MOOD DISORDERS

Describe the evidence for and against the monoamine

hypothesis of depression?= Monoamine hypoth

Why is it no longer satisfactory to consider mood disorder as

solely due to a chemical imbalance in the brain?=
Development

One long-term goal of the NHS is to reduce the annual

suicide rate. What could neuroscience contribute towards
this goal?= therapies

Discuss the contribution of pharmacology to current views

on the causes of a brain disorder of your choice. -

Newish review;
http://www.nature.com/nrn/journal/v2/n5/full/nrn0501_343a.
html

By the year 2020, projections by the WHO estimate that major depression
is likely to become the 2nd major cause of disability. Mood disorders have a
significant impact on the quality of life, life expectancy and economic burden of
disease and disability, and in the UK alone, 2 million people suffer from some
form of mood disorder, 15% of whom go on to commit suicide. Unravelling the
pathophysiology of affective disorders presents a unique challenge, since
depressive syndromes are not only heterogeneous with diverse aetiologies, but
are diffcult to model experimentally, as it is virtually impossible to produce an
assay for guilt and suicidal mentality.
The traditional hypothesis for major depression has a neurochemical basis,
where functional deficits of monoamine neurotransmitters in specific areas of
the brain is the primary cause of depression, and that antidepressant agents
exert their effects by increasing extracellular monoamine levels. This hypothesis
was initially put forward by Schildkraut (1960s) to explain the therapeutic effect
of the first antidepressant drugs, the tricyclic antidepressants(TCAs), (inhibit
noradrenaline and 5-HT reuptake transporters); and monamine oxidase inhibitors
(MAOIs). This is supported by evidence that depletion of tryptophan, the
precursor of monoamines, lowers mood in vulnerable patients (Smith et al 1997).
However, the monoamine hypothesis cannot account for the delayed clinical
response, whereby monoamine levels are raised within days of treatment yet
several weeks required to observe therapeutic benefits. Moreover there is
frequent remission/absent responses to antidepressant pharmacotherapy in
patients and antidepressant drugs often cause unacceptable side effects and
therefore difficulty with patient compliance.
These observations suggest that this hypothesis needs to be revised.
Recent studies have associated this complex disorder with regional reductions in
central nervous system (CNS) volume, as well as in the numbers and/or sizes of
glia and neurons in discrete brain areas, and new approaches to depression
focus on the hypothalamic-pituitary-adrenal(HPA) axis and the plasticity of neural
pathways in the hippocampus in response to stress. Improved techniques for
visualising the human brain and better animal models hold promise for the
development of novel therapeutic agents in the future.
 The observed volumetric decreases in the hippocampus and other
forebrain regions in depressed patients has supported a popular hypothesis for
depression involving a decrease in neurotrophic factors, which regulate plasticity
within adult brain as well as in neurodevelopment. These studies mainly focus on
Brain Derived Neurotrophic Factor. Animal models such as the social defeat or
learned helplessness model, show that several forms of stress reduce BDNF-
mediated signalling in the hippocampus, whereas chronic treatment with
antidepressants increases BDNF-mediated signalling and thus promotes adaptive
plasticity (Monteggia et al 2006). A wide range of anti-depressant treatments
have been found to alter the BDNF levels, including Lithium which is used as an
effective adjuvant to anti-depressant therapy, and as a mood stabiliser with anti-
manic properties for the treatment of bipolar disorder. Lithium also induces the
expression of BDNF and subsequent activation of TrkB, the receptor for BDNF in
cortical neurons which may promote secondary neuroplastic changes in the
brain(Chuang et al 2004).

BDNF also promotes neuronal survival and neurogenesis, and several

studies suggest that the therapeutic effect of anti-depressants occurs via an
effect on neurogenesis (Kempermann and Fred Gage 2002). Several
antidepressant treatments are shown to increase adult neurogenesis in
hippocampus and blockade of hippocampal neurogenesis by specific irradiation
has been demonstrated to inhibit the therapeutic-like effects of most
antidepressant treatments in rodent models (Santarelli et al 2003). BDNF may
act through the actions of cAMP response element binding protein (CREB) or
other transcriptional regulators to mediate the antidepressant/ proneurogenic
properties found in rodents, and there is also evidence that neurotrophic Factors
can have anti-apoptotic effectrs by activating the mitogen-activated protein
(MAP) kinase signaling pathway and the phosphotidylinositol-3 kinase (PI-3K)/Akt
pathway, increasing the expression of the antiapoptotic protein Bcl-2. However,
there are also studies which dispute the role of BDNF and neurogenesis in
mediating the behavioural effects of anti-depressants such as fluoxetine(reif
2006). A study by Gratagos et al 2007, shows a single-nucleotide polymorphism
(G196A; Val 66 → Met 66) in the gene encoding BDNF, which significantly impairs
the intracellular trafficking and activity-dependent release of BDNF, that also
decreases hippocampal volume- does not alter genetic vulnerability to
depression.

