Neurobiology and aetiology

Presentation

Neurobiology and aetiology

1 / 8
Major depressive disorder: Neurobiology and aetiology
1 / 8
Introduction to neuroanatomy
1 / 8
Organisation of the nervous system
Slide information
References

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]

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th Edition. John Wiley & Sons, 2009.

Martin JH. Neuroanatomy Text and Atlas. 3rd Edition. McGraw-Hill, 2003.

1 / 8
Neurones
Slide information
References

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
 

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th Edition. Sinauer Associates, 2008. [Purves, Augustine, & Fitzpatrick et al., 2008]

Martin JH. Neuroanatomy Text and Atlas. 3rd Edition. McGraw-Hill, 2003. [Martin 2003]

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th Edition. McGraw-Hill, 2000. [Kandel, Schwartz & Jessell, 2000]

Oxford Concise Medical Dictionary. 2nd Edition. © Oxford University Press, 1998.

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th Edition. John Wiley & Sons, 2009.

1 / 8
Anatomical regions of the brain
Slide information
References

The brain is divided into four anatomical regions: the diencephalon, brainstem, cerebrum, and cerebellum, as described on the slide.[Kandel, Schwartz & Jessell, 2000; Tortora & Derrickson, 2009]

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th Edition. McGraw-Hill, 2000.

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th Edition. John Wiley & Sons, 2009.

1 / 8
Cerebrum
Slide information
References

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]

  • motor areas that control voluntary movement (primary, secondary, and association motor areas)
  • sensory areas that allow for visual, auditory, gustatory, olfactory, and sensory perception (primary, secondary, and association sensory areas)
  • areas associated with higher mental functions.

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.
 

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th Edition. John Wiley & Sons, 2009.

Price SA, Wilson LM. Pathophysiology: Clinical Concepts of Disease Processes. 6th Edition. Mosby, 2003. 

Martin JH. Neuroanatomy Text and Atlas. 3rd Edition. McGraw-Hill, 2003.

1 / 8
Lobes of the brain
Slide information
References

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]

Martin JH. Neuroanatomy Text and Atlas. 3rd Edition. McGraw-Hill, 2003.

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th Edition. John Wiley & Sons, 2009.

Price SA, Wilson LM. Pathophysiology: Clinical Concepts of Disease Processes. 6th Edition. Mosby, 2003. 

1 / 8
Neurosynaptic transmission
1 / 8
Neurotransmission
Slide information
References

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]

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th Edition. McGraw-Hill, 2000.

1 / 8
The synapse
Slide information
References

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.
 

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th Edition. McGraw-Hill, 2000.

1 / 8
Process of chemical neurotransmission
Slide information
References

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.

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th Edition. Sinauer Associates, 2008.

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th Edition. McGraw-Hill, 2000.

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th Edition. John Wiley & Sons, 2009. 

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009.

1 / 8
Neurotransmitters
1 / 8
Some important neurotransmitters and receptors
Slide information
References

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]

  • be present within the presynaptic neurone
  • be released in response to presynaptic depolarisation, and the release must be calcium-dependent
  • have specific receptors on the postsynaptic neurone

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th Edition. Sinauer Associates, 2008.

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th Edition. McGraw-Hill, 2000.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.

1 / 8
Serotonin
Slide information
References

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]

  • mood
  • sleep
  • cognition
  • sensory perception
  • pain perception
  • movement
  • regulation of internal temperature 
  • appetite 
  • sexual behaviour 
  • hormone secretion

Brunton LL, Lazo JS, Parker KL (eds). Goodman & Gilman’s the Pharmacological Basis of Therapeutics. 11th Edition. McGraw-Hill, 2006.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th Edition. Sinauer Associates, 2008.

1 / 8
Noradrenaline
Slide information
References

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]

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th Edition. Sinauer Associates, 2008.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013. 

Dunn AJ, Swiergiel AH. The role of corticotropin-releasing factor and noradrenaline in stress-related responses, and the inter-relationships between the two systems. Eur J Pharmacol 2008; 583 (2–3): 186–193.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 2nd Edition. © Cambridge University Press, 2000.

1 / 8
Dopamine
Slide information
References

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.

 

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th Edition. Sinauer Associates, 2008.

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th Edition. McGraw-Hill, 2000.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.

