DEPRESSION AFFECTS up to one fi fth of the popula-tion worldwide and is a leading cause of disability in both developed and developing nations. In New Zealand, major depressive disorder affects 16 per cent of the population, with higher risk for women and Mâori.

Depression increases a person’s risk of developing cardiovascular and other chronic physical illness and other mental disorders, as well as their risk of death from all causes.

The causes of depression are complex and largely unknown. Research has mainly focused on abnormal neurotransmission in key regions of the brain asso-ciated with mood and emotions. This has driven, and

in turn been driven by, development of drug thera-pies that regulate levels of neurotransmitters in the brain. The high rate of therapeutic failure for these drugs has widened research and broadened thinking about causes and treatments in depression. There is still much to be learned in this fi eld.

To best support people taking drugs to treat their depression, nurses need a detailed understanding of the effects of drugs on neurotransmission, and of the theoretical role disordered transmission plays in the development of mood disorders. Other mecha-nisms that may cause or contribute to depression need to be understood so future therapeutic devel-opments may be placed in context.

20 Kai Tiaki Nursing New Zealand * vol 19 no 8 * September 2013

By Georgina Casey

INTRODUCTION

The New Zealand Mental Health Survey1 shows a lifetime prevalence of mood disorder for New Zealanders of 20 per cent. The term “mood disorders” includes major depressive disorder (MDD), dysthymia (a

chronic, usually less severe form of depression) and bipolar disorder. For those with MDD, severity ranges from 35 per cent with severe depres-sion, 56 per cent with moderate, to nine per cent with mild symptoms.2

MDD is the second leading cause of disability worldwide after heart disease and is expected to become the leading cause in developed nations by 2030.3 It is also associated with an increased risk of death. Globally, there are 3000 suicide deaths each day, and for each completed suicide, there are 20 or more attempts.4 Suicide rates in New Zealand currently stand at 11.5 deaths per 100,000 population per year, with the highest rates seen in young males and Mâori.5

All-cause mortality is also increased in the presence of depression – people with depressive symptoms are twice as likely to die prematurely than those without. This risk increases to 3.32 times more likely in those with severe MDD, regardless of antidepressant therapy.2 People with concurrent depression and cardiovascular disease have increased risk of fatal myocardial infarction or stroke and poorer recovery rates following non-fatal episodes.2

Depression also places signifi cant burdens on individuals, their fami-lies and society. Those with depression are more likely to suffer from impaired social and intimate relationships, decreased employment and education opportunities, and reduced lifetime income.2 Family resources are often mobilised to address depression with on-going economic and social costs.

Antidepressants: their role intreating depression

LEARNING OUTCOMES After reading this article and completing the associated online learning activities, you should be able to:• Describe the normal events in neurotransmission within the brain.• Discuss risk factors associated with the development of major depressive disorder.• Outline possible physiological events underlying the development of depression.• Describe the actions of the main classes of drugs and other therapies in the treatment of depression.• Outline potential future treatments in the management of mood disorders.

PHOTO: istockphoto.com

21Kai Tiaki Nursing New Zealand * vol 19 no 8 * September 2013

By reading this article and doing the associated online learning activities, you can receive a cer-tifi cate for two hours of continuing professional development (CPD).Go to www.cpd4nurses.co.nz to complete the learning activities for this article. The online service costs $19.95 per article.

These articles are supplied by CPD4nurses, an independent education company. CPD4nurses is not an NZNO service.

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Individual and family costs, combined with treatment costs for depression (and associated physical disease), and loss of work productivity place an economic toll on society.6 In 2000, the cost of treatment, mortality and morbid-ity associated with MDD in the United Kingdom was calculated at £9 billion. Work and productivity costs of depression – absentee-ism, replacement/recruitment and “presenteeism” (being at work but not productive) – were estimated at £26 billion in 2007.7

Even when therapy is success-ful, there remains for many people a risk of recurrence, as well as the presence of residual symptoms that affect quality of life. Key symp-toms associated with MDD include depressed mood, anhedonia (loss of

At the same time, the neurotrans-mitter binds to receptors on the membrane of the axon terminal. This binding acts as a negative feedback and inhibits further release of the neurotransmitter.

Following receptor activation, the neurotransmitter diffuses away from its receptors and is taken back up into the presynaptic axon terminal for recycling. It is either reused or broken down by the enzyme mono-amine oxidase, which is found in the mitochondria of the axon.

