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Depression is one of the most common mental disorders that has a high prevalence. Its characteristic effects are low state of mood, loss of interest in previously enjoyed activities, suicidal tendencies, weight changes and general feeling of despair and helplessness. It has been a major subject of research in its pathophysiology to try and determine the underlying causes. It is evident from several pieces of research literature that focus has been on neurotransmitter systems of dopamine, serotonin and norepinephrine for possible causes. Even though the exact mechanisms are not made clear, it has gone a long way to at least identify which receptors have made effective drug targets. Glutamate is the most abundant excitatory neurotransmitter and as such glutamatergic transmission has also been implicated in depression and has had interest steadily rise in its receptor pharmacology, with studies on individual receptors providing useful information on how different drug classes could possibly interact. Animal models have also provided a better understanding of the effect of potential antidepressant drugs. The most two common animal models are behavioural paradigms i.e. forced swim test (FST) and tail suspension test (TST), both of which assess the animals desire to escape an uncomfortable situation. These models have a good face and predictive validity and they are also inexpensive to carry out. The current review found that most of the drugs reported to have an antidepressant effect targeting glutamate were either its agonists, antagonists or drugs designed for monoamine targets, suggesting a similar mechanism of action. Acknowledgments
I would like to pass my gratitude to Dr F Freeman for her help and support in her supervisory role, my mother Mary Mufaya and colleague Nsama Mulongoti for their words of wisdom and encouragement. I would also like to extend my thanks to Usman Malik for helping to proof read the works and all well wishers.
List of Figures Page
Figure 1- Arrangement of glutamatergic synapse showing transporters and the main receptor subtypes..........................................................................10
Figure 2- Schematic representation of glutamate receptor
types and subunits...................................................11
List of Tables Page
Table 1-. shows the most common behavioural paradigms, the class of antidepressants and their advantages/drawbacks... ..........9
Table 2- Clinical data of patients with major depressive disorder....20
The past twenty years have seen a rise in the interest on depression and the amount of research being carried out on the underlying causes, possible drugs and targets of its treatments. There are several reviews available that focus on certain aspects e.g. involvement of different neurotransmitter systems such as monoaminergic and glutamatergic transmission (Hashimoto, 2009; Covington et al., 2010) to name but few. A lot of research has been carried out on the roles they could play in either cause or as targets of drugs.
This review aims to compare the use of glutamate based antidepressants with comparison to biogenic amines, paying attention to mechanisms of actions. The research involved review of current and past literature, comprising of both review and original research articles on different aspects of the topic. These were analysed to give a summary of main findings in relation to depression. This review also looks to examine other drugs classes that have potential for antidepressants, portraying antidepressant effects or merely because they share similar mechanisms with glutamatergic or monoaminergic receptors, such as G protein coupling (Kew and Kemp, 2005) or ions channel inhibition (Wegerer et al., 1997).
2 LITERATURE REVIEW
This chapter looks at the current literature on depression, assessment of symptoms and suggested theories of its etiology. It also examines current animal models used and the limitations associated.
2.1 What is Depression?
Depression is a devastating mood disorder which presents with several physiological symptoms such as significant weight changes, appetite loss, irregular sleep patterns and low concentration. The patient may also have feelings of helplessness, guilt, suicidal tendencies and little interest in activities once enjoyed (Hashimoto 2009; Krishnan and Nestler, 2008). Weight loss is not uncommon especially when stress is involved (Lou, et al., 2008). The disorder can be referred to as major depressive disorder (Yang et al., 2008) or manic depression/ bipolar disorder (Zhang et al., 2007).
It can be inferred that depression is a combination of symptoms; neurological, pathological and social (Segrin, 2000) and in young adults its manifestation can be as a result of them feeling inadequate as they progress through life. Anxiety and a degree of drug abuse can also contribute to the development of depression with the possibility of an incidence episode occurring with at least one in five chance a lifetime (Ansorge et al., 2007) with untreated incidences going on for more than several months (Kalia, 2005). It can negatively affect the quality of everyday aspects life and activities such as social and work (Kulkarni and Dhir, 2007). Not only is it debilitating to an individual or family, it also puts a burden with health services costs on treatment in the billions of dollars (Dardennes et al., 1999) and the development of drugs aimed to have as few side effects yet effective, given the span of symptoms.
