To understand psychiatric disorders, it is important to have a working understanding of the normal structure and function of the nervous system. The central nervous system (CNS; brain, spinal cord) and peripheral nervous system (PNS) are made up of neurones and glial cells (sometimes called neuroglia) as explained on the slide.[Tortora & Derrickson, 2009; Martin, 2003]
The neurone constitutes the functional unit of the nervous system; there are over 100 billion neurones in the brain.[Purves, Augustine, & Fitzpatrick et al., 2008; Martin 2003] Each neurone has the ability to interact with and influence many other cells, which creates a system of intricate complexity.[Purves, Augustine, & Fitzpatrick et al., 2008] There are several different classes of neurones – a simplified neurone is shown on the slide, along with explanations of its various component parts.[Martin 2003]
Although there are different types of nerve cells, the complexities of human behaviour stem not from the specialism of different types of neurones, but rather from the association of a great many neurones into coherent, and precise, anatomical circuits.3 In this way, nerve cells with similar properties can effect a variety of different functions, depending on how they are interconnected.[Kandel, Schwartz & Jessell, 2000]
Neurotransmitters – chemicals in the nervous system that transmit nerve impulses between neurones.Action potential – in neurophysiology, an electrical charge that moves through an axon
The cerebral cortex is the main functional unit of the cerebrum.1 The three main functional areas of the cerebral cortex are:[Tortora & Derrickson, 2009; Price & Wilson, 2003]
The surface of the brain is highly convoluted, with folds and grooves.[Martin, 2003] These convolutions are an evolutionary adaptation that allows a greater surface area to fit within the confined, and limited, space of the skull.[Martin, 2003] The elevated convolutions are called ‘gyri’, and the grooves are called ‘sulci’, as shown on the slide.[Martin, 2003]
Gustatory – relating to the sense of taste.Olfactory – relating to the sense of smell.Nuclei – in neuroanatomy, localised masses of grey matter in the CNS.
The brain can be thought of as comprising five ‘lobes’ – the four lobes of the cerebral cortex and a fifth lobe, the insula, deep within the brain, as shown on the slide.[Martin 2003; Tortora & Derrickson, 2009; Price & Wilson, 2003] The lobes of the cerebral cortex are named after the cranial bones that overlie them (frontal, parietal, occipital, and temporal).[Martin 2003]
The lobes have distinct functions. The frontal lobe has a diverse range of behavioural functions, including movement, speech, cognition, and emotion.[Martin 2003] The parietal lobe mediates perceptions of touch, pain, and proprioception.[Martin 2003] The occipital lobe can be thought of as the visual processing centre, containing the primary visual cortex.[Martin 2003] Finally, the temporal lobe controls a range of sensory functions, and is important in memory and emotion.[Martin 2003]
Information moves through the nervous system via two integrated forms of communication – electrical neurotransmission and chemical neurotransmission, as shown on the slide.[Kandel, Schwartz & Jessell, 2000]
An action potential is generated at the origin of the axon following sufficient excitatory stimulation of the neurone. The action potential is created by movement of electrically charged particles (ions) in and out of the neurone through pores (ion channels) in the cell membrane in a particular pattern, travelling along the length of the axon.[Kandel, Schwartz & Jessell, 2000] When the action potential reaches the axon terminal it stimulates the release of chemical neurotransmitters.[Kandel, Schwartz & Jessell, 2000] After the action potential has induced the release of chemical neurotransmitters, the neurotransmitters pass information to the next neurone.[Kandel, Schwartz & Jessell, 2000]
Neurones do not physically touch one another; two neurones are separated by a gap, known as a synaptic cleft.[Kandel, Schwartz & Jessell, 2000] Because neurones do not touch, and an action potential cannot ‘jump’ across a synaptic cleft, the signal must be converted to a chemical signal to enable communication between neurones to occur.[Kandel, Schwartz & Jessell, 2000] The presynaptic neurone uses chemical signals (neurotransmitters) to increase (excite) or decrease (inhibit) the generation of action potentials in the postsynaptic neurone. It is also possible to effect other biochemical processes, such as cell signalling pathways, in the postsynaptic neurone. This complex interconnectivity gives rise to the rich functional communication network that is the central nervous system.[Kandel, Schwartz & Jessell, 2000]
Presynaptic neurone – a neurone from which an electrical impulse is transmitted across a synaptic cleft to a postsynaptic neurone by the release of a chemical neurotransmitter. Postsynaptic neurone – a neurone to which an electrical impulse is transmitted across a synaptic cleft by the release of a chemical neurotransmitter from the axon terminal of a presynaptic neurone.