Not all of the neurotransmitter is taken back up and recycled. Some of it diffuses away from the synapse and acts on different receptors in neighbouring neurons (and some-times even on their own neuron). These alternative receptors are cou-pled to second messenger systems

PHOTO: istockphoto.com

pleasure in life), irritable mood, diffi culty concentrating, and neuroveg-etative symptoms (disturbances to sleep and appetite).8

Current antidepressant drug therapies include selective serotonin reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors and the older, less specifi c monoamine regulating drugs. Recent controversy around use of ketamine in treatment-resistant depression has highlight-ed interest in new targets for drug therapy and alternative paradigms regarding the underlying pathophysiology of depression.

MONOAMINES IN DEPRESSIONThe development, nearly 50 years ago, of the monoamine hypothesis of depression has been a driving force behind research and drug develop-ment in the decades since.9 The monoamine hypothesis was developed following observation of antidepressant effects in drugs that increase synaptic concentrations of monoamine neurotransmitters. This has led to increasingly refi ned therapies that target specifi c aspects of neuro-transmission in the brain. The focus on monoamines has arguably been to the detriment of more novel research and drug development, but this is changing.10

Monoamine neurotransmitters are a family of complex chemicals that include 5-hydroxytryptamine (5-HT, or serotonin), noradrenaline, dopa-mine, histamine and melatonin. These are synthesised from a variety of amino acids through closely related pathways. The monoamine that is synthesised in a particular neuron or region of the brain depends on the presence of specifi c enzymes. Each monoamine neurotransmitter has its own receptors, transporter molecules, storage vesicles and associated signalling pathways but, because they share similar molecular structures, drugs targeting one type of monoamine will also affect others in varying degrees.

Normal neurotransmission When an action potential travels along a nerve and arrives at the axon terminal, it triggers the secretion of a neurotransmitter that allows the passage of a signal from one neuron to its neighbour via the synaptic cleft. Binding of a neurotransmitter to its receptor on a neighbouring cell’s membrane (the post-synaptic membrane) causes opening of ion channels. These may trigger an action potential in that neuron, or may prevent the fi ring of an action potential – inhibition (see Figure 1, p21).

inside the cells. Activation of these second messenger systems alters neuronal activity – this may include increasing or decreasing neurotrans-mitter synthesis, changing numbers or sensitivity of other receptors, remodelling the neuron and its synapses, and new neuronal growth.

Thus neurotransmitters have rapid, brief effects on neighbouring neu-rons by triggering or inhibiting action potentials, and slower, long-last-ing effects through modulation of the neurons’ structure and function. This second action probably accounts for the prolonged time it takes for antidepressant drugs to attain full therapeutic effect.

The monoamine hypothesisThe two key neurotransmitters implicated in the monoamine hypothesis are noradrenaline and serotonin. Noradrenaline in the central nervous system (CNS) is linked with arousal, motivation, reward and mood control.11 The roles of serotonin include regulation of sleep, wakefulness, appetite and mood. Excess stimulation of serotonin receptors by illicit drugs such as LSD and ecstasy causes hallucinations.11

Dopamine may also play a role in depression – many older antide-pressant therapies affected dopamine neurotransmission as well as noradrenaline and serotonin. Dopamine’s roles in the CNS are complex but, in relation to depression, they include motivation, reward, pleasure, addiction and perception of reality.11

The monoamine hypothesis suggests that, in the brain of the de-pressed person, there is dysfunction in neurotransmission of serotonin and/or noradrenaline, and perhaps dopamine, due to any of the follow-ing:1) Impaired neurotransmitter synthesis2) Impaired exocytosis and release of neurotransmitter3) Increased enzymes that break down the neurotransmitter4) Increased reuptake – either increased activity or increased numbers of transporters5) Decreased sensitivity or numbers of target receptors 6) Increased inhibitory feedback on the axon terminal

Support for the monoamine hypothesis comes from observations that drugs designed to increase neurotransmitters in the brain relieve symptoms of depression. Also, experiments where the concentration of serotonin is reduced will cause a relapse of depressive symptoms in people with depression who are in remission (but not in people who do