2.2 Diagnosis of Depression
2.2.1 Test Scales
There have been a number of methods and different techniques used to assess depressive symptoms. In most cases, included are questionnaires like the Beck Depressio inventory (BDI) and the Centre for Epidemiological Studies Depression Scale (CES-D) which have a list of self-answer questions that assess the severity of symptoms. Other methods used were the Schedule for Affective Disorders and Schizophrenia (SADS), which is interview based and also (DIS) Diagnostic Interview Schedule (Gotlib et al., 1995). BDI and CES-D differ in that the BDI was used with people who already suffered from depression to give an indication of the depth of symptoms while CES-D can be used in young adults (Gotlib et al., 1995) making it a better initial tool for diagnosis. Most of the effects of any antidepressant medication is used with reference to either a change in the answers provided by the patients (Skolnick, 2007) or observations in animal models used (McArthur and Borsini, 2006)
Now more recently, the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV or DSM) is deemed to be cardinal as a guide when it comes to diagnosing depression (Kalia, 2005). Published by the American Psychiatry Association, since the first edition in 1952 (Sanders, 2010) it has been revised to be non biased and provide a backbone for diagnosis of several types of mental conditions.
The Hamilton depression rating scale (HAM-D) is another test scale that has a questionnaire style with multiple choice questions between 17 and 21. The severity of depression is gauged on the responses and is also a good indicator if any drug being assessed for antidepressants use is having an effect (Dilsaver et al., 1995).
2.3 Theories and Aetiology of depression
There are several proposed models and theories of depression based on environmental/behavioural changes and neurotransmitter pathophysiology (Kalia, 2006).
2.3.1 Monoamine Theory
Monoamine receptors include receptors for amine based neurotransmitters e.g. dopamine, serotonin, and noradrenaline. These are involved in different aspects of behaviour, for example, dopamine is associated with pleasure and reward (Lemke et al., 2006).
Parkinson's Disease (PD) sufferers have shown signs of depression (Lemke 2006). One of the underlying causes of Parkinson's disease is the progressive loss of dopaminergic neurons and this in turn weighs down the dopamine reward pathway and hence the reduced desire for pleasure (Lemke, 2006). This reduced dopamine availability can be related to the monoamine depletion theory of depression (Yang et al., 2008). It can be deduced that there is less amount of these neurotransmitters at monoaminergic synapses (Krishnan and Nestler, 2008; Yang et al., 2008) and this can be supported by reported low levels that have been noted in cerebral-spinal fluid (Ansorge et al., 2007; Hashimoto, 2009 and Stockmeier, 2003). Depression can also be caused by drugs that decrease the availability of monoamines for example Reserpine, used in the treatment of hypertension has depression like side effects (Krishnan and Nestler, 2008; Kalia, 2005) and is now rarely used. Drugs such as that increase the availability of these neurotransmitters have been seen to be useful as antidepressants (Ansorge, 2007) and work by either preventing the breakdown at the synapse or reuptake into the neuron. Examples are classes of SSRIs (selective serotonin reuptake inhibitors), SNRI (serotonin-norepinephrine reuptake inhibitors and MAOI (monoamine oxidase inhibitor) which have the advantage of having an instant effect. Slower treatments for mood depression take a while to have effect (Kalia, 2005). There is no particular way of pinpointing brain areas affected by depression as some of the associated symptoms can be difficult to observe in terms of brain activity (Krishnan, Nestler 2008)) in animal models as it is a manifestation of different presentations (Ansorge et al.2007).
Stress studies carried out by Lou, et al. (2008) on the hippocampus provide support to the involvement of serotonin in depression as the hippocampus plays a cardinal role in the limbic system, having direct connections to the reward pathway (amygdala, frontal cortex, nucleus accumbens) affecting cognition and mood changes.