The idea that neurotransmission occurs at synapses and is mediated by chemicals was, at first, a contentious issue.[Purves, Augustine & Fitzpatrick et al., 2008] It was in the first half of the 1900s that experiments proved chemical neurotransmission occurred.[Purves, Augustine & Fitzpatrick et al., 2008]
The process is outlined in brief on the slide.[Purves, Augustine & Fitzpatrick et al., 2008; Kandel, Schwartz & Jessell (eds), 2000; Tortora & Derrickson, 2009; Sadock, Sadock & Ruiz (eds), 2009] Briefly, an action potential arrives at the terminal end of the presynaptic neurone, which means that the membrane potential at the terminal is altered.[Purves, Augustine & Fitzpatrick et al., 2008] This altered potential causes voltage-gated ion channels to open, leading to a rapid influx of calcium (detail not shown on slide).[Purves, Augustine & Fitzpatrick et al., 2008] The increased calcium within the neurone terminal (which is just a transient effect) causes vesicles to fuse with the membrane, and release their contents into the synaptic cleft.[Purves, Augustine & Fitzpatrick et al., 2008] Among the released contents are neurotransmitters, which bind to specific receptors on the postsynaptic neurone.[Purves, Augustine & Fitzpatrick et al., 2008] The effect of this binding varies, but usually leads to altered conductance of the postsynaptic neurone, and the propagation of the action potential.[Purves, Augustine & Fitzpatrick et al., 2008]
Vesicle – a membrane-enclosed sac that stores or transports substances.
Receptor – a protein molecule on a cell membrane that binds to a specific chemical, such as a neurotransmitter or drug, and produces a specific physiological effect.
Reuptake – a mechanism by which a neurotransmitter is taken back into the axon terminal that released it; the most common mechanism for removal and inactivation of neurotransmitters.
Astrocyte – a class of glial cells; functions include maintenance of extracellular ionic environment, and structural and metabolic support of neurones.
Diffusion – in regard to neurotransmission, a mechanism by which neurotransmitters drift out of the synaptic cleft.
There are many different neurotransmitters in the CNS, each binding to a specific receptor type which has a distinct distribution and role within the CNS.[Purves, Augustine & Fitzpatrick et al. (eds), 2008; Kandel, Schwartz & Jessell (eds), 2000; Stahl, 2013] Some common neurotransmitters are listed in the table on this slide. Defects in many neurotransmitter pathways have been implicated in psychiatric disorders.
The variety of neurotransmitters that operate within the CNS adds to the functional complexity of the brain.[Purves, Augustine & Fitzpatrick et al., 2008] Different neurotransmitters can produce different responses on the same neurone; e.g., a neurone might be excited by serotonin but inhibited by the binding of GABA.[Purves, Augustine & Fitzpatrick et al., 2008]
Exactly what constitutes a neurotransmitter has been the subject of some disagreement but, generally, a neurotransmitter must:[Purves, Augustine & Fitzpatrick et al., 2008]
Serotonin (also known as 5-HT) is a neurotransmitter that is found throughout the body.[Brunton, Lazo & Parker (eds)., 2006; Stahl, 2013; Purves, Augustine & Fitzpatrick et al., 2008] The wide dispersal of serotonergic neurones throughout the brain enables serotonin to be involved in modulating diverse body functions. Body functions modulated by serotonin include:[Brunton, Lazo & Parker (eds)., 2006]
Noradrenaline acts on two classes of adrenergic receptor, α and β.[Purves, Augustine & Fitzpatrick et al., 2008] Noradrenergic neurones project widely throughout the brain, and there are many brain areas where serotonin, noradrenaline and dopamine projections overlap, allowing interactions.[Stahl, 2013]
