NMS and Catatonia: Differences  Extreme (lead pipe) rigidity uncommon in catatonia  Stereotypic signs of catatonia unusual in NMS  Excitement then hyperthermia pre-neuroleptic in lethal catatonia; rigidity then hyperthermia post- neuroleptic in NMS  Potentially effective treatments for NMS (dopamine agonists, dantrolene) less proven in catatonia

35. Similar Conditions: DDx  Malignant Hyperthermia  Anticholinergic Delirium  Heatstroke  Manic Delirium  Serotonin Syndrome  Abusable alcohol or drug withdrawal (eg: delirium tremens) and intoxication (eg: Ecstasy)  Status epilepticus and other CNS conditions  Systemic Conditions: infection, hyperthyroidism, pheochromocytoma, adrenal cortical abnormalities, other causes of rhabdomyolysis (eg: collapse)

36. Catatonia  In the modern era, the most likely psychiatric cause for catatonia is Bipolar Disorder, esp. Mania More likely when severe mania Kahlbaum, Bleuler, Kraepelin all noted mood disturbance preceding catatonia From: Taylor MA, Am J Psych 2003

37. Prevalence of Catatonia and Mania From: Taylor MA, Am J. Psych 2003

38. Pathogenic Mechanisms: Catatonia  Neurochemical substrates: D2 antagonists can worsen catatonia GABA-B, 5-HT1A agonists promote catatonia GABA-A, 5-HT2A, NMDA agonists reduce catatonia  G. Northoff (2000): www.bbsonline.org/documents/a/00/00/22/44/bbs00002 244-00/bbs.northoff.htm 54 page paper “Top Down Modulation”: subcortical and cortical circuits reciprocally connect More GABA-mediated, rather than D2 mediated

39. From: Northoff 2000

40. Modulation in Catatonia From: Northoff 2000

41. The Frontal Lobes and its Connections From: Northoff 2000

42. Catatonia and PD: Differences GABA (lorazepam) - Gaba-ergic mediated neuronal inhibition in medial orbitofrontal cortex - Modulation of functional and behavioral inhibition NMDA (Amantadine) - Down-regulation of glutamatergic-mediated overexcitation in prefrontal and orbitofrontal-parietal pathways - Down-regulation of glutamatergic- mediated overexcitation in subcortical pathways Dopamine - Top-down modulation of striatal D-2 receptors predisposing for neuroleptic-induced catatonia -Compensation for striatal D-2 receptor deficit with "normalization" of "bottom-up modulation CatatoniaParkinson

43. Catatonia Treatment: Review of Lit. Hawkins et al., Int. J. Psych. Med. 1995; 25(4): 345-69  N=178, 1985-1994 published cases  Benzo’s effective in 70% (Lorazepam)  ECT effective in 85%  Antipsychotics effective in 7.5%, or may even worsen symptoms (neuroleptic- induced catatonia)

44. Catatonia: Treatment  Rule out medical condition  Lorazepam 1-12mg/day, up to 72hrs. Trial Specific GABA-A agonist  Dantrolene to be considered if rigidity  ECT is treatment of choice  May consider mECT if recurrent  Others: Atypical Antipsychotic? (not for lethal catatonia) Amantadine? Memantine?

45. NMS Treatment: Biological  Discontinue Antipsychotic Drug  Supportive Medical Treatments  Mild to Moderate NMS: Bromocryptine 2.5-5 mg q8h (up to 30mg/d) Amantadine 100mg q8h (to 200-400mg/d) May use Benzo (eg: Lorazepam 1-8 mg/d)  Moderate to Severe NMS: Dantrolene IV 1-2.5mg/kg (1mg/kg q6h) ECT (bilateral, may even be daily)

46. NMS and ECT: Review of Lit. Trollor and Sachdev, Aust.NZ J. of Psych 1999; 33:650-59  45 published cases from 1966, and 9 new cases  Catatonia manifested in 76% of cases  63% complete and 28% partial recovery with ECT  Onset of ECT response average 4 treatments, generally by 6 treatments  4 cases of cardiovascular complications  Supports the use of succinylcholine unless familial malignant hyperthermia—only one case of hyperkalemia following ECT for NMS

47. NMS and ECT: Potential Use  Trollor and Sachdev: Severe NMS Differental between NMS and catatonia uncertain Psychotic depression is the underlying disorder Catatonia predominates in NMS

48. Catatonia Treatment Algorithm Filip Van Den Eede et al. European Psychiatry 2005

49. Conclusions  It can be difficult to differentiate NMS and catatonia in practice, and definitive treatments are similar  Use of antipsychotics with less dopamine blockade is probably less likely to produce NMS and less likely to be severe, according to the dopaminergic hypothesis  Both NMS and catatonia can be safely and effectively treated with ECT, providing precautions are considered