the neurobiology and pharmacotherapy of bipolar
DESCRIPTION
An update on current thinking in the neurobiology of bipolar and how the drug treatment of the condition is linked to this.TRANSCRIPT
The neurobiology and pharmacotherapy of bipolar
Dr. Nick StaffordConsultant Psychiatrist,
Lichfield CMHT
Declarations
• AstraZeneca• Otsuka• Bristol Myers Squibb• GSK• Pfizer• Eli Lilly• Lundbeck• Servier Laboratories• GW Pharma
• Nuffield Health• UGLE
Contents of lecture
• Neurobiology• Oxidative stress• Inflammatory processes• Genetics• Epigenetics• Neurobiology informing therapeutics• Treatment of mania• Treatment of bipolar depression
NUEUROBIOLOGY OF BIPOLAR
Comorbid conditions in bipolar
Bipolardisorder
Impulsecontrol
ADHD
Personalitydisorders
Migraine
Anxietydisorders
Eatingdisorders
Substanceabuse
Obesity
Cardio-vascular
Diabetesmellitus
Paindisorders
McIntyre, et al. Hum Psychopharmacol 2004;19(6):369-386
Disease and treatment are complicated by frequent psychiatric and physical comorbidities
ADHD=Attention deficit hyperactivity disorder
Morphometric changes in BD
Structural MRI International ‘Mega-analysis’n(BP type I) = 321 n(controls) = 321
• Increased right lateral ventricular volume• Increased left temporal lobe volume• Increased right putamen volume• Lithium bipolars – increased hippocampal and amygdala
volumes• Cerebral volume reduction associated with increased
illness durationHallahan et al. FOCUS Psychiatry Online. 2011
Progression & kindling
Kessing et al. (1998) Br J Psychiat, 172: 23-28
0
1
2
3
4
5
Episode number
Leng
th o
f int
er-e
piso
de
inte
rval
(yea
rs)
n=2,902
n=2,029
n=1,429n=1,034 n=756
n=172 n=34
1 2 3 4 5 10 15
With time:Shorter intervalsMore autonomous emergencePsychosocial stressors
More poorly Rx responsive over time
• More poorly Rx responsive: a function of no. of episodes
• Cognitive deficits (even if euthymic) are proportionate to the no. of episodes (or depression duration)
• Tolerance pattern is indicative of another type of illness progression (pharmacodynamic as occurs at highest doses)
• Discontinuation-induced treatment resistance (e.g. lithium)
• Episodes when off medication are more damaging than episodes when on Rx
OXIDATIVE STRESS
Oxidative stress in bipolar
Andreazza et al. Journal of Neurochemistry 2013
Postmortem study
ROS – Reactive Oxygen Species
Mitochondrial dysfunction in BD
Systemic oxidative stress - Obesity
• Occurs as function of episodes/duration of illness• 55-74% bipolars are overweight or obese• More likely to be obese compared to population• Prevalence of obesity in BD increases with time• Obesity more common in BD cf. RDD & anxiety• Rates of DM, HT, IHD, CVA increased (SMR = < +2)• Lithium treatment – all cause reduction in SMR
INFLAMMATORY PROCESSES
Inflammation & treatment resistance
Raison et al. Psychiatric Times. 2013
Cytokine alterations in BD – meta-analysis
• 30 studies with 2599 subjects• (1351 BD, 1248 healthy controls):
• Cytokine levels elevated in:– IL-4, IL-6, IL-10– Soluble IL-2 receptor; sIL-6r– TNF-alpha; sTNF receptor-1
Modabbernia A et al. Biol Psychiatry. 2013.
Cytokine sabotage mechanisms
Raison et al. Psychiatric Times. 2013
CYTOKINES SABOTAGE AND CIRCUMVENT MECAHANISMS OF ACTION OF ANTIDEPRESSANTS
Glia and immune cell signaling
Proposed role of activated microglia in the modulation of inflammatory mediators, neurotransmitter synthesisand synaptic plasticity in bipolar disorder (BD). CRP, C-reactive protein; IDO, indoindoleamine 2,3-dioxygenase; 5-HT-serotonin; RNS, reactive nitrogen species; ROS, reactive oxygen species.
