Psychotic Depression and the Psychotic Depression Assessment Scale (PDAS)

Psychotic Depression and the Psychotic Depression Assessment Scale (PDAS) Psykiatriveka, Stavanger, March 15 th 2019 Søren Dinesen Østergaard, MD PhD Professor Aarhus University Hospital - Psychiatry Denmark Email: soeoes@rm.dk

Agenda What is psychotic depression? Clinical manifestation (typical delusions/hallucinations) Why (I) study psychotic depression Is psychotic depression a distinct entity? Does the distinction (non-psychotic/psychotic) matter? Treatment of psychotic depression Rating scales and psychometrics (case: HAM-D 17 ) The Psychotic Depression Assessment Scale (PDAS) Questions

International Classification of Disease (ICD-10) Criteria for Unipolar Psychotic Depression Core symptoms: 1. Depressed mood 2. Loss of interest or pleasure 3. Decreased energy Accompanying symptoms: 1. Loss of confidence and self-esteem 2. Self-reproach /inappropriate guilt 3. Thoughts of death or suicide 4. Diminished ability to think/concentrate 5. Agitation or retardation 6. Sleep disturbance of any type 7. Change in appetite Severe unipolar depression: - 3 core symptoms and minimum 5 accompanying symptoms* - Duration at least 2 weeks - No underlying organic cause - No previous epsiodes of hypomania, mania or mixed symptoms Severe depression with psychotic features (F32.3 & F33.3): - Meets criteria for severe unipolar depression - Presence of - Delusion - Hallucination - Stupor Mood-congruent / Mood-incongruent - Does not meet criteria for schizophrenia/schizoaffective disorder * Note: If important symptoms such as agitation or retardation are marked, the patient may be unwilling or unable to describe many symptoms in detail. An overall grading of severe episode may still be justified in such a case. ICD-10 criteria, Geneva, 1994

Typical delusions in psychotic depression Themes: guilt, punishment, disease, death, poverty, nihilism & apocalypse We are bankrupt and will end up living on the street I have made a mistake at work my company will not survive My newborn will not breastfeed because I am evil and my milk is toxic The water pipes under the house are leaking and the foundation is crumbling The roof construction is infested by termites My bowel movements have stopped and my intestines are rotten My heart no longer beats and the blood stopped flowing in my veins My wife and children are dead I am dead Patients do not necessarily act on their delusions, but when they do, the consequences can be extremely grave (suicide, extended suicide, homicide, filicide)

Psychotic depression & Suicide Suicide attempts: Completed suicides: Specific delusions and suicide attempts:

Hallucinations in psychotic depression Often linked to the delusions: - Reproaching voices - Sees deceased relatives - Smells rot/cadavers (e.g., from himself/herself) - Ekbom s syndrome (delusion of infestation) Psychotic depression vs. Delusional depression

Why I study Psychotic Depression? Aalborg Psychiatric Hospital Rothschild AJ. Clinical Manual for Diagnosis And Treatment of Psychotic Depression. American Psychiatric Publishing, Inc. Washington DC, USA 2009.

A distinct entity? 1. Clinical presentation 2. Biology 3. Delimitation from other disorders 4. Specific heritability 5. Course and prognosis (6. Treatment response) Robins & Guze, 1970 Robins E, Guze SB. Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia. Am J Psychiatry 1970; 126: 983-987.

1. 2. 3. Clinical presentation Biology Specific heritability Psychotic symptoms Psychomotor disturb. Cognitive problems Diurnal variation HPA-axis dysregulation activity of DβH = Corticosteroid-dopamine hypothesis for PD Heritability in depression heritability in PD Familial aggregation in PD Maj M, Pirozzi R, Magliano L, Fiorillo A, Bartoli L. Phenomenology and prognostic Significance of delusions in major depressive disorder: a 10-year prospective follow-up study. J Clin Psychiatry 2007; 68: 1411-1417. Schatzberg AF, Rothschild AJ, Langlais PJ, Bird ED, Cole JO. A corticosteroid/dopamine hypothesis for psychotic depression and related states. J Psychiatr Res 1985; 19 Maj M, Starace F, Pirozzi R. A family study of DSM-III-R schizoaffective disorder, depressive type, compared with schizophrenia and psychotic and nonpsychotic major depression. Am J Psychiatry 1991; 148: 612-616. 4. 5. 6. Delimitation from other disorders Diagnostic criteria Psychotic symptoms Quality of the psychosis Episodic vs. chronic Course & Prognosis Recurrence rate Psychosocial impairment Mortality Risk of suicide Treatment response Placebo Antidepressants Combination AD+AP ECT Rothschild AJ. Clinical Manual for Diagnosis and Treatment of Psychotic Depression. American Psychiatric Publishing, Inc. Washington DC, USA 2009. Coryell W, Leon A, Winokur G, Endicott J, Keller M, Akiskal H, Solomon D. Importance of psychotic features to long-term course in major depressive disorder. Am J Psychiatry 1996; 153: 483-489. Rothschild AJ. Clinical Manual for Diagnosis and Treatment of Psychotic Depression. American Psychiatric Publishing, Inc. Washington DC, USA 2009. Østergaard SD et al. Considerations on the ICD-11 classification of psychotic depression. Psychotherapy and Psychosomatics. 2012;81:135 144