Noradrenaline and the locus coeruleus are thought to have important input into the control the CNS exerts over mood, cognition, stress, arousal, pain, and other functions.[Stahl, 2013; Dunn & Swiergiel, 2008] Malfunction of the locus coeruleus is thought to underlie disorders such as depression, anxiety, and disorders of attention and information processing.[Stahl, 2013]
Low or abnormal noradrenaline activity is, theoretically, characterised by impaired attention; concentration, working memory and information processing difficulties; as well as psychomotor retardation, fatigue, and apathy.[Stahl, 2000] In addition, abnormalities in the noradrenergic projection to the hypothalamus, which mediates stress response, are indicated in depressive and anxiety disorders.[Dunn & Swiergiel, 2008]
Dopamine is believed to be involved in motivation, reward, and reinforcement.[Purves, Augustine & Fitzpatrick et al. (eds), 2008] Dopamine also plays an essential role in the control and coordination of movement.[Purves, Augustine & Fitzpatrick et al. (eds), 2008]
Dopamine receptors all influence the activity of the second messenger, cyclic AMP, which is involved in many biochemical processes within a neurone.[Kandel, Schwartz & Jessell (eds), 2000] Dopamine receptor subtypes D1 and D5 increase the levels of cyclic AMP, whereas D2, D3, and D4 subtypes decrease the levels of cyclic AMP.[Kandel, Schwartz & Jessell (eds), 2000] Thus, depending on which receptor subtype the neurotransmitter binds with on the postsynaptic neurone, dopamine can increase or decrease cellular activity.[Kandel, Schwartz & Jessell (eds), 2000]
Dopamine, and its actions within the CNS, is critical to the underlying disease state of many conditions, including Parkinson’s disease, which is characterised by a dearth of dopamine, and schizophrenia, which appears to be caused by an overactivity of dopamine within certain brain regions.[Stahl, 2013] Furthermore, many addictive substances work by altering the effect of dopamine within the brain.[Purves, Augustine & Fitzpatrick et al. (eds), 2008] For instance, the drug cocaine appears to act by inhibiting the reuptake of dopamine, which leads to an increased concentration of dopamine in the synapse, prolonging its action.[Purves, Augustine & Fitzpatrick et al. (eds), 2008]
Delusion – a disturbance in thought leading to false beliefs.Hallucination – a false sensory perception, such as hearing voices or seeing things that are not there.Prolactin – a hormone, produced and released into the bloodstream by the pituitary gland, that is involved in the secretion of milk and breast growth; unusually high amounts are responsible for impotence and loss of libido in both men and women.
Control of the CNS can be thought of in terms of a balance between ‘go’ (excitatory) and ‘stop’ (inhibitory) signals.[Purves, Augustine & Fitzpatrick et al. (eds), 2008; Stahl, 2013] If the sum of the ‘go’ signals that a neurone receives outweighs the sum of the ‘stop’ signals, then that neurone will exist in an active state, and will continue to signal to the downstream neurone.[Purves, Augustine & Fitzpatrick et al. (eds), 2008; Stahl, 2013] The main excitatory neurotransmitter in the CNS is glutamate; the main inhibitory neurotransmitter is gamma-aminobutyric acid (GABA).[Purves, Augustine & Fitzpatrick et al. (eds), 2008]
Glutamate is arguably the most important neurochemical for normal brain function.[Purves, Augustine & Fitzpatrick et al. (eds), 2008] Nearly all excitatory neurones in the CNS are glutamatergic – more than half of the neurones in the brain.[Purves, Augustine & Fitzpatrick et al. (eds), 2008] It is noteworthy, though, that high concentrations of glutamate are neurotoxic.[Purves, Augustine & Fitzpatrick et al. (eds), 2008] There are three types of receptor to which glutamate can bind (named after the agonists that activate them), each of which has slightly different properties:[Purves, Augustine & Fitzpatrick et al. (eds), 2008]