2.3.2 Neurobiolgical Theories:Brain derived neutrotrophic factor
Brain derived neurotrophic factor (BDNF) has been implicated in the aetiology of depression with different levels in different brain areas exhibiting different depressive states (Covington, 2010). Prolonged treatment with fluoxetine has been shown to increase the excitatory signalling of BDNF (Ampuero et al., 2010) and this has been shown to lead to an increase in neurogenesis. BDNF has also been found to play a maintenance role in adult neurons and neuroplasticity (Yoshimura et al., 2009) and also found in lower than normal amounts in depressed patients, with a significant increase after treatment with antidepressants.
2.4 Animal Models
Animal models have to meet a certain validity criteria to represent as closely as possible the condition being modelled. The criteria according to McArthur and Borsini (2006) are face, (similarity to clinical condition), construct (closeness of how symptoms/treatments change) etiological (causes) and predictive validity (matching predictions in humans with the animal).
2.4.1 Forced Swim Test
The forced swim test (FST) is a behavioural paradigm that involves subjecting a rat to swim in a narrow tube out of which they cannot escape, usually over six minutes and after some time, the animal gives up and just does enough to keep afloat (Li et al., 2006). The immobility time is then recorded and noted as a factor of depression (McArthur and Borsini, 2006). Treatment with antidepressant drugs reveal that the animals would take longer before they gave up swimming, thereby spending less time depressed.
2.4.2 Tail Suspension Test
Like the FST, the tail suspension test (TST) is another paradigm is used to observe effect of treatment with antidepressants on behaviour of the mice. The mouse is suspended by the tail and usually carried out over six minutes (Gould et al., 2007; Kulkarni and Dhir, 2007), taking into account time before the animal gives up kicking the legs or trying to climb its tail. The time that the animal spends immobile is taken as a measure of depression as the struggle becomes a stressor (McArthur and Borsini, 2006) hence the animal is taken to be depressed.
The FST and TST enable a comparison to be made when treated with anti depressants as it would be expected of them to spend reduced time immobile (Deussing, 2006; McArthur and Borsini, 2006).
2.4.3 Chronic Unpredicted Mild Stress
Lou et al. (2008) carried out investigations which involved subjecting group of rats to chronic unpredicted mild stress (CUMS) and observed different aspects of behaviour which were related to depressive symptoms such as anhedonia, loss of weight, general isolation and also how they behaved in the forced swim test. Other experimental exposures included cage tilt, starvation, alternation of light/dark cycle. They found that the CUMS subjected rats lost a significant amount of weight compared to the unstressed control, had also a less preference for sucrose. There was a reduced expression of 5HT and NPY and concluded that the reduced expression of these two led to depression like symptoms in the rat.
The rats were treated with 5HT and NPY injected into the hippocampus and this effectively eliminated by way of blocking all the signs of depression like behaviours, with NPY being more effective at reducing the signs than serotonin. The rats were more mobile in the forced swim test and reared and groomed more than the CUMS exposed but not 5HT or NPY treated. These studies correlate with a review by Covington (2010) who reports emotional imbalance when hippocampal serotonin levels are low in knock-out mice. The CUMS thus serves as a model in its own right as the symptoms are reproducible in the animal.
2.4.4 Learned Helplessness/ Resident Intruder
Another model is learned helplessness, which affects the animals desire for a reward after subjection to unpleasant factors from which it cannot escape (McArthur and Borsini, 2006)) and no longer motivated. Sucrose preference aims to match the animals desire for reward (Lou, et al., 2008) as does intercrannial self stimulation. Mice were classed according to their aggressiveness after an electroconvulsant shock and then exposed to uncomfortable conditions such TST. Eventually, it was found that the most submissive mice preferred water to sucrose, and this was interpreted to anhedonic behaviour in depressed patients.
