Neuroimmunology of schizophrenia and depression · 2018-10-05 · • Brief overview of psychiatry...

Neuroimmunology of schizophrenia and depression

Belinda Lennox

Belinda.lennox@psych.ox.ac.uk

@blennox4

Overview

• Brief overview of psychiatry

• Immunology of depression

• Immunology of schizophrenia

1. Mental illness is a big problem

Figure 4

The Lancet 2013 382, 1575-1586DOI: (10.1016/S0140-6736(13)61611-6)

Copyright © 2013 Elsevier Ltd Terms and Conditions

2. It’s a global problem

1950 chlorpromazine antipsychoticsD2 theory schizophrenia

1990s atypical antipsychotics

1950s Iproniazid antidepressantsImipramine 5HT theory depression

1980s selective serotonin reuptake inhibitors

3. Our current treatments are limited (and based on serendipity)

1. Depressed mood most of the day, nearly every day.2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day.3. Significant weight loss when not dieting or weight gain, or decrease or increase in appetite nearly every day.4. A slowing down of thought and a reduction of physical movement (observable by others, not merely subjective feelings of restlessness or being slowed down).5. Fatigue or loss of energy nearly every day.6. Feelings of worthlessness or excessive or inappropriate guilt nearly every day.7. Diminished ability to think or concentrate, or indecisiveness, nearly every day.8. Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.

These symptoms must cause the individual clinically significant distress or impairment in social, occupational, or other important areas of functioning. The symptoms must also not be a result of substance abuse or another medical condition.

Depression DSM Vfive or more symptoms during the same 2-week period and at least one of the symptoms should be either (1) depressed mood or (2) loss of interest or pleasure

4. Our diagnoses are based on symptoms alone

Copeland et al J Am Acad Child Adoles Psychiatry 2011, 50(3):252-261

Cumulative prevalence of DSM IV psychiatric disorder by age 21 in population based study 1420 children in Great Smoky Mountains study.

Almost everyone meets diagnostic criteria at some point

“A century ago we had large public institutions for serious mental illness, tuberculosis and leprosy. Of these three, today only mental illness, especially schizophrenia, remains unchanged in prevalence and disability” Insel 2010

Result = no new treatments, lack progress

Epidemiology of depression

Prevalence men: 12.7%women: 21.3%

Suicide: 1 million deaths per year (16/100,000) WHO 60% due to depression

Risk factors: genetic: 32-37% heritability

Environmental: Alcohol misuse, social deprivation, obesity, pain, medical illnesses

Antidepressants effective in 40-60%

1. Having an infection is a bit like being depressed

Sickness behaviour –lethargy, low mood, loss appetite, poor concentration

What’s the evidence that depression is a disorder of immune system?

Dowlati et al Biol Psychiatry 2010

A Meta-Analysis of IL-6 in Major Depression

2. There are raised inflammatory markers in depression

A Meta-Analysis of Tumor necrosis factor-α in Major Depression

Dowlati et al Biol Psychiatry 2010

1991-1993

2002-2004

Association CRP and IL6 with depression – 12 year follow-up Whitehall II study Gimeno et al Psychological Medicine 2009 39(3)

3. Inflammation predicting later depression?

IL6 and CRP at baseline predicted depression 12 years later.

Possible mechanism of effect - cytokine effects on neuronal function causing depression

Klein R, Garber C, Howard N Nature Immunology 2017 18

4. pro/anti-inflammatory drugs and depression

• Interferon Alpha treatment for Hep C depression in 40% (F:M 2:1) (Bonnacorso et al J. Affective Disorders 2002)

• TNF-α inhibitors antidepressant action (trials in rheumatoid arthritis, psoriasis orcancer)

Abbott et al J. Psychosomatic Research 2015 79(3)

Trial infliximab in depression

Raison et al JAMA Psychiatry 2013 70(1)

…subdivided by CRP

Raison et al JAMA Psychiatry 2013 70(1)

Summary (1)

Depression is associated with some inflammatory changes

Inflammation may predate depression

No direct evidence that inflammation causes depression, yet.

