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

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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

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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

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upto

1 p

resc

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2 to

5 p

resc

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6 to

10

pres

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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