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Looking Beyond The Monoamine Hypothesis: Johan A Den Boer

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Reference Section

Looking Beyond the Monoamine Hypothesis

a report by
Johan A den Boer

Professor of Biological Psychiatry, Department of Psychiatry, State University Groningen

The monoamine hypothesis has dominated research depressives relative to controls using PET and (11C)
into the pathophysiology and pharmacotherapy of WAY-100635. A similar reduction was evident in the
depression for a long time. This has led to the parietal cortex, striate cortex and left orbital
development of antidepressants that are now more cortex/ventrolateral pre-frontal cortex. These data are
selective than the early tri- and tetracyclics from consistent with those of Sargent et al.,7 who found
which they have evolved. Alternative hypotheses decreased 5-HT1A-receptor-binding potential (BP) in
such as those involving adult neurogenesis or unmedicated depressed patients relative to healthy
components of the hypothalamicpituitaryadrenal controls in the raphe, mesiotemporal cortex, insula,
Johan A den Boer is Professor of (HPA) axis are either too premature or have not led anterior cingulate, temporal polar cortex, ventrolateral
Biological Psychiatry in the to drugs with improved antidepressant activity. pre-frontal cortex and orbital cortex. However, a
Department of Psychiatry at State
University Groningen, The Recent new approaches include DNA techniques subgroup of the subjects was scanned both pre- and
Netherlands. In 1989, he was the (identifying genes and gene expression)1,2 and post-paroxetine treatment and the 5-HT1A receptor
recipient of the Scientific Award
from the Dutch Society of Psychiatry,
proteomics (a complete inventory of all proteins).3,4 BP did not significantly change in any area.
the Ramaer medaille, for To date, they have not contributed to the
outstanding scientific research on the development of new drugs. Although many exciting Most brain imaging studies conducted in patients
biological determinants of anxiety
disorders. Since 1996, he has been developments are occurring, it does not appear as easy with major depression episodes (MDE) have been
a member of the board of directors to develop the next generation of antidepressant drugs able to identify abnormalities associated with
of the Graduate School for
that do not influence monoamines. In the meantime MDE.8,9 There is a large inter-individual variability
Behavioral and Cognitive
Neuroscience (BCN) at the University there may be no choice other than to make the best in severity and psychopathological features associated
of Groningen. In addition to clinical of the existing hypotheses. This is not as hopeless as it with MDE. This might be related to the habit of
neuroscientific studies in which
neuroimaging plays an important may seem, because there is still considerable potential treating major depression as a unitary construct,
role, he is involved in pre-clinical in the concept of monoamine reuptake inhibition. while recent evidence suggests that depression
research into gender differences and consists of several sub-components.
molecular biological consequences of
stress. Professor den Boer has Monoamines, Neuroimaging and
published in clinical, psychiatric, Sub-components of the A recent PET study with 11C-labelled 3-amino-
neuroscientific and pre-clinical
scientific journals. He is a
Depressive Syndrome 4-(2-dimethylaminomethylphenylsulfanyl) benzo-
Distinguished Fellow of the nitrile ((11C)DASB), a selective radioligand for the
International Society of Affective The monoamine hypothesis of depression5 does not 5-HT transporter (5-HTT), in patients suffering
Disorders (ISAD) and was appointed
President of the Interdisciplinary only propose the crucial involvement of monoamines from MDE investigated the contribution of
Society of Biological Psychiatry from in the therapeutic effects of antidepressant drugs but another factor associated with depressed moods
1992 to 1997. He is a member of
several international scientific
also suggests that depression is directly related to namely, the presence of dysfunctional attitudes and
organisations. Professor den Boer is decreased monoaminergic transmission. In view of the relationship thereof with the 5-HTT binding
also the Editor-in-chief of the Wiley recent developments in molecular biology, it is potential.10 Dysfunctional attitudes are negatively
Series on Clinical and Neurobiological
Advances in Psychiatry of which the relevant to consider what the actual position of this biased assumptions and judgements about the
first five volumes have been hypothesis is and whether recent findings (e.g. based world and oneself and constitute a negative
published. He is the Editor of the
on neuroimaging techniques) still support its validity. cognitive interpretative bias of the future. Most
Handbook of Depression and Anxiety
and Clinical Management of Anxiety studies have investigated the relationship with
and Co-Editor of the Textbook of There are new data that fit well into the monoamine depression as a syndrome and have ignored the
Biological Psychiatry. Professor den
Boers interdisciplinary interest is hypothesis. Many of them originate from positron presence of other variables such as dysfunctional
reflected in his recent book emission tomography (PET) studies. By using selective attitudes. Interestingly, no differences in 5-HTT
Neurophilosophy: Brain, radioligands, evidence was found for reduced pre- and BP were found among the entire sample of
Consciousness and Free Will (2003).
post-synaptic 5-hydroxy-tryptamine (5-HT)1A depressed patients compared with healthy controls.
receptor binding in depression. Drevets et al.6 Depressed patients with high regional 5-HTT BP
demonstrated that the mean 5-HT1A-receptor- (up to 21%) had higher levels of dysfunctional
binding potential (BP) was reduced in the attitudes. It has been suggested that an increased
mesiotemporal cortex and raphe area in unmedicated density of the 5-HTT may lead to increased 5-HT