22 Kai Tiaki Nursing New Zealand * vol 19 no 8 * September 2013

not have depression to start with).12There is, however, considerable experimental and clinical evidence

to refute the central role of monoamines in depression. First is the observation that, while the drugs cause an immediate increase in the concentrations of monoamines in the brain, the therapeutic effects are delayed for some weeks. Secondly, some classes of drugs effective in treating depression do not act on monoamines and one drug (taneptine – not available in New Zealand) actually increases reuptake of serotonin. Thirdly, drugs that acutely increase monoamine neurotransmitters, such as cocaine and amphetamines, are not effective in depression.12 Fourth-ly, the rate of success for treatment with drugs addressing monoamine transmission is disappointing (approximately 70 per cent) and there is a high occurrence of residual symptoms and relapses.3,13

ANTIDEPRESSANT DRUGS AND MONOAMINESTricyclic antidepressants (TCA), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrena-line reuptake inhibitors (SNRIs) all increase the concentration of mono-amine neurotransmitters in the synaptic cleft, with varying degrees of specifi city. Older classes of antidepressants – TCAs and MAOIs – are very nonspecifi c, affecting serotonin, noradrenaline, and, to a lesser degree, dopamine. By contrast, the most recent antidepressant drug approved in the United States – levomilnacipran – is the fi rst to specifi cally target the noradrenaline reuptake transporter with much less effect on the serotonin transporter.14

All these classes of drugs cause immediate increase in neurotransmit-ter concentrations in the synapse, but do not have an immediate thera-peutic effect. In fact, therapeutic failure is not considered until after a person with depression has been taking medication for at least three to four weeks with no or minimal improvement. Full therapeutic effect may not be seen for up to 12 weeks.8 This strongly implies that it is the more complex actions of these drugs – neuroplastic changes such as altered receptor numbers and activity, and altered synaptic connections in the brain – that are most relevant.

Tricyclic antidepressantsThis class of drugs includes amitriptyline, nortriptyline, clomipramine, imipramine, doxepin, and the closely related mianserin. All these drugs act on the reuptake transporter molecules in the axon terminals (see Figure 1, C, right). They are not very specifi c to serotonin or noradrena-line, and have some action on dopamine transporters.

Also, TCAs act as antagonists on the receptors for noradrenaline, acetylcholine and histamine in both the CNS and peripheral nervous system. Blocking the action of these neurotransmitters accounts for many adverse effects of these drugs: postural hypotension, sedation, dry mouth, constipation and urinary retention. TCAs are also associated with numerous drug-drug interactions and are dangerous in overdose. They may cause QT-interval prolongation and sudden cardiac death in overdose or in those with high risk of cardiac dysrythmia.11

Monoamine oxidase inhibitors (MAOIs)Phenelzine and tranylcypromine are irreversible inhibitors of the mono-amine oxidase enzyme (MAO). MAO is associated with mitochondria and is the enzyme responsible for breaking down monoamines in the presyn-aptic terminal of neurons, reducing their availability for neurotransmis-sion. Inhibition of the enzyme increases the amount of noradrenaline, serotonin and dopamine in axon terminals. This causes “leakage” of monoamines into the synapse. If a person ingests other types of amines, such as tyramine or amphetamines, there is an abrupt increase in the release of neurotransmitters that may cause dangerous adverse effects.11

MAOIs are very non-specifi c, acting not only on MAO but on various

other enzymes throughout the body. This has a number of consequences, some of which are life-threatening. MAOIs cause hypotension, excita-tion, agitation and insomnia, increased appetite that can cause extreme weight gain and, rarely, liver damage. Most importantly, and the reason for their declining use in clinical practice, MAOIs interact with fermented amines in food to cause acute hypertension.

Ingested tyramine, found in alcohol, cheese, marmite-like spreads, fi sh, soy sauce and processed meats, is normally inactivated by MAO in the gut wall and liver, so has no effect on the body. In the presence of MAOIs, however, tyramine is able to enter the circulation and act on pe-ripheral nerve terminals to acutely displace noradrenaline and other neu-rotransmitters. The resulting abrupt dangerous increase in blood pressure gives rise to severe headaches and possible cranial haemorrhage.11

Other drugs that should be avoided while taking MAOIs include ephed-rine and amphetamine preparations, cough and cold remedies (contain-ing dextromethorphan), nasal decongestants, sinus and hayfever drugs and all other classes of antidepressants.