GABA is the main inhibitory neurotransmitter found in the brain.[Purves, Augustine & Fitzpatrick et al. (eds), 2008] GABA is synthesised predominantly from glutamate, by the enzyme glutamic acid decarboxylase that is found almost exclusively in GABAergic neurones.[Purves, Augustine & Fitzpatrick et al. (eds), 2008] The ionotropic GABA receptors are usually inhibitory, because when activated they allow the flow of negative chlorine ions across the membrane – reducing the potential for neuronal signalling.[Purves, Augustine & Fitzpatrick et al. (eds), 2008]
Chemicals that function as GABA agonists have been used to treat various conditions, and include anticonvulsants, anxiolytics, benzodiazepines, and hypnotics.[Stahl, 2013]
The broad range of symptoms associated with MDD implicates several brain circuits and regions, and multiple neurotransmitter systems.[Blier, 2014] Increasing any one neurotransmitter (serotonin, noradrenaline, or dopamine) is thought to elevate mood, whereas other aspects of depression may be particularly responsive to an individual neurotransmitter.[Stahl, 2013; Nutt, 2008]
A treatment that targets a single monoamine system is unlikely to produce remission in all patients because, based on the variety of symptoms observed, it is evident that the pathophysiology of MDD implicates different anomalies of the serotonin, noradrenaline, and dopamine systems.[Blier, 2014] In addition, the serotonergic, noradrenergic, and dopaminergic circuits are functionally connected.[Hamon & Blier, 2013] Consequently, a treatment that enhances the activity of one monoamine system may lead to a decrease in the activity of other monoamine systems.[Blier, 2014] For example, an increase in serotonergic activity can result in a decrease in noradrenergic and dopaminergic activity.[Blier & El Mansari, 2013] The most effective treatments, therefore, will use more than one mechanism to achieve remission, and will balance the activity of the three neurotransmitter systems.[Blier, 2014]
The broad range of symptoms associated with MDD implicates several brain circuits and regions, and multiple neurotransmitter systems.[Blier, 2014] Increasing any one neurotransmitter (serotonin, noradrenaline, or dopamine) is thought to elevate mood, whereas other aspects of depression may be particularly responsive to an individual neurotransmitter.[Stahl, 2013; Nutt, 2008]
A treatment that targets a single monoamine system is unlikely to produce remission in all patients because, based on the variety of symptoms observed, it is evident that the pathophysiology of MDD implicates different anomalies of the serotonin, noradrenaline, and dopamine systems.[Blier, 2014] In addition, the serotonergic, noradrenergic, and dopaminergic circuits are functionally connected.[Hamon & Blier, 2013] Consequently, a treatment that enhances the activity of one monoamine system may lead to a decrease in the activity of other monoamine systems.[Blier, 2014] For example, an increase in serotonergic activity can result in a decrease in noradrenergic and dopaminergic activity.[Blier & El Mansari, 2013] The most effective treatments, therefore, will use more than one mechanism to achieve remission, and will balance the activity of the three neurotransmitter systems.[Blier, 2014]
One class of antidepressant drugs, selective serotonin reuptake inhibitors (SSRIs), specifically target the availability of serotonin in order to treat the symptoms of depression.[Stahl, 2013] The introduction of SSRIs transformed the way that depressive disorder was treated, as they became a widely prescribed treatment for MDD.[Stahl, 2013] The class of drugs works by inhibiting the serotonin transporter protein (SERT), which is responsible for reuptake of serotonin from the synapse back into the neurone, thereby increasing the concentration of active serotonin.