1 EUROPEAN NEUROLOGICAL DISEASE 2006


Looking Beyond the Monoamine Hypothesis

clearance from the synapse, leading to reduced accumulating against a direct relationship between
availability of synaptic 5-HT. depression and a monoamine deficiency.21,22 For
example, current evidence concerning serotonin
Milak et al.11 have investigated the association between does not imply depression but rather aggressiveness,
different psychopathological clusters of the Hamilton failing impulse control and violent suicide as directly
Depression Rating Scale (HDRS) and resting glucose related to impaired brain serotonergic function.23
metabolism using 18 fluoride-fluorodeoxyglucose Moreover, most antidepressant drugs do not limit
((18F)-FDG) PET. They found distinct correlations therapeutic action to depression, but are also
between three HDRS factors and regional glucose successfully applied in anxiety disorders.2429
metabolism. The first factor, psychic depression, Differences in gene polymorphism and subsequent
showed a positive correlation with metabolism in the differential protein expression of the serotonin
basal ganglia, thalamus and cingulate cortex. The transporter do not appear to be related to familiar
second factor, sleep disturbance, showed a positive depression.30 However, a recent study indicates that
correlation with metabolism in limbic structures and the number of life events in combination with a
basal ganglia, and the third factor, loss of motivation, 5-HTT polymorphism could be an important factor
was negatively correlated with parietal and superior in precipitating symptoms of depression.31 Although
frontal cortical areas. Interestingly, this study shows that the monoamine hypothesis has been challenged by
positive correlations with aspects of depression severity several new data, it can safely be concluded that there
are subcortical ventral, ventral pre-frontal and limbic is sufficient evidence to support its use as conceptual
structures, whereas negative correlations are found in framework, in particular for pharmacotherapy.32
dorsal cortical areas.11
New Developments in
According to these neuroimaging studies, serotonin Augmentation Strategies
is likely to play a role in the neurobiology of
depression in at least a subgroup of patients, but is 5-HT1A receptor partial agonists have weak
not necessarily confined to the syndrome of antidepressant properties.3336 Pre-clinical studies have
depression. A more fruitful approach would be to shown that 5-HT1A receptor agonists induce the rapid
search correlates between processes in the brain and desensitisation of 5-HT1A receptors.37 In theory, co-
subcomponents of MDE, such as motivation, administration with a 5-HT1A receptor partial agonist
anhedonia, depressed mood, dysfunctional attitudes may improve the efficacy of an SSRI and reduce its lag
and sleep disturbances, instead of trying to find time, depending on the size and rate of desensitisation
neuronal correlates for depression as a syndrome. induced by the 5-HT1A receptor partial agonist.
Clinical evaluation of this concept has shown beneficial
Tryptophan Depletion effects, although the evidence is not conclusive.3841

