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S Afr Fam Pract
ISSN 2078-6190 EISSN 2078-6204

REVIEW

BD is highly heritable and genome-wide association studies
(GWAS) have uncovered significant insights into the biological
mechanisms involved in its development. Potential genetic
variants implicated in disease aetiology include CACNA1C that
encodes the alpha subunit of brain L-type voltage-gated calcium
ion channels and ANK3 that encodes an adaptor protein essential
for the assembly of voltage-gated sodium channels.3 Some
mood stabilizers such as lithium, valproate and lamotrigine
stabilize neuronal conduction by modulating these channels.4 In
addition, valproate has been shown to enhance neuro-inhibitory
GABA effects5 while possibly attenuating neuro-excitatory
glutamate’s effects by up-regulating calcium chaperone protein,
GRP 78.6

Intracellular actions of lithium and valproate that may also be
relevant to their actions in BD include stimulating cell survival
pathways and increasing levels of neurotrophic factors to improve
cellular resiliency.7-9 Both agents inhibit pro-apoptotic glycogen
synthase kinase (GSK-3ß) and increase anti-apoptotic protein Bcl-
2 levels in the frontal cortex, ultimately resulting in downstream
regulation of gene expression and neuroprotection.10,11Recent
GWAS results have implicated a risk locus which encodes ADCY2,
a protein that is involved in cAMP signal transmission within
neurons, and a locus containing MIR2113 and POU3F2, which
are thought to play a role in neuro-developmental processes,
lending further support to the importance of neuronal integrity
in BD.12 Interestingly, valproate has effects on DNA histone
acetylation and may thereby regulate epigenetic phenomena
as well.13

The pathophysiology and treatment model of mood disorders
has thus expanded to include anomalies of neuroplasticity, or
the brain’s ability to form new neural connections in response
to environmental changes including injury. Structural and
functional neuroimaging studies have re-enforced this neuronal

injury hypothesis and have highlighted amongst others,
heritable changes in cortical and corpus callosum volumes,
abnormal myelination in several brain regions implicated in BD
as well as hippocampal cell damage and loss.14-17 The hypothesis
supports the clinical observation that the more episodes a
person experiences, the more he or she will have in the future,
underscoring the need for long-term maintenance treatment.
(18) Besides lithium, valproate or lamotrigine, recommended
maintenance monotherapy includes the second generation
antipsychotics (SGA) olanzapine, aripiprazole, quetiapine and
risperidone long acting injection.1,19, 20

Because serotonin, noradrenaline and dopamine are strongly
implicated in the pathophysiology of mania, pharmacological
strategies include gradually discontinuing conventional
antidepressants and stimulants that increase the levels of any
of these neurotransmitters. Agents that antagonise serotonin
and dopamine receptors, including olanzapine, aripiprazole,
quetiapine, risperidone, paliperidone and ziprasidone, have
demonstrated excellent anti-manic efficacy when used alone.
Lithium or valproate are also valuable first line options. The
combination of either, with one of the above SGAs, confers
additive efficacy presumably because different sites are
targeted.1,19

There is insufficient evidence for conventional antidepressants
in bipolar depression, possibly indicating an aetiology that is
sufficiently distinct from major depressive disorder. These agents
may also trigger mania.20 Instead, first-line monotherapy options
for severe bipolar I depression include the neuronal stabilizing
and protective agents lithium, valproate or lamotrigine,
and paradoxically, the atypical antipsychotics, quetiapine or
olanzapine.19 Their mechanism of antidepressant action is
speculative.6 Olanzapine and quetiapine antagonise serotonin
5HT2A receptors while stimulating 5HT1A receptors and this is

Abstract

Bipolar Disorder (BD) is characterised by alternating discrete episodes of depression and mania.1 Rational pharmacotherapy
necessitates an appreciation of these different phases and of the possible underlying pathophysiology. A greater understanding of
the pathogenesis of BD has boosted awareness of how anti-bipolar drugs work, and vice versa.2 This bidirectional relationship has
amplified knowledge in both disciplines.