.But it s so rare why bother? Prevalence: - Among patients with major depression = 15% 1 - Among inpatients with major depression = 25% 1 - Among elderly inpatients with major depression = 40% 1 Under-diagnosted: - 27% of patients diagnosed with non-psychotic major depression at four large university hospital departments met criteria for psychotic depression 2 Under-treated: - Approximately 50% of patients diagnosed with psychotic depression do not receive adequate doses of antidepressants and antipsychotics 3 1. Rothschild AJ. Clinical Manual for Diagnosis and Treatment of Psychotic Depression. American Psychiatric Publ., Inc. Washington DC, USA 2009. 2. Rothschild AJ et al. Study of Pharmacotherapy of Psychotic Depression. Missed diagnosis of psychotic depression at 4 academic medical centers. J Clin Psychiatry 2008; 69: 1293-1296. 3. Andreescu C et al. Persisting low use of antipsychotics in the treatment of major depressive disorder with psychotic features. J Clin Psychiatry 2007; 68: 194-200.

Does the distinction matter?

Georgios Petrides et. al The outcome of an acute ECT course in 253 patients with nonpsychotic (n=176) and psychotic (n =77) unipolar major depression was assessed in the first phase of an ongoing National Institute of Mental Health supported four-hospital collaborative study The overall remission rate was 87% for study completers. Among these, patients with psychotic depression had a remission rate of 95% and those with nonpsychotic depression, 83%. Improvement in symptomatology, measured by the HRSD, was more robust and appeared sooner in the psychotic patients compared with the nonpsychotic patients.

Charles H. Kellner et. al - A score of 3 or 4 on the HAM-D suicide item = Suicidal ideas, gestures or outright attempts at suicide. - 3 ECT sessions per week

Venlafaxine Quetiapine (375 mg/day, 600 mg/day) vs. Venlafaxine (375 mg/day)

What do the guidelines say? *** First line choice when severe suicidality or a threatening somatic condition is present

And psychiatrists do?

Primary outcome measures used in studies of PD The 17-item Hamilton Depression Rating Scale The 21-item Hamilton Depression Rating Scale The 24-item Hamilton Depression Rating Scale The Modified Hamilton Rating Scale for Depression The Montgomery Asberg Depression Rating Scale The Bech-Rafaelsen Melancholia Scale The Calgary Depression Scale The Brief Psychiatric Rating Scale The Schedule for Affective Disorders and Schizophrenia The Spiker Psychoticism Scale The Positive and Negative Symptom Scale The Dimensions of Delusional Experience Rating Scale

Quantitative psychiatry Status: Complete absence of sufficiently predictive biological markers for the presence/severity of mental illness in clinical practice. Rating scales: Systematic assessment of symptoms to allow for measurement of severity - particularly for clinically inexperienced health care professionals.

Hamilton Depression Rating Scale (HAM-D 17 ) 1. Depressed mood 2. Feelings of guilt 3. Suicidal ideation 4. Insomnia early 5. Insomnia middle 6. Insomnia late 7. Work and activities 8. Retardation 9. Agitation 10. Psychic anxiety 11. Somatic anxiety 12. Somatic - Gastrointestinal 13. Somatic - General 14. Genital symptoms 15. Hypochondriasis 16. Loss of weight 17. Insight

Clinical validity Total-score of rating scale Admission After 3 weeks Unidimensionality/ Scalability No Illness Extreme Illness Global Severity (gold standard) No illness Extreme illness Symptom item Symptom item Symptom item Symptom item Symptom item Symptom Psychomotor item retardation Each individual item adds unique information about the severity of the latent syndrome being rated The symptoms are endorsed in an orderly fashion as the severity of the latent syndrome increases