Studies using tryptophan depletion support the role of Augmentation with 5-HT1A and
serotonin in the modulation of mood, as witnessed by 5-HT1B Receptor Antagonists
the ability of tryptophan depletion to lower mood.12
Smith et al.13 studied the effect of relapse following Microdialysis studies in rats have shown that the
tryptophan depletion on the cognitive function of increase in extracellular 5-HT elicited by a single dose
depressed patients. They reported an attenuation of of an SRI is augmented by co-administration of a
the task (verbal fluency) and related activation in 5-HT1A receptor antagonist.4247 In addition to the
the anterior cingulate during relapse, which was somatodendritic 5-HT1A autoreceptor-mediated feed-
correlated to an increase in depressive symptoms. In back, 5-HT release is also controlled by terminal
addition, tryptophan depletion produced a transient 5-HT1B receptors. A microdialysis study in ventral
exacerbation of depressive symptoms in obsessive- hippocampus has compared augmentation by a
compulsive disorder (OCD) patients responding to 5-HT1A with a 5-HT1B receptor antagonist.47
selective serotonin reuptake inhibitors (SSRIs).14 Augmentation by the 5-HT1B receptor antagonist
Moreover, inhibition of 5-HT synthesis by occurred irrespective of the dose of SSRI. However, in
p-chloropheny-lalanine or L-tryptophan depletion1518 cases of the 5-HT1A receptor antagonist, augmentation
caused a relapse of symptoms in depressed patients who was only seen at the highest doses of SSRI.
were successfully treated with SSRIs.19,20 Studies that
interfere with the synthesis of serotonin clearly Clinical Studies with Pindolol
demonstrate that this neurotransmitter plays a crucial
role in the therapeutic effect of SSRIs. A preliminary study with previously untreated
depressed patients suggested improvements in both
Some studies therefore support the monoamine latency and efficacy by combining treatment with
theory of depression, although evidence is also paroxetine and pindolol.48 Since then, many open-

EUROPEAN NEUROLOGICAL DISEASE 2006 2


Reference Section

label and controlled studies with pindolol have progenitor cells of newly formed cells in male rat
followed, albeit with variable success.49 It soon became brains. Interestingly, there appear to be gender
evident that the observed clinical effects of pindolol co- differences in response to chronic stress in rats, in that
administration could not readily be explained by the same stressor in female rats led to the increased
complete antagonism of somato-dendritic 5-HT1A survival of newly generated neurons.55,56
receptors. Based on pre-clinical studies, evidence has
been obtained that pindolol may exert its activity The inhibition of 5-HT synthesis influences
through the -adrenergic receptor and not by means of neurogenesis, whereas 5-HT1A and 5-HT2A receptor
an interaction with the 5-HT1A receptor.50 antagonists reduce the number of dividing cells.57 A
number of compounds, such as 5-HT1A agonists that
Augmentation by 5-HT2C Receptor possess anxiolytic and (albeit) weak antidepressant
Antagonists Pre-clinical Studies effects in patients, enhance the formation of new cells
in the hippocampal area.58,59 In addition, the brain-
Recently, evidence was presented for a novel derived neurotrophic factor (BDNF) has positive
augmentation strategy based on 5-HT2C receptor effects on the survival of newly born neurons.60,61
antagonism.51 Augmentation of extracellular 5-HT
was observed in rat hippocampus and cortex with A variety of other molecules play a role in
citalopram, sertraline and fluoxetine. The effect was neurogenesis, including epidermal growth factor
at least of a similar magnitude to that seen with (EGF), insulin-like growth factor (IGF) and
5-HT1A and 5-HT1B receptor antagonists.47 Genetic transforming growth factor-alpha (TGF-).62 As so
elimination of these receptors in mice (5-HT2C- many different influences may have an impact on the
knock-out mice) also augmented the effects of SSRIs proliferation and survival of newborn cells, more
on extracellular serotonin levels in the brain. research is needed to disentangle various molecular
Antagonism of the 5-HT2C receptor resulted in a processes involved in neurogenesis in order to
significantly increased antidepressant effect of SSRIs. establish its exact role in antidepressant therapy.