There are other models such as social isolation where the animal is introduced to a more aggressive animal and olfactory bulbectomy that aim to establish any associations that might be underlying in terms of neurological connections by lesioning (Duessing, 2006) but they are limited by the face and construct validity. The FST, TST and stress mentioned have a high sensitivity, cheaper and are easier to monitor changes upon treatment (Deussing, 2006). Because of this face and predictive validity, the FST and TST are the most commonly used paradigms when it comes to testing potential antidepressive drugs. Other considerations made in the employment of animal models such as TST and FST would be different strains of mice eliciting different behaviour (Kulkarni and Dhir, 2007a), with the mice facing a danger of hypothermia in the FST and TST only being applied to mice, not rats (See Table 1)
Forced swim test
Sensitive to antidepressants
Sensitive to acute treatment only
Easy to perform
Validity for non-monoamine
Risk of hypothermia
Modified forced swim test
Sensitive to antidepressant
Sensitive to acute treatment only
Easy to perform
Validity for non-monoamine
Risk of hypothermia
Tail suspension test
Sensitive to antidepressant
Sensitive to acute treatment only
Easy to perform
Validity for non-monoamine
Not applicable in rats
Applicable only in certain mousestrains
Measure of affective state and motivation
Further validation needed in modelsof depression
Responds to chronic antidepressant treatment
Measure of affective state and motivation
Further validation needed in modelsof depression
Responds to chronic antidepressant treatment
Table 1 shows the most common behavioural paradigms, the class of antidepressants and their advantages/drawbacks (Deussing, 2006)
GLUTAMATE AND DEPRESSION
Recently, interest has been in interest in the role of glutamate and its receptors in depression and the possibility of being the target for treatment.
Of all excitatory neurotransmitters, glutamate is the most predominant in the central nervous system and activates two different types of receptors; ionotropic and metabotropic.
(Cherlyn et al. 2010)
Figure 1- Possible arrangement of glutamatergic synapse showing transporters and the main receptor subtypes.
Glutamate is formed from the transamination of glutamine, a reaction catalysed by the glutaminase enzyme (Cherlyn et al., 2010). Glial cells then reconvert it to glutamine, where the vesicular glutamate transporters (figure 1) pack it into vesicles. The vesicular transporters (vGluT1 and vGluT2) load glutamate into vesicles presynaptically. Released glutamate reuptake is achieved via the glial cells, astrocytes and postsynaptic glutamate transporters (excitatory amino-acid transporters, EAAT1-5). The glutamate is converted between glutamine and glutamine form as opposed to producing metabolic waste after excitation from the synapse (Valentine and Sanacora, 2009) providing a very efficient recycling system. The advantage of having the glutamine/glutamate cycle also helps in neuroprotection as glutamine is inert; this offers some protection mechanism from excitotoxicity.
(Figure 2) Schematic representation of glutamate receptor types and subunits (Molnar and Nadler, 2001)
3.1 Ionotropic Glutamate Receptors
The ionotropic glutamate receptors, N-methyl-D-aspartate (NMDA), kainate and -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtypes, are the main receptors and mediate fast synaptic transmission. Figure 2 shows a broad schematic of glutamate and its receptors with their main activation mechanisms.
The ionotropic glutamate receptors NMDA, AMPA and Kainate are so called because they take their names from the most selective agonists that were tested on i.e. N-methyl-D-aspartate, α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid and 2-carboxy-3-carboxymethyl-4-isopropenylpyrrolidine respectively (Kew and Kemp, 2005) and they allow direct ion channel opening upon neurotransmitter binding to facilitate the passage of ions such as Na+ and K+ for generation of an action potential.
The NR1 subunit has eight splice variants while the NR2 has A-D. Two NR1 and two NR2 subunits combine in a heterotetramer formation to make an NMDA receptor channel (Ampuero et al., 2010) whereas the AMPA receptors channels are formed from either the same subunit or different subunits, in most cases GluR1 and GluR2/GluR3 subunits. AMPA receptor activation is paramount before the NMDA receptor can bind glutamate (Santos et al., 2003). This is because membrane depolarisation is required to remove the magnesium ion block on the NMDA receptor, which is achieved by exchange of sodium and potassium ions in and out of the postsynaptic cell (Poleszak et al., 2007). The NMDA receptors require co release of glutame, (Glycine or D-cycloserine) before the channel opens (Skolnick et al., 2009).