Moclobemide is a reversible inhibitor of MAO with fewer adverse ef-fects. Dietary restrictions are not considered necessary unless a person is particularly sensitive to tyramine, or ingests a very large quantity of tyramine-containing foods. It is recommended moclobemide be taken at

Figure 1. Events in neurotransmissionA – Action potential reaches axon terminal and triggers opening of calcium channels. Calcium enters axon terminal and initiates movement of vesicles to the membrane.B- Exocytosis of neurotransmitter contained within vesicles. Neurotransmitter dif-fuses across synaptic cleft and attaches to receptors on post-synaptic membrane. Receptor response activated.C – Neurotransmitter taken back up into presynaptic axon terminal by reuptake transporter proteins.D - Neurotransmitter repackaged for reuse or broken down by monoamine oxidase enzyme.E – Neurotransmitter also binds to presynaptic receptors that inhibit further secre-tion – a negative feedback mechanism.

post-synaptic membrane

presynapticinhibitoryreceptor

synapticvesicle

neurotransmitter

reuptaketransporter

receptor

monoamineoxidase

axon terminal

}synaptic cleft

SOURCE: Wikimedia Commons

23Kai Tiaki Nursing New Zealand * vol 19 no 8 * September 2013

the end of a meal to avoid MAO inhibition in the gut wall during meals.

SSRIs and SNRIsThese reuptake inhibitors, as the names suggest, target the reuptake transporter molecules in the axon terminal and prevent the removal of serotonin and noradrenaline from the synapse. This action is similar to that of TCAs but without any receptor antagonism that causes the main adverse effects of TCAs. SSRIs – fl uoxetine, citalopram, etc – are highly selective for the serotonin transporter. SNRIs, such as venlafaxine, target serotonin and, at higher doses noradrenaline transporters with some spill-over to dopamine transporters.

SSRIs are recommended fi rst-line drug therapy in New Zealand for treatment of depression that does not require specialist referral.8

An adverse effect of these drugs is an increase in the risk of abnormal bleeding, elevated in the presence of anticoagulant or antiplatelet ther-apy or nonsteroidal anti-infl ammatory drugs. Serotonin is an essential component in platelet activation. Drugs that affect serotonin transport-ers will interfere with platelet activation and, in combination with drugs that impair the coagulation cascade or with other aspects of platelet activation, bring a risk of increased bruising and abnormal bleeding.

Citalproam and some other SSRIs are associated with an increased risk of cardiac dysrhythmias (QT-interval prolongation) that can precipitate sudden cardiac death. This risk is lower than for TCAs.11

One further medication available in New Zealand for the treatment of depression is mirtazapine, which belongs to the class of alpha-2 antago-nists. This drug acts on alpha-2 adrenergic receptors and serotonin re-ceptors on the presynaptic membrane (the axon terminal). Here it blocks the negative feedback that would normally inhibit the further release of neurotransmitter into the synapse (Figure 1, E).

All these drugs are designed to increase the amount of neurotransmit-

ter available in the synaptic cleft. Because this alleviates the symptoms of depression for a majority of people, the supposition is that lack of seotonin and perhaps noradrenaline is the cause of depression. However, it is not determined whether the diminished response to seotonin in depression is a cause of depression, an outcome of depression, or merely a separate outcome of the process that leads to the development of de-pression.15 Other potential causes of depression are being investigated.

ATROPHY AND INFLAMMATIONPost-mortem examination and, more recently, functional neuroimaging have shown regional decreases or alterations in brain volume and activ-ity in depression. Most affected are regions such as the basal ganglia and thalamus – controlling alertness, arousal and salience – and the pre-frontal cortex and hippocampus – believed to mediate cognitive aspects of depression, such as feelings of guilt and diminished self-worth.10,12

Loss of function and neurons in these regions may be driven by infl ammation, which could account for depression linked with chronic illness or prolonged or extreme psychosocial stress.3,16 Interestingly, low levels of omega-3 fatty acids, used by the body to synthesise anti-infl ammatory protective mediators, have been linked with depression.16

The underlying processes are complex but infl ammation is believed to cause loss of the signalling chemicals that promote new neuronal growth and plasticity. Most attention is focused on brain-derived neurotrophic factor (BDNF) but toxicity due to excess glutamate – the main excitatory factor in the brain – is also considered a potential contributor.10,16 The term neuroplasticity refers to the formation of new synaptic connections between neurons. This process is now considered to underlie all changes in brain function both positive – eg the long-term actions of antidepres-sant drugs, motor learning and recovery after brain injury – and negative