South African Family Practice 2016; 58(3):14-16

Open Access article distributed under the terms o f the
Creative Commons License [CC BY-NC-ND 4.0]
http://creativecommons.org/licenses/by-nc-nd/4.0

Evidence that changes the way you practice
Bipolar Disorder: Mania and depression explained
K Outhoff

Senior Lecturer
Department of Pharmacology, Faculty of Health Sciences, University of Pretoria, Pretoria
Corresponding author, email: kim.outhoff@up.ac.za

S Afr Fam Pract 2016;58(3):14-1616

The page number in the footer is not for bibliographic referencingwww.tandfonline.com/oemd 16

thought to contribute to their antidepressant effects. In addition,
prefrontal cortical dopamine levels are indirectly elevated by
this 5HT1A partial agonistic mechanism. Rapid dissociation of
quetiapine from the dopamine D2 receptors as well as altered
expression of glutamate receptor subunits may also contribute
to its antidepressant efficacy in BD.6 Incidentally, quetiapine is
recommended first line for the milder depression associated
with Bipolar II.1,19 Based on drug responsiveness studies and a
wider appreciation of its pathophysiology, rational second-line
options for bipolar I depression include adjunctive risperidone,
olanzapine and fluoxetine combinations, or lithium combined
with either valproate, lamotrigine or an antidepressant.19

References

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revised second edition—recommendations from the British Association for
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2. Stahl SM. Stahl’s essential psychopharmacology: neuroscientific basis and
practical applications: Cambridge University Press; 2013.

3. Ferreira MA, O’Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, et al.
Collaborative genome-wide association analysis supports a role for ANK3 and
CACNA1C in bipolar disorder. Nature genetics 2008;40(9):1056-8.

4. Goldsmith DR, Wagstaff AJ, Ibbotson T, Perry CM. Spotlight on lamotrigine in
bipolar disorder. CNS drugs 2004;18(1):63-7.

5. Rosenberg G. The mechanisms of action of valproate in neuropsychiatric
disorders: can we see the forest for the trees? Cell Mol Life Sci. 2007
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6. Yatham LN, Goldstein JM, Vieta E, Bowden CL, Grunze H, Post RM, et al. Atypical
antipsychotics in bipolar depression: potential mechanisms of action. Journal of
Clinical Psychiatry 2005;66(Suppl 5):40-8.

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of anticonvulsants: are they relevant for the treatment and course of bipolar
disorders? Journal of Affective Disorders 2002;69(1):1-14.

8. Mathew SJ, Manji HK, Charney DS. Novel drugs and therapeutic targets for
severe mood disorders. Neuropsychopharmacology 2008;33(9):2080-92.

9. Chen G, Zeng WZ, Yuan PX, Huang LD, Jiang YM, Zhao ZH, et al. The mood‐
stabilizing agents lithium and valproate robustly increase the levels of
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Psychiatrica Scandinavica 2005;111(s426):13-20.

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12. Mühleisen TW, Leber M, Schulze TG, Strohmaier J, Degenhardt F, Treutlein J, et
al. Genome-wide association study reveals two new risk loci for bipolar disorder.
Nature communications 2014;5.

13. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS. Histone
deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood
stabilizer, and teratogen. Journal of Biological Chemistry 2001;276(39):36734-41.

14. Sarrazin S, Poupon C, Linke J, Wessa M, Phillips M, Delavest M, et al. A
multicenter tractography study of deep white matter tracts in Bipolar I Disorder:
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2014;71(4):388-96.

15. Sussmann JE, Lymer GKS, McKirdy J, Moorhead TWJ, Maniega SM, Job D, et al.
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16. Houenou J, Frommberger J, Carde S, Glasbrenner M, Diener C, Leboyer M,
et al. Neuroimaging-based markers of bipolar disorder: evidence from two
meta-analyses. Journal of Affective Disorders 2011;132(3):344-55.

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implications. Journal of Psychiatric Research 2007;41(12):979-90.

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Table 1: South African treatment guidelines for Bipolar Disorder19

Maintenance monotherapy Acute mania Bipolar I* depression Bipolar II** depression

First line monotherapy First line monotherapy First line monotherapy

Lithium Lithium Lithium

Valproate Valproate Valproate

Lamotrigine Lamotrigine

Olanzapine Olanzapine Olanzapine

Quetiapine Quetiapine Quetiapine Quetiapine

Aripiprazole Aripiprazole

Risperidone LAI Risperidone

Paliperiodone

Ziprasidone

Drugs that may trigger mania Drugs that may trigger
depression

Drugs that may trigger
depression

Antidepressants such as SSRIs and
SNRIs alone/with mood stabilisers

Antipsychotics such as
chlorpromazine antihypertensive
agents and corticosteroids

*Bipolar I is characterised by one or more episodes of mania with or without major depressive episodes usually leading to severe impairment of social or occupational function.
**Bipolar II disorder is characterised by one or more episodes of hypomania as well as at least one major depressive episode with no psychotic features and usually no major impairment of function.