Another class of drugs used in the treatment of depressive disorders are the serotonin–norepinephrine reuptake inhibitors (SNRIs).[Stahl, 2013] This class of drugs works by combining robust inhibition of the serotonin transporter protein, along with varying degrees of inhibition of the norepinephrine (noradrenaline) transporter.[Stahl, 2013] Theoretically, according to the monoamine hypothesis of depression, targeting two different monoamine neurotransmitters (in the way that SNRIs do) could lead to a therapeutic advantage.[Stahl, 2013]
A somewhat contentious class of drugs used in the treatment of MDD are the, so-called, norepinephrine–dopamine reuptake inhibitors (NDRIs).1 The leading theory behind the mechanism of action of NDRIs is that the combined inhibition of the norepinephrine transporter and the dopamine transporter leads to an increase in the levels of dopamine and noradrenaline in the brain.[Stahl, 2013] This increased dopamine and noradrenaline is thought to partially counteract the monoamine deficit that characterises MDD.[Stahl, 2013]
The monoamine hypothesis of depression, as previously described, focuses on the neurotransmitters serotonin, noradrenaline, and dopamine in its attempt to explain depression.[Sanacora, Zarate, Krystal & Manji, 2008; Sanacora, Treccani & Popoli, 2012] One of the key flaws of the monoamine hypothesis is the observation that although the effects of antidepressants on the availability of monoamine neurotransmitters are almost immediate, clinical improvements in mood symptoms typically take weeks to emerge.2 What is the reason for this delay? One potential answer is the involvement of the glutamate system.[Sanacora, Zarate, Krystal & Manji, 2008; Sanacora, Treccani & Popoli, 2012]
In addition to being used as a dissociative anaesthetic, a certain NMDA (glutamate receptor) antagonist has been extensively studied in patients with MDD.[ Jaso, Niciu & Ladarola et al.] Strikingly, treatment with this glutamate antagonist appears to effect a rapid and lasting relief of mood symptoms.[Sanacora, Treccani & Popoli, 2012] More research is needed, but the glutamate hypothesis of depression may present novel targets for drug development in the treatment of depression.[Sanacora, Treccani & Popoli, 2012]
In the past, levels of GABA had been studied in patients with depression in plasma, cerebrospinal fluid, and even in resected cortical tissue.[Luscher, Shen & Sahir, 2011] However, more modern techniques, such as proton magnetic resonance spectroscopy (MRS), allow the direct, non-invasive investigation of GABA levels in the brain.Chiapponi, Piras, Piras & et al., 2016; Sanacora, Mason & Rothman et al., 1999] Some studies using MRS have shown GABA deficits in the brains of patients with depression.[Luscher, Shen & Sahir, 2011; Chiapponi, Piras, Piras & et al., 2016]
Although much is now known about the changes in GABAergic signalling that occur in depression, more research is needed to fully understand the connection between the two, and to fully interrogate whether changes in GABA levels can be used as a biomarker of depression.[Luscher, Shen & Sahir, 2011]
The serotonergic, dopaminergic, and noradrenergic circuits are functionally connected, as shown on the slide.[Hamon & Blier, 2013; Blier, 2014] Consequently, a treatment that enhances the activity of one monoamine system may lead to a decrease in the activity of other monoamine systems.[Blier, 2014] For example, an increase in serotonergic activity can result in a decrease in dopaminergic and noradrenergic activity.[Blier & El Mansari, 2013]
As shown on the slide, there are many changes that are evident in the brains of patients with MDD, changes which are likely to have functional consequences.[Drevets, Price & Furey, 2008; Sadock, Sadock & Ruiz (eds), 2009; Stahl, 2013]
Evidence for the neural circuits affected by mood disorders come from neuroimaging and neuropathological studies, and from studies of patients with brain lesions in specific areas.[Drevets, Price& Furey, 2008] The circuits implicated from these studies point to brain networks that normally regulate the evaluative, expressive and experiential aspects of emotional behaviour.[Drevets, Price& Furey, 2008]
A meta-analysis found 225 publications that used magnetic resonance imaging (MRI) or x-ray computed tomography (CT) to compare the brains of patients with MDD with those of control subjects.[Kempton, Salvador & Munafò et al., 2011] The findings were that depression is characterised by a reduction in brain volume in the areas involved in mood and emotion, including parts of the limbic system (hippocampus), and the striatum (caudate, putamen).[Kempton, Salvador & Munafò et al., 2011] The striatum, specifically the ventral striatum, has been linked to networks of reward.[Kempton, Salvador & Munafò et al., 2011]
Depression is characterised by a reduction in brain volume in the areas involved in mood and emotion, including the parts of the limbic system (hippocampus), and the striatum (caudate, putamen).[Kempton, Salvador & Munafò et al., 2011] The hippocampal volume reduction is thought to result from a reduction in glial matter, as well as some neuronal death.[Sadock, Sadock & Ruiz P (eds)., 2009] There is also evidence of pituitary enlargement and an excess of white matter hyperintensity volume.[Kempton, Salvador & Munafò et al., 2011] Interestingly, the coexistence of hippocampal reduction and pituitary enlargement points to the importance of the hypothalamic–pituitary–adrenal axis in MDD,[Kempton, Salvador & Munafò et al., 2011] which is discussed later.