Wat
kins
et a
l. Tr
ansl
ation
al P
sych
iatr
y 20
14
Wnt/GSK-3b pathway (in microglia)
The Wnt pathway is a highly conserved signaling cascade that is criticalfor synaptic plasticity, circadian rhythms and cell survival
Wnt proteins:
Secretedsignalingmoleculesthat regulatecell-to-cellinteraction
Wat
kins
et a
l. Tr
ansl
ation
al P
sych
iatr
y 20
14
GENETICS
Genetic mechanisms 1Implicated genes Mechanism
CACNA1C Calcium channel (Increased intracellular calcium in blood elements of UP & BP)? Altered calcium channel dynamics? Altered mitochondrial calcium dynamics
ANK 3 Neurotransmitter release mechanisms in hippocampus
Val-66-val allele of proBDNF Better functioning. Larger proportion of population. Associated with increased risk of bipolar; earlier onsets; rapid cycling; could be associated with increased activity in mania. ? increase in functional connectivity amongst brain regions. ? reversal of the usual inverse metabolic connections between Frontal Cortex - Amygdala and Frontal Cortex - Cerebellum.
Val-66-met allele of proBDNF Less efficient functioning. Smaller proportion of population. Limited transport to dendritic areas; associated with decreased long term potentiation in hippocampal slices; subtle memory deficits in normals; reduced hippocampal volumes and activation; reduced prefrontal areas in normals.
Genetic mechanisms 2Implicated genes Mechanism
CLOCK genes & related circadian rhythm genes
In mice defects lead to many behaviours mimicking mania. Chronic administration of lithium to these mice normalizes this behaviour. CLOCK mutant mice have increased DA activity in ventral striatal area and their manic behaviour is rescued by expressing a functional CLOCK protein in the VTA.There are genetic connections between the circadian rhythms of the SCN and DA transmission and increased cocaine reward in the VTA. ? link between bipolar and increased proclivity of substance abuse.
GSK-3beta Key to circadian rhythm genetics. Crosses the nuclear membrane connecting nuclear circadian systems with cytoplasmic circadian systems. Conformational change in GSK-3beta ‘derails’ this link. ? Lithium corrects conformational change in GSK-3beta
EPIGENETICS
Gene environment interactions
Earlier onset, Increased stress, Substance misuse = Poorer outcomes
Epigenetic code
Epigenetic mechanisms
D’Amato at al. Nature Rev Neurosc. 2009
Long lasting effects on HPA actionGR – glucocorticoid receptor
In low-licking and grooming pups –Mediated in hippocampus by:Hyper-methylation of the exon-17
of the GR promoter&Hyper-acetylation of histone H 3-lysine-9,Which reduces binding to nerve growth factor-inducible protein-A (NGFI-A)
In high-licking and grooming pups –Lower methylation of exon-17 of GR promoterLower acetylation of histone and moreBinding of NGFI-A
Central infusion of histone-deacetylase inhibitor can alter this effect and HPA responsiveness
INCREASED MATERNAL GROOMING OF NEONATES LEADS TOLIFE LONG INCREASED RESILIENCE TO STRESS RESPONSIVENESS
Epigenetics – defeat stress paradigm
MORE EXTREME NEONATAL AND CHILDHOOD STRESS CAN CAUSE LONGLASTING CHANGES
Mifepristone BD cognitive impairment
Young et al. Neuropsychopharmacology. 2004
Mifepristone (any BD mood episode)
Cochrane, Gallagher et al. 2008
Antiglucorticoids under investigation
• R1219189• 561678 GSK• SSR149415• Metyrapone
NEUROBIOLOGY INFORMING CLINICAL THERAPEUTICS
Rationale for medication
• With Lithium, CBZ, VPA:
1. Prevent episode related decreases in BDNF and increases in oxidative stress and other neurotoxic phenomenon
2. Likely mediate neurotrophic, neuroprotective effects on their own via their ability to increase BDNF and also neurogenesis (Li, VPA)
SGAs and ADs in BD
• Quetiapine & Ziprasidone prevent stress induced decreases in hippocampal BDNF
• Quetiapine increases BDNF directly• ADs largely ineffective in BD and effects of AD
in BD on hippocampal BDNF not replicated
TREATMENT OF MANIA
Mania and DA hyperactivityMania is associated with hyperactivity of neurotransmission in the brain
Hyperactivity in mesocortical pathway Hyperactivity in the mesolimbic pathway
Hyperactivity in nigrostriatal pathway
Activity in tuberoinfundibular pathway
Adapted from: Stahl SM. Essential Psychopharmacology of antipsychotics and mood stabilizers. Cambridge University Press; 2009.