1 / 8
Glutamate
Slide information
References

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]

  • NMDA (N-methyl-d-aspartate)
  • AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate)
  • kainate (kainic acid)

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th Edition. Sinauer Associates, 2008. 

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.
 

1 / 8
GABA – gamma-aminobutyric acid
Slide information
References

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]

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th Edition. Sinauer Associates, 2008.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.

1 / 8
Hypotheses about the underlying causes of depression
1 / 8
Neurochemical factors – the monoamine hypothesis
Slide information
References

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]

Blier P. Rational site-directed pharmacotherapy for major depressive disorder. Int J Neuropsychopharmacol 2014; 17 (7): 997–1008.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.

Nutt DJ. Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry 2008; 69 Suppl E1: 4–7.

Hamon M, Blier P. Monoamine neurocircuitry in depression and strategies for new treatments. Prog Neuropsychopharmacol Biol Psychiatry 2013; 45: 54–63.

Blier P, El Mansari M. Serotonin and beyond: therapeutics for major depression. Philos Trans R Soc Lond B Biol Sci 2013; 368 (1615): 20120536.

1 / 8
Neurochemical factors – the monoamine hypothesis
Slide information
References

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]

Blier P. Rational site-directed pharmacotherapy for major depressive disorder. Int J Neuropsychopharmacol 2014; 17 (7): 997–1008.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.

Nutt DJ. Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry 2008; 69 Suppl E1: 4–7.

Hamon M, Blier P. Monoamine neurocircuitry in depression and strategies for new treatments. Prog Neuropsychopharmacol Biol Psychiatry 2013; 45: 54–63.

Blier P, El Mansari M. Serotonin and beyond: therapeutics for major depression. Philos Trans R Soc Lond B Biol Sci 2013; 368 (1615): 20120536.
 

1 / 8
Serotonin
Slide information
References

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.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.

Blier P, El Mansari M. Serotonin and beyond: therapeutics for major depression. Philos Trans R Soc Lond B Biol Sci 2013; 368 (1615): 20120536.

Cassano P, Fava M. Tolerability issues during long-term treatment with antidepressants. Ann Clin Psychiatry 2004; 16 (1): 15–25.

Nutt DJ. Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry 2008; 69 (Suppl E1): 4–7.
 

1 / 8
Noradrenaline
Slide information
References

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]

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.

Cassano P, Fava M. Tolerability issues during long-term treatment with antidepressants. Ann Clin Psychiatry 2004; 16 (1): 15–25. 

Cipriani A, Koesters M, Furukawa TA, et al. Duloxetine versus other anti-depressive agents for depression. Cochrane Database Syst Rev. 2012; 10: CD006533.

Moret C, Briley M. The importance of norepinephrine in depression. Neuropsychiatr Dis Treat 2011; 7 (Suppl 1): 9–13.

Nutt DJ. Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry 2008; 69 Suppl E1: 4–7.

1 / 8
Dopamine
Slide information
References

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]

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.

Nutt D, Demyttenaere K, Janka Z, et al. The other face of depression, reduced positive affect: the role of catecholamines in causation and cure. J Psychopharmacol 2007; 21 (5): 461–471.

Nutt DJ. Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry 2008; 69 (Suppl E1): 4–7.
 

1 / 8
Glutamate
Slide information
References

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]

Sanacora G, Zarate CA, Krystal JH, Manji HK. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov 2008; 7 (5): 426–437.

Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 2012; 62 (1): 63–77.

 Jaso BA, Niciu MJ, Ladarola ND, et al. Therapeutic modulation of glutamate receptors in major depressive disorder. Curr Neuropharmacol 2017; 15 (1): 57–70.

1 / 8
GABA
Slide information
References

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]

Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry 2011; 16 (4): 383–406.

Chiapponi C, Piras F, Piras F, et al. GABA system in schizophrenia and mood disorders: a mini review on third-generation imaging studies. Front Psychiatry 2016; 7: 61.

Sanacora G, Mason GF, Rothman DL, et al. Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 1999; 56 (11): 1043–1047.