The kainate receptors GluR5-7 and KA1-2 (now known as GluK1-7) do not have much done on them as has been done on NMDA and AMPA receptors (Jane et al., 2009). Most of the studies carried out to investigate their function have relied on cloning of the receptors and also faced limitations with suitable antagonists as even the kainate agonist activated the AMPA receptors, presenting quite a challenge (Jane et al., 2009). Contractor et al., (2000) found that kainate receptor activation in the hippocampal CA3 region had either increased or attenuated plasticity at mossy fibres and perforant pathways respectively. There is not much evidence for the involvement of kainate receptors in depression although their regulatory role on glutamate could be investigated further (Lauri et al., 2007).
3.2 Metabotropic Glutamate receptors
Metabotropic or G-protein coupled receptors are so called because their structure has seven trans-membrane domains and upon activation, they trigger events that would indirectly result in ion channel opening or effect within then cell via second messenger systems such as Ca2+ (Kew and Kemp, 2005).
There are three groups of metabotropic glutamate receptors (mGluR) i.e. group I, group II and group III (Figure 2). They differ in the their mechanism in that group I mGluR use G proteins Gq and G11 to couple to phospholipase C (PLC) while the remaining two groups inhibit adenyl cyclase activity through Gi/Go coupling (Kew and Kemp, 2005) and are more defined in the presynaptic neurones where they play a part in the control of neurotransmitter release and also synaptic plasticity (Qian and Noebels, 2006).
Role of glutamate in depression
The group I mGluR1 and mGluR5 have been found to be involved in the pronunciation of glutamate excitability. The mGluR5 receptors have been found to play a role in producing anti antidepressant effects when treated with antagonist MPEP (2-methyl-6-(phenylethynyl)-pyridine) (Li et al., 2006).
AMPA receptors located in the prefrontal cortex have been reported to play a part in mood (Gould et al., 2007) and hence present a target of mood stabilisers. High levels of glutamate have been found in in plasma levels of depressed patients (Valentine and Sanacora, 2009), indicative of a fault in the glutamertergic system as glutamate is supposed to be reuptaken in the glia cells (Cherlyn et al., 2010). Even post-mortem studies on the frontal cortex of depressed patients showed increased glutamate levels (Valentine and Sanacora, 2009). However, there are limitations with post-mortem studies and hence the use of proton magnetic resonance spectroscopy (H-MRS), which allows for visualisation of specific molecules in the living brain, in this case glutamate although the total glutamate can be measured without distinction between extra/intra cellular levels.
As stress was also found to be a contributing factor to depression (Segrin, 2000), tail pinching of the rat was reported have caused an elevation of glutamate levels in the prefrontal cortex and hippocampus, which gradually decreased over a three hour pinching session (Valentine and Sanacora, 2009). This was thought to be because of the reuptake mechanism of the glial cells and EAAT working harder to avoid excitotoxicity.
3.3.1 NMDA receptor antagonists
Antidepressant effects have been observed with treatment of NMDA antagonists such as ketamine (Belozertseva, 2007; Skolnick, 2009), and this has led to a growing interest in the possibility of glutamatergic targets for antidepressant drugs (Pilc et al., 2008). NMDA receptors are heavily involved in the induction of long term potentiation (LTP) in the hippocampal region, and stress tests were found to interfere with its induction (Skolnick et al., 2009), causing depressive state.
Ketamine is an NMDA receptor antagonist that blocks the NMDA receptor response. As a result, there is more unbound glutamate which then binds to AMPA receptors (Hashimoto, 2009). Hashimoto (2009) went to report that antidepressant effects in treatment resistant patients were quick to show from a 40min i.v infusion of 0.5mg/kg of ketamine showing that at low doses, ketamine did have antidepressant effects. In addition, almost three quarters of the patients shill exhibited ketamine induced antidepressant effects after a week.