Unidimensionality/Scalability Prevalence 100 75 Symptom 2 + 2 Item 50 Symptom 18-9 Item Symptom 88 / 8 Item Symptom 17 x 24 Item Symptom 34 2-2Item 3 Log Symptom 56 / log Item 2 25 0 Basic Average Expert ç

Validation of the HAM-D 17 Patients with depression 2 experienced psychiatrists Global assessment 0-10 (Gold standard) 2 young psychiatrists HAM-D 17 rating

HAM-D 17 HAM-D 6 Statistical analysis Depressed mood Work & interests Feelings of guilt Psychomotor retardation Anxiety (Psychic) Somatic symptoms (tiredness)

Prevalence HAM-D 17 is multidimensional HAM-D 6 (Bech) is unidimensional 100 75 50 25 0 Mild Moderate Severe ------ Locations

Depressed mood Tiredness / General somatic Guilt feelings Work and interests Psychic anxiety Psychomotor retardation Retardation

The drugs don t work The HAM-D 17 doesn t work.

Clinical and psychometric validation of the Psychotic Depression Assessment Scale (PDAS) 1. Decreased sleep 2. Tiredness 3. Work and interests 4. Depressed mood 5. Difficulty concentrating 6. Anxiety (psychic) 7. Emotional withdrawal 8. Guilt 9. Worthlessness 10. Disorientation 11. Anxiety (somatic) 12. Hypochondria 13. Obsessions 14. Compulsions 15. Suicidal ideation 16. Suspicion/persecution 17. Hallucinations 18. Delusions 19. Derealisation/depersonalization 20. Lack of insight 21. Conceptual disorganization 22. Decreased verbal activity 23. Decreased motor activity 24. Agitation 25. Catatonia 26. Blunted affect 27. Hostility 28. Mood-congruence

Development of a dedicated rating scale for psychotic depression 50 in/out patients with psychotic depression (ICD-10) Semi-structured interview video-recorded Rating on 28 symptom items by two psychiatry residents Global severity assessment of PD by two experienced psychiatrists Test of clinical validity and unidimensionality of the PDAS Is the total score of the PDAS a valid measure for the severity of PD?

US Collaboration @

Based on data from the STOP-PD trial (Meyers et al., 2009)*: 259 patients with DSM-IV psychotic (delusional) depression 12 week RCT: Olanzapine+Placebo or Olanzapine+Sertraline Measures: Weekly ratings on the HAM-D 17, BPRS, CGI-S, and CGI-I Outcome measure: Remission = HAM-D 17 < 10 and no delusions (DAS) * Meyers BS, Flint AJ, Rothschild AJ, Mulsant BH, Whyte EM, Peasley-Miklus C, Papademetriou E, Leon AC, Heo M, STOP-PD Group: A double-blind randomized controlled trial of olanzapine plus sertraline vs olanzapine plus placebo for psychotic depression: the study of pharmacotherapy of psychotic depression (STOP-PD). Arch.Gen.Psychiatry 2009;66:838-847.

1. Are the HAM-D 17 and the HAM-D 6 subscale clinically valid and responsive measures of the severity of psychotic depression? 2. Are the HAM-D 17 and the HAM-D 6 subscale unidimensional/scalable measures of the severity of psychotic depression? 3. Which items on the BPRS correlate with the severity of delusions and hallucinations in psychotic depression? 4. Is a composite rating scale consisting of the HAM-D 6 plus BPRS items covering delusions/hallucinations a valid measure of the severity of psychotic depression?

1. Are the HAM-D 17 and the HAM-D 6 subscale clinically valid and responsive measures of the severity of psychotic depression? Clinical validity Responsiveness HAM-D 17 & HAM-D 6 Total score CGI-I (psychiatrist) CGI-S (psychiatrist) ΔHAMD 17 & ΔHAMD 6 Total score Week 4 Week 8 Week 12 (n=185) (n=144) (n=135) HAM-D 17 0.76 0.80 0.82 HAM-D 6 0.74 0.78 0.82 Week 4 Week 8 Week 12 (LOCF) (LOCF) (LOCF) HAM-D 17-0.80-0.79-0.81 HAM-D 6-0.77-0.80-0.83