Mania – WFSBP, Category A
• Aripiprazole• Asenapine• Carbamazepine• Haloperidol• Lithium
• Olanzapine• Quetiapine• Risperidone• Valproate• Ziprasidone
Atypical antipsychotics in mania
*First olanzapine study is a combination of 2 substudies—1 that separated from placebo, 1 that did not; †Second olanzapine study was 4 weeks; ‡Second quetiapine study was 12 weeks; 1Tohen M et al. (1999), Am J Psychiatry 156(5):702-709; 2Tohen M et al. (2000), Arch Gen Psychiatry 57(9):841-849; 3Keck PE et al. (2003), Am J Psychiatry 160(4):741-748; 4Hirschfeld RM et al. (2002), Poster; 5Kramer et al. (2002), Poster; 6Brecher et al. (2003), Poster; 7Jones et al. (2003), Poster; 8Keck PE et al. (2003), Am J Psychiatry 160(9):1651-1658; 9Data on file (2003), Bristol-Myers Squibb Company and Otsuka America Pharmaceutical, Inc.; 10Sachs et al. (2003), Poster
Placebo Drug Placebo-corrected change
16
Imp
rove
men
t af
ter
3 w
eeks
n
Man
ia R
atin
g S
cale
02468
101214
Olan1*Olan2† Zipras3 Risp4 Risp5 Quet6 Quet7‡ Arip8 Arip9 Arip10
Addition of AP to lithium/valproate
1. Sachs GS, et al. Am J Psychiatry 2002;159:1146–1154; 2. Yatham LN, et al. Br J Psychiatry 2003;182:141–147; 3. Tohen M, et al. Arch Gen Psychiatry 2002;59:62–69; 4. Sachs G, et al. Bipolar Disord 2004;6:213–223; 5. Vieta E, et al. Am J Psychiatry 2008;165:1316–1325
• ≥50% reduction YMRS total score, except in Sachs et al. 2002, where data refers • to patients much improved/very much improved on CGI-I
Data from positive individual controlled studies, representative of the literature on atypicals adjunctive to/in combination with mood stabilisers in bipolar mania. Cross-study comparisons cannot be made
Risperidone + Li/Val
Olanzapine + Li/Val
Quetiapine + Li/Val
Aripiprazole + Li/Val
Placebo + Li/Val
0
10
20
30
40
50
60
70
80
90
100
Sachs et al.1 Yatham et al.2 Tohen et al.3 Sachs et al.4 Vieta et al.5
Res
po
nse
rat
e* a
t en
dp
oin
t (%
)
62.8%
48.5%
p<0.01
54.3%
32.6%
p=0.005
67.7%
44.7%
p<0.001
59%
41%
p<0.05
53%
30%
p=0.002
TREATMENT OF BIPOLAR DEPRESSION
Bipolar depression – single agentsMedication WFSBP Strength of
evidenceRecommended grade
Quetiapine A 1
Fluoxetine B 3
Lamotrigine B 3
Olanzapine B 3
Valproate B 3
Lithium D 5
Carbamazepine D 5
Paroxetine E -
Aripiprazole E -
Ziprasidone E -
WFSBP
Bipolar depression - >1 agentDrugs in combination WFSBP Strength of
evidenceRecommendation grade
Pramipexole & lithium or valproate
B 3
Olanzapine & fluoxetine combination
B 3
Lamotrigine & Lithium B 3
Modafanil & ongoing treatment
B 3
Imipramine & lithium B 3
N-acetylcysteine & lithium or valproate
B 3
Lithium reduces bipolar suicide
• Large effect size on reducing suicide risk with longer use
Gen P
op
upto
1 p
resc
riptio
n
2 to
5 p
resc
riptio
n
6 to
10
pres
crip
tion
11 o
r mor
e pr
escr
iptio
ns0
0.2
0.4
0.6
0.8
1
Suicide risk drops as you take lithium for longer
Kessing et al, Arch Gen Psych 2005, 62, 860-866
ISSUES ON THE USE OF ANTIDEPRESSANTS IN BIPOLAR
OFC
Adjunctive ADs for bipolar depression
Sachs et al. 2007
Current consensus on the use of ADs
Conclusions: Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants.
Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors.
The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder.
Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.
ISBD, Pacchiarroti et al. Am J Psych 2013
Conclusion & future possibilities
• Oxidative stress• Inflammatory processes• Genetics• Epigenetics
• Pharmacotherapy• Prevention strategies• Psychological• Psychosocial
Tailored byInforming
Acknowledgements
• Prof Heinz Grunze• Prof Allan Young• Prof Richard Morriss• Dr. Daniel Smith• Prof Stephen Bazire• Dr. Francesc Colom