Berlozertseva et al., (2006) repots findings of mGluR5 receptors being targeted for antidepressant effects by their antagonists MTEP and MPEP. This could be in part to their post synaptic localisation, putting them in a better position to enhance glutamate excitation. Berlozertseva et al., (2006) then carried out investigations to compare the effects of MTEP and MPEP with that of Imipramine (tricyclic mood stabiliser). The treatments all resulted in reduced immobility in the forced swim test and tail suspension test.
mGluR7 receptors have been reported to play a role a role in depression through knock out studies (Hashimoto, 2009). When exposed to the forced swim test and tail suspension test, knock-out mice spent less time immobile. Wild type mice showed antidepressant behaviour when treated with mGluR7 agonist AMN082, like the knock outs. When treated with AMN082, the knockout mice showed no change in behaviour. Even though not much exact mechanism is unknown, the mGluR7 was found to be a potential target (Hashimoto, 2009).
From the literature reviewed so far on the etiology of depression and treatment targets, the past twenty years have seen the role of glutamate becoming a major of interest (Skolnick et al., 2009), because of the wide spread of glutermatergic transmission. This chapter aims to highlight the mechanisms of existing drugs and compounds that have the potential to be used as antidepressant drugs.
4.1 Drugs used in depression
Treatment of depression focuses on increasing the availability of monoamine neurotransmitters and this can be either by minimizing reuptake or breakdown (Krishnan and Nestler, 2008; Pilc et al., 2007) such as selective serotonin reuptake inhibitors and monoamine oxidase inhibitors but on the downside, they are with limits as it takes time to stabilise the mood related aspect of depression despite a relative quick response after administration (Kulkarni and Dhir, 2007a). Drugs such as Imipramine work to reduce the lack of motivation as observed after exposure to the learned helplessness paradigm (McArthur and Borsini, 2006).
4.1. 1 Lithium
There have been findings of short and long term lithium treatement having an anti depressive effect via the AMPA receptors, even though the mechanisms are not exactly clear (Gould et al., 2007) but bordered around changes in receptor numbers. To investigate the effect of lithium on the AMPA receptors, the tail suspension test (TST) and forced swim test (FST) models were employed. Two groups of mice were used with one treated with lithium by mixing it in food and the other to serve as a control. It was found that the treated rats spent less time immobile over six minutes compared to the control group. To test the involvement of AMPA receptors, an AMPA recptor anatagonist NBQX was administered after lithium treated food. The antidepressant effects were significantly reduced in both FST and TST and GluR1 and GluR2 membrane levels in the hippocampus were also significantly increased. It goes to say that the effect of lithium on AMPA receptors would be via the modulation of the GluR1 and GluR2 cell surface receptors (Gould et al., 2007) as there is no evidence to suggest that the antidepressive effects would be via peripheral administration but more on a neuronal level.
Another possible mechanism of the observed effect of lithium would be modulation of monoaminergic pathways (Bourin and Prica, 2007) i.e. dopamine and serotonin with evidence of increased 5HT1A receptor influenced behaviour.
Lithium on its own however would have detrimental effects because of the high dose that would be required in human. It is for this reason that it usually is used in conjunction with other antidepressant drugs (Bschor et al., 2007) especially with patients that show resistance to fist line treatment such as tricyclics or mood stabilisers (Bhagwagar and Goodwin, 2002). Lithium treated patients in combination also had a lower suicide rate than non lithium treated as reported by Bhagwagar and Goodwin, 2002).