These confounding results may have come about because animal studies
into the role of BDNF using transgenic and knock-out mice do not take epigenetic
mechanisms into account such as covalent changes to DNA and non-
transcriptional gene silencing mechanism which may explain several aspects of
depression, including the high discordance rates between monozygotic twins, the
chronic relapsing nature of the illness, and the strikingly greater prevalence of
depression in women. Histone acetylation, which is associated with
transcriptional activation and decondensed chromatin, may be a key substrate
for antidepressant action and increased histone acetylation at the BDNF
promoter in the hippocampus was shown to be required for the ability of
chronically administered imipramine to reverse the effects of social defeat
(Tsankova et al 2004). Moreover, histone deacetylase (HDAC) inhibitors show
antidepressant-like effects in the social-defeat assay(tsankova 2006), and efforts
are underway to develop more potent agents that are designed to target specific
HDACs, such as HDAC5.

Several other mechanisms have also been suggested which support the
hypothesis that secondary changes in gene expression and/or synaptic plasticity
may underlie the therapeutic mechanisms of antidepressant drugs. This includes
enhancement of serotonin receptor subtype function and their downstream
signalling involving the p11 trafficking protein (Svenninsson 2006) and
attenuation of the sensitivity or transmission of NMDA-glutamatergic receptors
(Krystal et al. 2002). Substantial evidence suggests that excessive glutamate
transmission, which may be precipitated by stress, plays a central role in atrophy
of CA3 pyramidal neurons in the hippocampus, and could be targeted
therapeutically. Moreover, sub-anaesthetic doses of intravenously infused NMDA
-antagonist ketamine, have been found to block hippocampal atrophy, and have
a transient antidepressant effect on individuals with treatment-resistant
depression (Zarate et al 2006), which has been recapitulated in mouse models of
forced swimming (Maeng 2008).
The association of an abnormal HPA axis with depression has been known
for many years (Board et al 1956) and it has been proposed that stress may
cause excitatory neurotoxicity for cells in brain regions involved in mood
regulation and several animal models of depression use behavioural paradigms
involving life events (social defeat/learned helplessness and forced swims).
There have been many reports of hypercortisolaemia in depression, and
depression-like symptoms can be produced in rodents by chronic administration
of glucocorticoids (McEwan et al 2007). Animal models have shown that neurons
in the CA3 subregion of the hippocampus are particularly vulnerable to stress
(Sapolsky 1996,) and sustained experimental elevation of cortisol levels causes
atrophy, decreases neurogenesis in the adult brain and produces reductions in
hippocampal volume, which are found in depression and post-traumatic
disorders (Gould 1992). In line with these findings, glucocorticoid and
corticotropin-releasing factor receptor antagonists are currently being tested in
clinical trials, and there is also significant interest in substance P, a neuropeptide
released during stress (berton et al 2007).

Brain imaging and postmortem studies have revealed several brain areas
other than the hippocampus are involved in depression. Philips et al showed that
increased neuronal activity within the amygdala and subgenual cingulate cortex
is strongly correlated with dysphoric emotions in depressed patienst and in
induced sadness studies; and this has been shown to revert to normal levels
after successful anti-depressant treatment. The hypothalamus has been studied
in the context of depression mainly with respect to its neuroendocrine role in the
HPA axis, whereas altered dopamine signalling in response to stress has been
recorded in the mesolimbic system, a key reward pathway. Decreased striatal
response to happy stimuli has been associated with anhedonia in depressed
patients, and Deep Brain stimulation of the mesolimbic structures could be
useful in treatment of anhedonia, and has shown an acute ameliorative effect in
refractory patients when applied to the nucleus accumbens (NAc), subgenual
cingulate or the anterior limb of the internal capsule. (Green et al).

Increasingly, abnormal circuitry is considered as a factor in depression,

and mood disorders are also seen in PD, Huntingtons and stroke which involve
lesions in the areas and circuits associated with major depression. Since the
emergence of neural networks theory, and unexpected success of DBS, other
techniques such as surgery disrupting projections from the amygdala and Vagal
nerve stimulation of limbic structures associated with altered activity are also
being considered. Electro-Convulsive Therapy reserved for those patients who do
not respond

In conclusion, 40 years of the monoamine hypothesis has been of great

significance in the attempts to understand depression and in developing safer
and effective antidepressants. Despite its drawbacks the Monoamine hypothesis
has paved the way for new generations of anti-depressants with increased
efficacy and reduced side effect profiles including serotonin selective re-uptake
inhibitors (SSRI’s) and also preclinically tested triple re-uptake inhibitors, which
inhibit the re-uptake of Dopamine in addition to 5-HT and Noradrenaline
(Skolnick et al 2003). In the future it will be imperative to look beyond mono-
amine and neurotrophic mechanisms and expand knowledge about
antidepressant pharmaco-genetics. Researchers must better understand the
biological basis for the efficacy of deep brain stimulation in depression and the
neural circuits involved, and once genes have been identified, we will be able to
develop more valid animal models and begin to explore the therapeutic
possibilities of viral-mediated gene delivery. Despite the caveats, advances in
neuropharmacology and the new biological perspectives on depression that
essay hold promise for the development of novel treatments- beyond those
offered by the monoamine hypothesis of depression.

- Most depressive patients only share 1 or 2 symptoms

- 35% of patients are refractory
- Electro-Convulsive Therapy reserved for those patients who do not respond
- CBT used in conjunction with pharmacotherapy

Evidence for Monoamines

- Catecholamine synthesis inhibition lowers mood in vulnerable patients.

- Markers- decreased levels of MHPG, a urinary marker of noradrenaline
degradation.
-decreased CSF levels of 5-HIAA, the main metabolite of 5-HT