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Neuroimmunology of schizophrenia and depression
Belinda Lennox
@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