Berberine is an extract from the Coptis japonica plant (Peng et al., 2007) and Berberis aristata that has its main effect as a monoamine oxidase inhibitor. It is mainly used an anxiolytic but also has anti-inflammatory and anti malaria. Peng et al., (2007) carried out a novel study to investigate its potential use as an antidepressant. Mice were treated with different classes of antidepressants i.e tricyclics (Desipramine), selective serotonin reuptake inhibitor (flouxetine) and MAO inhibitor (moclobomide) and serotonin-norepinephrine reuptake inhibitor (maprotiline) inhibitors. The mice were then subjected to FST and TST and their immobility taken as a measure of depression. It was found that there was a significant effect of BER in reduction of depressive behaviour induced by the FST and TST but insufficient to warrant use as a monotherapy (Peng et al., 2007; Kulkarni and Dhir, 2007b). The brain samples after the experiment contained more serotonin, noradrenaline and dopamine than the control animals, indicating a MAO inhibiting mechanism of berberine. The two studies carried out by Kulkanrni and Dhir (2007b) and by Peng et al., (2007) had more or less the same conclusion on the mechanism of bereberine, with the major difference that Kulkarni and Dhir were able to link the action with the involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway. Although it did not reach the same levels of efficacy as established antidepressants, the results of these two studies reveal that it could be used as a combination drug on administration with other drugs.
Flouxetine (FLX) is a selective serotonin reuptake inhibitor (SSRI) that is used as an antidepressant (Ampuero et al., 2010; Kulkarni Dhir, 2007a). In investigations to find out its effects, FLX was found to reduce immobility time in the FST and TST in a dose dependant manner, with the higher dose having the shortest immobility time (Kamei et al., 2003) and making it suitable for use as a monotherapy (Kulkarni and Dhir, 2007a). Fluoxetine works by preventing the reuptake of serotonin into the presynaptic and thus ensuring a greater amount of available at the synapse (Kamei et al., 2003). Drugs targeting specific pathways such as the SSRI are more favourable as they would have less interference with other neurotransmitter systems (Kulkarni and Dhir, 2007a).
The effects of fluoxetine are not immediate after administration but rather overtime, giving rise to speculation that is more than likely stabilizing structures and plasticity of neuronal structures e.g. formation of dendritic spines (Ampuero et al,. 2010). One way this is thought to happen is via anchoring of glutamate receptors onto the post synaptic density (PSD) with the help of scaffolding proteins such as PSD95 (El-Husseini et al., 2000). To this effect, dendritic spines were found to be in great abundance in brains with a greater expression of PSD95 (El-Husseini et al., 2000). In a study carried out by Ampuero et al (2010) to investigate the chronic treatment of fluoxetine in mice, it was found that there were resultant changes to the numbers of NMDA NR1/NR2 and AMPA GluR1/GluR2 subunits , especially at synapses with higher NR2 to NR1 ad GluR2 to GluR1 ratios.
Yang et al., (2008) carried out an investigation on the availability of the dopamine D2 /D3 receptor and dopamine transporter (DAT) on patients who satisfied the HAM-D scale. Using an imaging technique SPECT (single photon emission computed tomography), They found that fluoxetine was able to elicit a rise in striatal D2 and DAT availability correlated with significant changes in the HAM-D score (Table 2). It was concluded that measuring DAT availability would be more suited as an indicator for treatment response.
Table 2. Clinical data of patients with major depressive disorder (Yang et al., 2008)
Illness duration (weeks)
AD dose (mg)
Before AD treatment
After AD treatment
Mean ± S.D.
50.5 ± 7.2
3.40 ± 7.17
25.2 ± 7.6
11.8 ± 5.9
Key: HAM-D: Hamilton Depression Rating Scale; Fx: Fluoxetine; Vl: Venlafaxine;
The table above shows the results of the treatment with different antidepressants (AD). There are significant changes in the HAM-D score overall but more particularly for fluoxetine treatment groups.