2. Are the HAM-D 17 and the HAM-D 6 subscale unidimensional/ scalable measures of the severity of psychotic depression? Methods: Mokken analysis gives an index of psychometric unidimensionality and values 0.40 are considered as a proof of acceptable unidimensionality Results: STOP-PD STAR*D Licht et al. 2005 (n=210) (n=2323) (n=1459) HAM-D 17 0.30 0.32 0.28 HAM-D 6 0.50 0.48 0.49

3. Which items on the BPRS correlate with the severity of delusions and hallucinations in psychotic depression? BPRS Items Spearman coefficient SADS - Delusions SADS Hallucinations 1.Unusual thought content 0.28 *** 0.26 *** 2. Grandiosity -0.02 0.05 3. Hallucinatory behaviour 0.11 0.87 *** 4. Tension 0.12 0.07 5. Emotional withdrawal 0.21 *** 0.10 6. Blunted affect 0.19 ** 0.13 * 7. Excitement 0.04 0.07 8. Mannerisms and posturing 0.01 0.00 9. Hostility -0.02 0.03 10. Uncooperativeness 0.13 * 0.06 11. Conceptual disorganization 0.10-0.01 12. Confusion 0.00 0.05 13. Depressive mood 0.06-0.01 14. Guilt feelings 0.02 0.08 15. Motor retardation 0.16 ** 0.03 16. Anxiety 0.18 ** -0.14 * 17. Somatic concern 0.15 * 0.02 18. Suspiciousness 0.27 *** 0.13 *

4. Is a composite rating scale consisting of the HAM-D 6 plus BPRS items covering delusions/hallucinations a valid measure of the severity of psychotic depression? Mokken analysis HAMD-BPRS 7 : HAM-D 6 + hallucinatory behaviour 0.44 HAMD-BPRS 8 : HAM-D 6 + hallucinatory behaviour + unusual thought content 0.43 HAMD-BPRS 9 : HAM-D 6 + hallucinatory behaviour + unusual thought content + suspiciousness 0.40 HAMD-BPRS 10 : HAM-D 6 + hallucinatory behaviour + unusual thought content + suspiciousness 0.40 + emotional withdrawal HAMD-BPRS 11 : HAM-D 6 + hallucinatory behaviour + unusual thought content + suspiciousness 0.41 + emotional withdrawal + blunted affect HAMD-BPRS 12 : HAM-D 6 + hallucinatory behaviour + unusual thought content + suspiciousness 0.37 + emotional withdrawal + blunted affect + somatic concern HAMD-BPRS 13 : HAM-D 6 + hallucinatory behaviour + unusual thought content + suspiciousness 0.37 + emotional withdrawal + blunted affect + somatic concern + uncooperativeness

4. Is a composite rating scale consisting of the HAM-D 6 plus BPRS items covering delusions/hallucinations a valid measure of the severity of psychotic depression? Clinical validity Week 4 Week 8 Week 12 (n=134) (n=144) (n=185) HAMD-BPRS 7 0.74 0.81 0.82 HAMD-BPRS 8 0.77 0.83 0.83 HAMD-BPRS 9 0.78 0.83 0.83 HAMD-BPRS 10 0.79 0.83 0.83 HAMD-BPRS 11 0.79 0.83 0.84 HAMD-BPRS 12 0.81 0.84 0.84 HAMD-BPRS 13 0.81 0.84 0.84 HAMD-BPRS x Total score Responsiveness Week 4 Week 8 Week 12 (LOCF) (LOCF) (LOCF) HAMD-BPRS 7-0.74-0.78-0.79 HAMD-BPRS 8-0.75-0.79-0.81 HAMD-BPRS 9-0.74-0.79-0.79 HAMD-BPRS 10-0.75-0.79-0.79 HAMD-BPRS 11-0.74-0.78-0.78 HAMD-BPRS 12-0.75-0.77-0.76 HAMD-BPRS 13-0.75-0.76-0.76 CGI-I (psychiatrist) CGI-S (psychiatrist) Δ HAMD-BPRS x Total score

The Psychotic Depression Assessment Scale 1. Depressed mood 2. Work and interests Depression (HAM-D 6 ) Psychosis (BPRS 5 ) 3. Somatic symptoms (general) 4. Psychic anxiety 5. Guilt feelings 6. Psychomotor retardation 7. Hallucinatory behaviour 8. Delusions 9. Suspiciousness 10. Emotional withdrawal 11. Blunted affect Content Validity Clinical Validity Unidimensionality Responsiveness Østergaard SD. Et al. Acta Psychiatrica Scandinavica 2014;129:211-220