The Neurogenesis Hypothesis Neuropeptides

Previous assumptions that neurogenesis does not Neuropeptides are able to modulate monoaminergic
occur in the adult brain appear to be false. In at least transmission in a regionally specific manner, leading
two areas, the subgranular layer (SGL) of the to their potential to augment the effects of SSRIs in
hippocampal dentate gyrus and the subventrical zone differential brain areas. Although there are numerous
(SVZ), neural stem cells have been demonstrated to candidates, the discussion considers substance P (SP),
proliferate. It has been proposed that adult neuro- corticotropin releasing hormone (CRH), oxytocin
genesis could play a role in both the neurobiology (OXT) and arginine-vasopressin (AVP).
and pharmacotherapy of depression.52,53
Substance P
A recent study by Banasr et al.54 investigated the role
of several 5-HT receptor subtypes in serotonin- It has been suggested that SP concentrations and
stimulated neurogenesis. Although the various neurokinin 1 (NK1) receptor densities are altered in
agonists and antagonists could have been more depression.6365 Furthermore, a study in socially stressed
selective, the study clearly suggests a role for 5-HT1A, tree shrews demonstrated that both the NK1 receptor
5-HT1B, 5-HT2A and 5-HT2B receptors in adult antagonist L-760735 and clomipramine were able to
neurogenesis in SGL and/or SVZ. This might be a normalise several neuroplasticity parameters.66 It is
confounding factor with augmentation strategies noteworthy that the NK1 receptor antagonists, when
based on the antagonism of these receptor subtypes, combined with an SSRI, augment 5-HT release in
with the possible exception of 5-HT1B receptors, mice by modulating substance P/5-HT interactions in
which decrease neurogenesis in SVZ upon activation. the dorsal raphe nucleus.67 Unfortunately, the outcome
of clinical trials was disappointing, which has prompted
The open question is therefore still whether several pharmaceutical companies to discontinue
antidepressants need an effect on neurogenesis and development of NK1 receptor antagonists.68
the survival of newborn neurons to enable them to
exert their antidepressant/anxiolytic effects. Corticotropin-releasing Hormone

Stress and glucocorticoids have repeatedly been Antidepressants have a common trait they restore
shown to decrease hippocampal neurogenesis.55 the negative feedback between corticosteroids and
Acute and particularly chronic unpredictable stress the HPA-axis, possibly by increasing corticosteroid
have also been shown to impair the proliferation of receptor gene expression. Notably, the CRH1

3 EUROPEAN NEUROLOGICAL DISEASE 2006


Looking Beyond the Monoamine Hypothesis

receptor antagonist R121919 significantly reduced CREB, a stimulus-induced transcription factor,


depression and anxiety scores,69 without a faster onset indicates that specific target genes may also be
of action than regular antidepressants. regulated by antidepressant treatments.87

CRH is also a modulator of neuronal activity in other BDNF is among the many potential target genes that
brain areas the question now arises of whether there could be regulated by CRE. Pre-clinical studies have
is a role for the augmentation of SSRIs with CRH reported the reduced expression of BDNF following
receptor antagonists. Interactions between CRH and stress, yet, more importantly, reduced CSF BDNF
5-HT in dorsal raphe nucleus may be of particular levels were also observed in depressed subjects.90 These
interest in the pathophysiology of depression, as findings support a potential role for BDNF in
witnessed by the increased CRH immunoreactivity depression and suggest its involvement in the actions of
in the dorsal raphe nucleus of depressed suicide stress and stress-related affective disorders.91 Further-
victims.70 Some authors have suggested that more, the neurotrophin intracellular cascade appears to
combining antidepressants with CRH1 and NK1 be a common target of antidepressants, independent of
receptor antagonists might help to individualise and their pharmacological profile.92 Together, these lines of
optimise efficacy and minimise side effects.71 evidence provide new insight into the mechanism of
antidepressant action and suggest novel targets
OXT and AVP regarding the development of therapeutic agents.