The hypothalamus–pituitary–adrenal (HPA) axis appears to be crucial in the development of the symptoms of depression.[Brites & Fernandes, 2015] Patients with depression frequently have high circulating levels of cortisol, the hormone released from the adrenal cortex.[Murphy, 1991] Providing evidence for the connection from the other direction, patients with Cushing’s syndrome (which is a hyperactivity of the adrenal cortex) often show symptoms of depression, symptoms which are relieved when the cortisol overactivity is treated.[Murphy, 1991]
Long term HPA overactivity has neurotoxic effects, particularly on the hippocampus.[Lam & Mok, 2008] One proposed mechanism for the neurotoxic effects of cortisol is via the molecule BDNF (brain-derived neurotrophic factor), which normally sustains the viability of neurones.[Lam & Mok, 2008; Stahl, 2013] Chronic elevated cortisol reduces BDNF levels, which can lead to loss of neurones in the brain, particularly the hippocampus.[Lam & Mok, 2008; Stahl, 2013; Boku, Nakagawa, Toda & Hishimoto, 2017] Interestingly, treatment with antidepressants appears to restore the monoamine depletion seen as a result of chronic stress; this restoration can increase BDNF levels (and other trophic factors) and, potentially, restore some of the changes to the brain seen in depression.[Stahl, 2013; Boku, Nakagawa, Toda & Hishimoto, 2017]
Neuroinflammation is simply the natural brain response to injury, infection, or disease.[Hurley & Tizabi, 2013] Inflammation is initiated and controlled by white blood cells in the body, but in the central nervous system (CNS) neuroinflammation is mediated principally by microglia.[Hurley & Tizabi, 2013] The microglial cells patrol the CNS, monitoring for signs of injury or infection.[Hurley & Tizabi, 2013] Activation of glial cells quickly leads to the release of both pro- and anti-inflammatory cytokines (see the next slide for more detail about the links between these immune system signalling molecules and depression).[Hurley & Tizabi, 2013] The final effect of glial activation is dependent on the balance between opposing responses; it has been suggested that glial activation initially serves a protective function, but that continuous activation can lead to exaggerated release of proinflammatory cytokines, and neuronal damage.[Hurley & Tizabi, 2013] As stated on the slide, the problem is showing the directionality of the link between depression and neuroinflammation.[Brites & Fernandes, 2015]
Cytokines are signalling molecules that the immune system uses, and are classically released in response to an infection.[Jeon & Kim, 2016] These molecules can signal to near-by cells, or to the hypothalamic–pituitary–adrenal axis.[Jeon & Kim, 2016] There are various types of cytokines, including interleukins, interferons, and chemokines.[Jeon & Kim, 2016] As shown on the slide, cytokines interact with several biological processes implicated in the pathogenesis of MDD.[Jeon & Kim, 2016]
The cytokine hypothesis of depression posits that stresses (internal or external) lead to imbalances in the levels of cytokines within the body that cause the symptoms of depression.[Jeon & Kim, 2016] There are several lines of evidence that support the importance of cytokine chemicals in the pathogenesis of MDD:[Jeon & Kim, 2016]
Several lines of evidence point to there being a genetic component to MDD, as outlined on the slide.[Flint & Kendler, 2014] Over the years there have been many detailed studies into MDD genetics, and many publications of candidate genes, but there has been little agreement.[Flint & Kendler, 2014] A meta-analysis of published genes implicated in the pathogenesis of MDD highlighted the following seven genes:[Flint & Kendler, 2014; GeneCards, 2017]
It is perhaps telling, that many of these genes appear to be involved in the normal functioning of monoamine neurotransmitters in the brain.