SOURCE: Wikimedia Commons

NATIONAL AND international guidelines for treating depression recommend use of antidepressants in conjunction with other thera-pies for the initial treatment of moderate to severe MDD and as a secondary measure in mild MDD.1 In recent years there has been considerable public debate about the effi cacy of antidepressant drugs over placebo and the “medicalisation” of low mood states with subsequent overprescribing of these drugs. Accusations of confl icts of interest and publication bias abound. Furthermore, the focus on strictly biological processes in mood disorders is described as ignor-ing the psychosocial, cultural and external factors infl uencing the development of depression.2

A series of infl uential papers published since 2008 used meta-analysis of trial data to look at effectiveness of antidepressant therapy over placebo.3,4 The authors concluded that in all but very severe depression, there was no difference in improvement for people taking active drug vs placebo. But these studies cannot demonstrate whether an individual will respond to antidepressant therapy, especially since it is well-recognised that responses vary enormously between individuals and also between drugs given to the same individual. Meta-analyses such as these are based on averages across populations where some participants respond strongly to drug therapy while others are treatment-resistant.

Also, the majority of these studies measured outcomes after six to eight weeks (full effectiveness is not really evident for up to 12 weeks after starting therapy), and usually involved measuring a de-crease in depressive symptoms (rather than full remission or cogni-

tive and social function or quality of life measures). Another meta-analysis, this time of double-blinded withdrawal studies, showed 41 per cent of people who were switched to a placebo suffered a relapse compared to only 18 per cent who remained on active drug therapy.5 This supports the argument for effi cacy of these drugs in the group of patients for which they actually work.

Dramatically increased use of antidepressant drugs has been con-demned in recent media reports around the world. Critics and media have pointed to the convenience of drug therapy over addressing personal and societal issues, and the lack of evidence of effi cacy.6

Other authors argue that increased use is related to prescribing for conditions other than depression (eg neuropathic pain) and that there has been a shift from short-term use, where effi cacy is diminished, to more appropriate treatment durations (six months or more).7

The issue is complex, but so is depression – a heterogeneous disor-der about which we know very little. Antidepressant drugs are not the be-all and end-all of treatment but nor should they be dismissed from the armamentarium. Every person with depression is entitled to access to a full range of tools to support their recovery:

“Antidepressants are but one element available in the treatment of de-pression, not a panacea. Like ‘talking treatments’ (with which antide-pressants are entirely compatible), they can have harmful side-effects, and they certainly don’t help everyone with the disorder. But they are not overprescribed. Careless reportage has demonised them in the public eye, adding to the stigmatisation of mental illness, and erecting unnec-essary barriers to effective care.” – Professor Ian Reid7 •

Box 1: Do antidepressants really work and are they being overused?

* References for this article can be found at www.cpd4nurses.co.nz.

24 Kai Tiaki Nursing New Zealand * vol 19 no 8 * September 2013

Georgina Casey, RN, BSc, PGDipSci, MPhil (nursing), is the director of CPD4nurses.co.nz. She has an extensive background in nursing education and clinical experience in a wide variety of practice settings.

– eg stress-induced changes leading to depression in the fi rst place.15Infl ammatory mediators synthesised in response to stress (physical or

psychosocial) can cross the blood-brain barrier and increase production of infl ammatory cytokines within the CNS. This leads to recruitment of immune cells to the CNS and production of reactive oxygen species and other free radical agents that may:161) Decrease synthesis of monoamine neurotransmitters or decrease the numbers and sensitivity of their receptors, storage and transport mechanisms.2) Decrease synthesis of BDNF and interfere with its signalling path-ways, leading to decreased neurogenesis and neuroplasticity with loss of cells and synaptic connections.3) Abnormal glutamate release, reuptake, or signalling, including excess activation of the glutamate receptor (NMDA receptor), leading to exci-totoxicity – reduced levels of BDNF and other neurotrophic factors and neuronal cell death.

It is this last that may account for the rapid action of ketamine in reversing the symptoms of depression. Ketamine is an NMDA receptor antagonist used as a short-acting anaesthetic agent. Sub-anaesthetic doses have been demonstrated to rapidly reverse depressive symptoms but are associated with euphoric and psychotic adverse effects. A single dose affects depressive symptoms for up to seven days, even after the drug has been eliminated from the body, suggesting the drug acts by more than just blocking NMDA receptors. Experimental models have shown that ketamine rapidly increases the number of synaptic connec-tions in regions of the brain affected by stress-induced synaptic losses, possibly via a BDNF pathway and involving a second glutamate receptor called the AMPA receptor.13,17

Unfortunately ketamine itself is not a good prospect for antidepres-sant therapy. It has very low oral bioavailability so must be administered intravenously; it causes transient hallucinations and changes in blood pressure following administration, so must be supervised; and it has high potential for abuse.18 However, it has suggested targets for drug development that are being explored – the glutamate system and more specifi c antagonists of the NMDA and AMPA receptors.