The neuropeptides OXT and AVP are long-acting Compounds that selectively target the CREB-BDNF
neuro-modudulators and, in addition to their pathway could have therapeutic merit. It is beyond the
peripheral functions, they may be involved in stress scope of this review to elaborate in detail on all the
responses, learning and memory. Furthermore, candidate targets; however, some key possibilities will
AVP is co-localised with CRH. In animal models, be highlighted. There are several components of the
OXT has anxiolytic effects while AVP has BDNF intracellular signalling cascade that could serve
anxiogenic effects. A recent study has shown that as a target for drug development, i.e. protein kinase
the CRH1 receptor antagonist SSR125543A, the A,9395 phosphatidylinositol 3-kinase (PI-3-K),96 B-cell
V1b AVP receptor antagonist SSR149415 and the lymphoma 2 (bcl-2),97 glycogen synthase kinase 3
clinically effective antidepressant fluoxetine all (GSK-3)98 and the mitogen-activated protein kinase
reverse chronic mild stress-induced suppression of (MAPK).99 Compared with drugs targeted at
neurogenesis in mice, probably through increased neurotransmitter receptors, compounds that act at
expression of the cyclic adenosine monophosphate intracellular sites are likely to be less selective, yet the
(cAMP) response element-binding protein (CREB) existence of multiple forms of these intracellular
in dentate gyrus.72 Post-mortem studies and clinical components could provide regional specificity, due to
studies in depressed patients suggest the their characteristic expression patterns in the brain and
involvement of AVP and OXT.7376 Interestingly, divergent regulatory mechanisms. Co-administration
the acute effects of SSRIs on OXT release are of agents with different primary mechanisms may even
mediated by 5-HT1A and 5-HT2A/C receptors, but prove to be effective in patients resistant to
not by 5-HT1B and 5-HT3 receptors.77,78 conventional antidepressants. An overview of enzymes
and proteins involved in the transduction of
Beyond Receptors neurotrophic signals and their cellular actions is given
in Table 1.
The interaction between neurotransmitters and their
receptors also involves the regulation of intracellular It should be in the interests of pharmaceutical
pathways and second messenger signals within cells, companies to extend their ambitions by developing
which in turn affects how these systems interact and compounds with the cAMP-BDNF pathway in mind.
function. Recently, the cAMP second messenger Serotonin seems to be a good starting point, as many
system has gained particular interest owing to its of its receptor subtypes are either directly coupled to
involvement in antidepressant action and its the cAMP system or influence this pathway at more
implication in the pathophysiology of depression.79,80 downstream sites, such as CREB. The multiple
Chronic administration of antidepressants induces signalling cascades possibly involved are very complex,
adaptations of the cAMP pathway at several levels. and due to the large overlap and convergence of these
Increased CREB protein expression, for instance, is pathways, further research is needed to elucidate
associated with cAMP-mediated gene transcription which signalling pathways are crucial in the regulation
and may be part of the mechanism underlying of the pathophysiological events associated with
antidepressant activity.8185 In contrast, chronic stress components of mood disorders and which are most
has been reported to decrease CREB-mediated relevant for the development of more efficient drugs
transcription in the brain.86 The up-regulation of with fewer side effects.

EUROPEAN NEUROLOGICAL DISEASE 2006 4


Reference Section

Table 1: Enzymes and Proteins Involved in the Transduction of Neurotrophic Signals and in Their
Cellular Actions