Imipramine is a tricyclic antidepressant that works to increase availability of monoamines by preventing their reuptake into the presynaptic neurons (Kulkarni and Dhir, 2007a). It is used as a mood stabiliser. In experiments compared to a dual reuptake inhibitor venlafaxine, Imipramine was found to exert similar effects, with a higher preference for serotonin 5HT receptors than norepinephrine receptors (Kulkarni and Dhir, 2007a). Continuous treatment showed a decrease in mGluR2 and mGluR3 inhibition of cAMP formation but at the same time it had increased phosphoinisitol responses in the hippocampus (Pilc et al., 2008). As mood stabilizers usually take two to three weeks for therapeutic effect (Kalia, 2005; Kulkarni et al., 2007a), a quicker acclimatisation would be desirable. Pilc et al., (2008) found that administration of Imipramine with another mGlu receptor agonist LY379268, resulted in quicker therapeutic effects. with synaptic plasticity heavily involving glutamate (Kew and Kemp, 2005), it would come as no surprise of the metabotropic glutamate receptor having an antidepressant effect.
Dopamine is one of the monoamines implicatied in the etiology of depression (Yang et al., 2008). Studies by Lemke et al., (2006) on PD patients with depression found that the dopamine D3 receptor antagonist pramipexole was able to reduce anhedonia with significant differences between depressed and non depressed patients. When used in conjunction with Levodopa, a PD drug, depressive symptoms were also seen to have been significantly reduced.
One of the challenges in treatment for depression is that there have been patients who do not respond to conventional or first line drugs classes such as serotonin reuptake inhibitors (Zhang et al., 2007), which has led to alternative classes of drugs such as anticonvulsants/ antiepileptics or anxiolytics to be used. One such drug is carbamazepine, an anticonvulsant that has been found to have mood stabilisation properties (Zhang et al., 2007) in bipolar disorder. Carbamazepine is a GABA potentiator whose anticonvulsant activity is as a result of enhancing the inhibitory effect of GABA by stabilizing the sodium channels at voltage gated receptor s (von Wegerer et al., 1997). This review hypothesised that this sodium stabilizing effect could be applied to gluatamate's ionotropic receptors which are ligand gated (Kew and Kemp, 2005). In a study carried out by Dilsaver et al (1995) on adults with bipolar disorder it was found that twenty one days after treatment with carbamazepine 400mg daily, the HAM-D score was reduced similar to Zhang et al., (2007). However after the treatment, more than half of the 27 patients tested by Dilsaver et al (1995) entered remission, giving a possible indicator that perhaps carbamazepine was not effective at the dose or would have done better with co administration of another mood stabiliser like lithium. Another possibility is that the therapeutic window had not yet been reached so perhaps the study could have gone for longer, given that mood stabilisers take time to have a full therapeutic effect (Kalia, 2005). Co administration was found to elicit a quicker response (Dilsaver et al., 1995).
Most of the literature reviewed did not show any specific glutamate drugs but rather showed the effect of established amine targeting and potential drugs based on the receptor pharmacology. Use of NMDA, AMPA and kainate agonists/antagonists in experiments and clinical investigations alongside existing drugs has gone a long way to show that the glutamate receptors are potential targets. Other drugs used in the treatment of depression are venlafaxine, which is a dose dependant dual serotonin and norepinephrine reuptake inhibitor used in mood stabilisation (Kulkarni and Dhir, (2007a)
Both SSRI and SNRI drugs however, do have a drawback only because they can take time before mood stabilization, which can be a problem for patients with suicidal tendencies (Skolnick et al., 2009). The beneficial effects outweigh the negative and hence their preference over tricyclics whose side effects are less than desirable.
There is still much to be learnt although progress is being made in discovering underlying causes and novel targets for the treatment of depression. The use of animal models has made it easier to mimic aspects of the condition and allows for a cheap and effective way of seeing the effects of potential and existing antidepressants. The different properties of receptors make for unique targets as each one responds differently and attention has until recently been on monoamine based treatments. Knowledge of the mechanisms of glutamatergic transmission and its possible role in depression has come a long way and makes for interesting targets of treatment.
Recommendations and Limitations
Future studies could expand the investigation on the use of non conventional antidepressant drug classes such as anxiolytics, as one way or the other pharmacology of different receptors shares similarities in the mechanisms and general course of action.