Journal of Affective Disorders 2014;160:68-73 Measuring treatment response in psychotic depression: The Psychotic Depression Assessment Scale (PDAS) takes both depressive and psychotic symptoms into account Østergaard SD, Meyers BS, Flint AJ, Mulsant BH, Whyte EM, Ulbricht CM, Bech P, Rothschild AJ Adding the antidepressant Sertraline to the antipsychotic Olanzapine (Zyprexa) decreases the severity of the depressive symptoms in psychotic depression

Clinical and psychometric validation of the Development of a dedicated rating scale Psychotic Depression Assessment Scale (PDAS) for psychotic depression 50 in/out patients with psychotic depression (ICD-10) Semi-structured interview video-recorded Rating on the PDAS items by two psychiatry residents Global severity assessment (0-10) of PD by two experienced psychiatrists Test of clinical validity and unidimensionality of the PDAS Is the total score of the PDAS a valid measure for the severity of PD?

Participants 50 subjects meeting predefined criteria (ICD-10 Unipolar psychotic depression, 18 years or older, inpatient/outpatient, informed consent). Recruited between Februar 2012 April 2013 from 13 centres across Denmark. 1 excluded due to incomplete interview, 1 excluded due to schizophrenia. 8 participants with suspected bipolar disorder (psychiatrists / HCL-32). Average age = 52 years (range: 18-88). Sex ratio 1:1. Average global severity of psychotic depression = 5.1 (range 0.0-9.5). Average global severity of psychotic depression = 6.0 (range 0.5-9.0). Average global severity of psychotic depression = 4.8 (range 0.0-10.0).

Validity of the PDAS Spearman coefficient: 0.82 (P<0.001) Mokken analysis = unidimensionality

Depression subscale Spearman coefficient: 0.78 (P<0.001) Mokken = unidimensionality Psychosis subscale Spearman coefficient: 0.81 (P<0.001) Mokken = unidimensionality

Validity of the PDAS Spearman coefficient: 0.82 (P<0.001) Mokken analysis = unidimensionality

Cotard s syndrom (Délire de négations) I would like to venture the term délire de négations to refer to those cases. in which patients show a marked tendency to denying everything 1 Carried to its extreme, this negating attitude led the patient to denying the existence of self or world, and such delusions may be the only symptom left during the chronic state of melancholia. 2 Jules Cotard (1840-1889) 3 3 1 Cotard J. Du délire de négations. Arch Neurol. 1882;4:152-170, 282-296 2 Berrios GE, Luque R. Cotard s delusion or syndrome? Compr Psychiatry. 1995;36:218-223 3 Berrios GE, Luque R. Cotard s syndrome: analysis of 100 cases. Acta Psychiatrica Scandinavica. 1995;91:185-188

An exploratory factor analysis extracted 3 factors: psychotic depression, Cotard type I and Cotard type II. The psychotic depression factor included patients with melancholia and few nihilistic delusions. Cotard type I patients, on the other hand, showed no loadings for depression or other disease and are likely to constitute a pure Cotard syndrome whose nosology may be closer to the delusional than the affective disorders. Type II patients showed anxiety, depression and auditory hallucinations and constitute a mixed group

Cheeky colleague: Is there an interview dedicated to gather information on the 11 items in the PDAS?

www.psychoticdepressionassessmentscale.com

Conclusions Psychotic depression is a severe condition, which is particularly prevalent among the elderly. The risk of suicide is substantial. It is important to distinguish psychotic depression from non-psychotic depression. First line treatments for psychotic depression are ECT or an AD+AP combination. The Psychotic Depression Assessment Scale (PDAS) is the first validated rating scale for severity measurement in psychotic depression The PDAS contains valid subscales for depression (HAM-D 6 ) and psychosis (BPRS 5 ) The PDAS, HAM-D 6 and BPRS 5 have displayed validity in very different settings (USA vs. DK, Turkey, The Netherlands, DSM-IV vs. ICD-10, RCT vs. clinic) The PDAS is available in Norwegian.

Acknowledgements Participating patients Professor Per Bech (1942-2018) Professor Anthony Rothschild and the STOP-PD group Professor Ole Mors, Aarhus University Hospital Psychiatry Translators incl. Kristin J. Fredriksen, Melissa Weibell, Liss Gøril Funders