Protein/Enzyme Function
Ras MAPK kinase kinase kinase
MEK1 MAPK kinase 1: it is responsible for the dual phosphorylation that activates ERK1 and 2
ERK1 and 2 MAP Kinases: they are involved in the transduction of neurotrophin signals and play important
roles in the adult brain modulating synaptic plasticity and neuronal survival. They are activated by
MEK1: phospho-ERKs can phosphorylate a broad variety of proteins and transcription factors
including microtubule-associated proteins, CREB and Fos.
PI-3-Ks The PI 3-kinase activities have been shown to be necessary for many different cell regulatory
pathways. Their functions are crucial during mitogenesis but also in terminally differentiated cells.
In neurons, they have a fundamental role in the neurotrophin-mediated survival.
Protein kinase B Serine/threonine kinase downstream the PI-3K. This enzyme plays a pivotal role in the
(Akt-1) modulation of survival in neurons regulating the activity and expression of several pro- and
anti-apoptotic proteins, including bcl-2, p-53 and GSK-3-.
p53 p53-protein functions include maintenance of DNA stability, control of mitochondria integrity and
regulation of apoptosis. p53-mediated apoptosis may involve multiple mechanisms, including the
interference with the growth factor-mediated survival signals. The inhibition of p53 functions and
expression appears to prevent apoptosis.
bcl-2 bcl-2 proteins are involved in the regulation of cell death. Many of these proteins show
widespread expression and are also expressed in the nervous system in developing and adult
organisms. A physiologic role for bcl-2 in neuron survival has been shown: these proteins have
been shown to protect neurons from a wide array of toxic insults.
GSK-3 Glycogen synthase kinase-3- (GSK-3-) is a serine/threonine protein kinase ubiquitously
expressed and involved in several neuronal functions including cytoskeleton stability and apoptosis.
GSK-3- has been show to be the target of several intracellular cascades. PKA and Akt have been
reported to phosphorylate GSK-3- inhibiting its pro-apoptotic activity.
bcl-2 = B-cell lymphoma 2, CREB = cyclic adenosine monophosphate (cAMP) response element-binding, ERK = extracellular signal-regulated kinase,
GSK-3 = glycogen synthase kinase 3, MAPK = mitogen-activated protein kinase, MEK1 = MAPK, PI-3-K = phosphatidylinositol 3-kinase. Source: Trentani et al. (2003).

Other factors that may be involved in the Conclusions


pathophysiology of depression are beyond the scope
of this article.68 Although several theoretical questions await further
investigation, recent studies indicate that various
Future Developments augmentation strategies are possible in the treatment of
depression. Firstly, augmentation with 5-HT1A
Traditionally, the focus in research has been on receptor antagonists remains an interesting but not
neurons, their neurotransmitters and receptor- convincingly proven strategy. Several pharmaceutical
subtypes, but recent evidence suggests that glial cells in companies have now been able to develop an SSRI
the brain (such as astrocytes) have a much wider range with potent 5-HT1A receptor antagonistic properties.102
of functions than originally thought, such as synaptic
formation and synaptic plasticity. It is now known that Augmentation with 5-HT1B receptor antagonists
the adult central nervous system (CNS) has an mght be the most powerful strategy to increase
impressive regenerative capacity through the extracellular 5-HT levels, although clinical studies
mechanism of neurogenesis. Interestingly, there appear are lacking.
to be neurogenic niches in the brain in which
astrocytes play a key role.100 Due to the fact that Augmentation with 5-HT2C receptor antagonists is
astrocytes are sensitive to changes in their immediate another interesting option. It may not be as potent as
environment they could be future drug targets, as they 5-HT1B augmentation but it has several advantages
may have the ability to restore neurogenesis. In compared with the strategies based on antagonism of
addition, astrocytes involved in synaptic regulation are the classic 5-HT autoreceptors.
able to respond to synaptic activity changes by releasing
neuro-transmitters, providing bi-directional signalling The neuropeptides discussed have been associated
pathways with neurons in their surroundings.101 Future with either HPA-axis activity, adult neurogenesis or
research will help to understand exactly how both. Accordingly, antagonists of neuropeptide
neurotransmitters are released by glial cells and perhaps receptors, with the likely exception of oxytocin
their potential as targets for new psychotropic drugs. receptors, may be suitable partners for SSRIs, in

5 EUROPEAN NEUROLOGICAL DISEASE 2006


Looking Beyond the Monoamine Hypothesis

particular regarding the stress-related symptoms of although life-events are not single events. The
depression. Finally, a remark is in place concerning available data suggest that a depressive episode may
the validity of the concept of major depression. be the result of a pile-up of negative stimuli and not
the result of single life-events.103 The chronicity of
Firstly, several previously described studies suggest depression may also be a myth people live by. In the
that depression cannot be regarded as a single same study it was found that 75% of the subjects with
construct. Secondly, in a recent study using time-to- depression recover within a year and 50% within
event data from a large epidemiological survey, it was three months. Part of the contradictory results in
found that for reversible depression the fractional neurobiological studies could be explained by the
probability of recovery is independent of the fact that these patients are included in studies, while
preceding history. There is no doubt that life-events in fact it can be questioned whether it is justified to
may lead to depression in susceptible individuals, judge these people as being ill.

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