Exercise is known to be effective in the treatment of mild to moderate depression and may act through the promotion of neurogenesis. BDNF, endorphins and serotonin levels are all increased by exercise and any of these will promote neurogenesis.19

Corticosteroid hormonesThe body increases production of corticosteroids in response to stress and, in at least some forms of depression, there is evidence of impaired control of corticosteroids leading to excess or diminished secretion. Corticosteroids have been shown to affect glutamate secretion and regu-lation in the brain, in a similar fashion to stress.13 Early-life exposure to stress affects functioning in the regulatory pathway for corticosteroids. This may cause inappropriate and exaggerated responses to environmen-tal stressors throughout life, leading to depressive illness.15

GENETIC AND EPIGENETIC FACTORSThere is no identifi ed specifi c gene that causes depression. There are, however, some genetic components, as shown by the increased risk associated with a family history of depression.12 Research has identi-fi ed a cluster of genetic polymorphisms (variations in genes) that affect neurotransmitter function in the brain. Polymorphisms associated with depression include those that regulate production and turnover of neu-rotransmitters and their receptors, second messenger systems, and the effect of BDNF on neural plasticity.15

There is, however, a great deal of inconsistency in the reports of genetic studies and increasingly there is discussion about the role of epigenetics in the development of mood disorders. Epigenetics describes

the link between gene and environment: exposure to external stimuli causes biochemical changes in cells that then alter the transcription of DNA. Thus, environmental events cause changes in cell activity without causing genetic mutations. Genes may be “silenced” or activated via this mechanism, or their activity reduced or increased. Epigenetic changes are long-lasting and may require active reversal – eg rats born to moth-ers who were poor nurturers showed life-long epigenetic modifi cations that could be reversed by fostering to more “maternal” rats.10 Some of the longer-term effi cacy of antidepressant drugs could involve reversal of epigenetic changes that have arisen through psychosocial stressors.

DISEASE AND MEDICATIONSCertain physical conditions are strongly associated with the development of depression, independent of the person’s life circumstances. The im-pact of systemic illness on mood may be due to direct impact on blood fl ow or a result of increased infl ammation, as described earlier.

Hypothyroidism and other endocrine disorders are common causes of depression. Mood disorders are also associated with neurodegenerative disorders such as Parkinson’s disease, multiple sclerosis and Alzheimer’s. Impaired blood fl ow to the CNS is also strongly implicated in the devel-opment of depression, eg due to vascular dementia, stroke, cardiovascu-lar disease, or microvascular changes associated with diabetes.12

Some drugs are particularly associated with increased risk of depres-sion. Among these are:20Psychoactive drugs: Alcohol, cannabis, barbiturates, opioids, anti-epileptic drugs and benzodiazepines.Cardiovascular drugs: Statins, beta-blockers, calcium channel blockers, digoxin and ACE-inhibitors.Hormone and metabolic therapies: Corticosteroids, oestrogens and alpha-interferon.

THE FUTUREWhile there are a number of theories about vulnerability to depression and contributing or causative factors, links between the biochemical/molecular events, neuronal functioning and symptoms of depression are largely missing. Research remains largely driven by drug development – the drug works, so its actions are then investigated.

Research on depression is hampered by a number of issues. The sub-jective nature of diagnostic criteria for depression affects the reproduc-ibility and reliability of clinical research. Animal models, however, must be interpreted with caution because they cannot replicate sophisticated or subtle behaviours associated with human responses in depression. Direct observation of the brain relies on post-mortem studies that do not allow functional analysis, and on neuroimaging techniques where changes in metabolic activity are assumed to refl ect neuronal activity.10 And we cannot yet determine whether any of the changes observed in the depressed brain are a cause or a consequence of depression.

Increasingly, the role of genetics in development of depression and responses to antidepressant therapies is being investigated. Genetic polymorphisms not only determine a person’s vulnerability to psycho-social stressors but also how their body responds to medication. Future therapies that target infl ammation may also provide benefi ts.

Over recent decades, few genuinely new antidepressant drugs have been marketed. With a shift away from focus on the monoamine hy-pothesis, there is an opportunity for new drugs that may provide more consistent benefi t to enter clinical practice. •

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