According to their website, the purpose of the Psychiatric Genomics Consortium (PGC) is “to unite investigators around the world to conduct meta- and mega-analyses of genome-wide genomic data for psychiatric disorders”.[Psychiatric Genomics Consortium, 2017] The PGC includes more than 800 investigators spread across 38 different countries.[Psychiatric Genomics Consortium, 2017] The PGC was founded in 2007, and was initially focussed on autism, attention-deficit hyperactivity disorder, bipolar disorder, MDD, and schizophrenia.[Psychiatric Genomics Consortium, 2017] However, the PGC has expanded into studying eating disorders, substance use disorders, obsessive–compulsive disorder/Tourette’s Syndrome, and post-traumatic stress disorder.[Psychiatric Genomics Consortium, 2017]
The MDD Working Group of the PGC published their results but, as outlined on the slide, despite the power of the analysis, no genetic variation was found to be significantly associated with MDD.[MDD Working Group of the Psychiatric GWAS Consortium, 2013]
The 23andme study has its detractors; there is particular controversy surrounding the use of self-report data, and the fact that 23andme is a commercial entity.[Abbasi, 2017] In the study, participants were simply asked, yes or no, whether they had been diagnosed with, or were being treated for, depression.[Abbasi, 2017; Hyde, Nagle &, Tian et al., 2016] This casts some doubt on the study, because people will not always correctly self-identify.[Abbasi, 2017] However, some argue that the advantages of the study size that the 23andme collaboration afforded outweigh the disadvantage of not being certain about the exact depression phenotype.[Abbasi, 2017]
MDD is thought to arise from a combination of genetic and environmental factors.[Sadock, Sadock & Ruiz (eds), 2009] In other words, the predisposition/susceptibility to the disease is inherited, rather than the disease itself; environmental factors interact with this genetic susceptibility in the development of depression.[Sadock, Sadock & Ruiz (eds), 2009]
The ‘Adverse Childhood Experiences Survey’ was conducted on a sample of 13,494 consecutive visitors to a Health Centre in San Diego, US, between August 1995 and March 1996.[Chapman, Whitfield & Felitti et al., 2004] Over 70% of those contacted returned the survey, which gave a population of 9,508.[Chapman, Whitfield & Felitti et al., 2004] The prevalence of a lifetime history of depressive disorder was 28.9% for women and 19.4% for men.[Chapman, Whitfield & Felitti et al., 2004] Among both men and women, the prevalence of each adverse childhood experience ranged from >3% reporting a criminal household member, to about 30% indicating that they had been physically abused while growing up.[Chapman, Whitfield & Felitti et al., 2004]
Each of the adverse childhood experiences studied were correlated with a lifetime risk of depressive disorder, as shown on the slide.[Chapman, Whitfield & Felitti et al., 2004] When this was examined cumulatively, a strong graded relationship appeared, suggesting that experiencing multiple forms of childhood adverse experiences have a particularly damaging effect on adult mental health.[Chapman, Whitfield & Felitti et al., 2004]
The DSM-5 makes it clear that, essentially, all major non-mood disorders increase the risk of developing MDD.[APA, 2013] In particular, substance use, anxiety, and borderline personality disorder increase the risk of MDD, and can confound its diagnosis.[APA, 2013]
It is known that stressful life events can, in some cases, lead to depression, as shown on the slide.[APA, 2013; Kendler & Karkowski, 1999; Lam & Mok, 2008] In a descriptive study of the life experiences of fourteen pairs of monozygotic twins discordant for major depression, the life histories of the twins were analysed.4 Although only a descriptive study, there were themes that emerged:[Kendler & Halberstadt, 2013]
According to the ‘Nedly depression hit hypothesis’, if a person is positive for four or more of the categories (positive, meaning having a ratio of at least 1:3 for the factors within that category) then this predicts a depressive episode.[Nedley & Ramirez, 2016] The theory is that these cumulative hits, or blows, together trigger the development of depression.[Nedley & Ramirez, 2016]
Testing the Nedly depression hit hypothesis, a sample of >4,000 participants from a community depression recovery programme in the US were followed over eight weeks.[Nedley & Ramirez, 2016] The relationship between the participants having four or more ‘hits’ and the DSM-5 MDD score showed a sensitivity of 90%.[Nedley & Ramirez, 2016] The authors concluded, therefore, that the ‘four-hit’ hypothesis seems to predict development of a depressive episode.[Nedley & Ramirez, 2016]