Epidemiology of schizophrenia

• 1% population • Onset in adolescence• Heritability: 80%• Environmental factors: cannabis, deprivation

Psychiatric Genomics Consortium Nature 2015

Schizophrenia – a ‘psychiatric’ neuropsychiatric disorder

• Positive symptoms – hallucinations, delusions,

• Negative symptoms – social withdrawal, apathy, alogia

• Cognitive impairment – present at onset, persistent, most disabling symptoms

• Neurological signs – movement disorder, catatonia,

• Antipsychotics effective for positive symptoms

1. Increased autoimmune disease in those with schizophrenia

Evidence schizophrenia is an immune disorder

Chen et al BJPysch 2012 (5)

Increased schizophrenia in those with autoimmune disease, and infection

Benros et al Am J Psychiatry 2011 168(12)

2. Parallels with Multiple Sclerosis

Season of birth

Age of onset

Genetic pleiotropyPGC and IMSGC Mol Psychiatry 2015

Nitta et al 2013 39(6): 1230–1241

3. Trials of anti-inflammatories

4. Parallels with autoimmune encephalitis

NMDA-receptor encephalitis:

• Progessive life threatening limbic encephalitis,

• Fits, cognitive impairment, autonomic instability, coma and dystonic movement disorder

• 20-50% paraneoplastic (ovarian teratomas)

• 66-80% women, age 5-80 (mean 23)

• 1% all admissions to ITU(Dalmau et al Lancet Neurology 2008, Irani et al Brain 2010 )

-20 -10 0 10 20 30 40 50 60 70 80 90 100 110 120

OCB (52%)

No CSF lymphocytes (32%)

No OCB (48%)

CSF lymphocytes (68%) p=0.0007

p<0.007

p=0.04

p=0.0002

Days since onset

-20 -10 0 10 20 30 40 50 60 70 80 90 100 110 120

Autonomic (72%)

Fall in consciousness (45%)

Movement disorder (89%)

Cognitive dysfunction (91%)

Seizures (82%)

Psychiatric (77%)

Days since onset

All investigations

in first 120 days

Cortical

Subcortical

Irani et al Brain (2010)

Occurrence in schizophreniaSleep dysfunction 30 to 80% (Cohr, 2008).

Seizures OR 11.1 (Makikyro, et al., 1998)

Cognitive dysfunction Associated with poor function and clinical outcome.

Movement disorders 9% of antipsychotic-naive patients spontaneous dyskinesias;

17% have spontaneous parkinsonism (Pappa and Dazzan,

2009)

Catatonia 7.6% - 38% (Taylor and Fink, 2003).

Autonomic dysfunction Neuroleptic malignant syndrome in 0.07 to 2.2%.

Abnormal CSF Lymphocytes/oligoclonal bands 14% (Bechter et al 2010)

All symptoms of AE also seen in schizophrenia

Al-Diwani et al Frontiers 2017

Responsive to early immunotherapy

Irani et al Brain 2010

Increased NMDAR antibodies in

acute psychosis

Palmer Cooper et al under review

Response to immunotherapy in those with

psychosis and NMDAR antibodies

Zandi et al Schiz. Research 2014

Feasibility of delivering immunotherapy in psychosis

Participant

Number

Antibody

type

Duration of illness

(months)

Treatment given

1 NMDAR 2 PLEX

2 NMDAR 10 PLEX + steroids

3 NMDAR 1 PLEX + steroids

4 NMDAR 2 PLEX

5 NMDAR 5 PLEX+steroids

6 VGKC 60 IVIG

7 VGKC 7 IVIG

8 VGKC 10 PLEX+steroids

9 VGKC 24 IVIG

10 GABAA 11 IVIG

Lennox et al JNNP 2018

30

50

70

90

110

130

150

170

190

0 1 2 3 4 5 6 7 8 9 1 0

PA

NSS

TO

TAL

PARTICIPANT NUMBER

baseline

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 1 0

GA

F SC

OR

E

PARTICIPANT NUMBER

Baseline

Follow up

Immunotherapy improves psychosis and functioning

Psychosis symptoms at baseline and 6 weeks (lower=better)

Functioning at baseline and 6 weeks (higher=better)

Lennox et al JNNP 2018

Summary (2)

• Association between schizophrenia and autoimmune diseases

• Overlap clinical phenotype autoimmune encephalitis and schizophrenia

• Increased prevalence of NMDAR antibodies in acute psychosis

• Psychosis improves with immunotherapy (maybe)

Summary (final)

• Mental illness poses a large disease burden

• Immunology offers potential to stratify patients and improve treatments

• Stongest evidence for ‘autoimmune psychosis’

• We need immunopsychiatrists and psychoimmunologists