1 / 8
Functional connectivity of serotonergic (5-HT), noradrenergic (NE), and dopaminergic (DA) neurones and their postsynaptic targets
Slide information
References

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]

Hamon M, Blier P. Monoamine neurocircuitry in depression and strategies for new treatments. Prog Neuropsychopharmacol Biol Psychiatry 2013; 45: 54–63.

Blier P. Rational site-directed pharmacotherapy for major depressive disorder. Int J Neuropsychopharmacol 2014; 17 (7): 997–1008.

Blier P, El Mansari M. Serotonin and beyond: therapeutics for major depression. Philos Trans R Soc Lond B Biol Sci 2013; 368 (1615): 20120536.

1 / 8
Functional brain abnormalities
Slide information
References

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]

Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct 2008; 213 (1–2): 93–118.

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.

Liu Y, Du L, Li Y, et al. Antidepressant effects of electroconvulsive therapy correlate with subgenual anterior cingulate activity and connectivity in depression. Medicine (Baltimore) 2015; 94 (45): e2033.

Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion perception II: implications for major psychiatric disorders. Biol Psychiatry 2003; 54 (5): 515–528.

Siegle GJ, Carter CS, Thase ME. Use of FMRI to predict recovery from unipolar depression with cognitive behavior therapy. Am J Psychiatry 2006; 163 (4): 735–738.

1 / 8
Structural brain abnormalities (I)
Slide information
References

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]

Kempton MJ, Salvador Z, Munafò MR, et al. Structural neuroimaging studies in major depressive disorder. Meta-analysis and comparison with bipolar disorder. Arch Gen Psychiatry 2011; 68 (7): 675–690.

 

1 / 8
Structural brain abnormalities (II)
Slide information
References

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.

 

Kempton MJ, Salvador Z, Munafò MR, et al. Structural neuroimaging studies in major depressive disorder. Meta-analysis and comparison with bipolar disorder. Arch Gen Psychiatry 2011; 68 (7): 675–690.

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009.

1 / 8
Stress and depression
Slide information
References

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]

Brites D, Fernandes A. Neuroinflammation and depression: microglia activation, extracellular microvesicles and microRNA dysregulation. Front Cell Neurosci 2015; 9: 476.

Murphy BE. Steroids and depression. J Steroid Biochem Mol Biol 1991; 38 (5): 537–559.

Lam RW, Mok H. Depression. Oxford University Press. 2008.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.

Boku S, Nakagawa S, Toda H, Hishimoto A. Neural basis of major depressive disorder: beyond monoamine hypothesis. Psychiatry Clin Neurosci 2017. [Epub].

1 / 8
Neuroinflammation
Slide information
References

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]

Hurley LL, Tizabi Y. Neuroinflammation, neurodegeneration and depression. Neurotox Res 2013; 23 (2): 131–144.

Brites D, Fernandes A. Neuroinflammation and depression: microglia activation, extracellular microvesicles and microRNA dysregulation. Front Cell Neurosci 2015; 9: 476.

Kempton MJ, Salvador Z, Munafò MR, et al. Structural neuroimaging studies in major depressive disorder. Meta-analysis and comparison with bipolar disorder. Arch Gen Psychiatry 2011; 68 (7): 675–690.

 

1 / 8
The ‘cytokine’ hypothesis
Slide information
References

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]

  • injection of cytokines into animals produces depression-like results
  • patients with depression have been observed to have elevated levels of certain cytokines
  • cytokines are known to trigger activity in the hypothalamic–pituitary–adrenal axis, as well as the catecholamine/sympathetic nervous system – two systems known to be involved in MDD
  • antidepressant drugs inhibit cytokine secretion from immune cells

Jeon SW, Kim YK. Neuroinflammation and cytokine abnormality in major depression: cause or consequence in that illness? World J Psychiatry 2016; 6 (3): 283–293.

1 / 8
Genetic factors
1 / 8
Studying the genetics of depression
Slide information
References

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]

  • 5HTTLPR/SLC6A4 – 5-hydroxytryptamine (serotonin) transporter
  • APOE – Apolipoprotein E
  • DRD4 – Dopamine receptor D4
  • GNB3 – G-protein subunit beta 3
  • HTR1A – 5-hydroxytryptamine (serotonin) receptor 1A, G-protein-coupled
  • MTHFR – Methylenetetrahydrofolate reductase
  • SLC6A3 – Dopamine transporter 1

It is perhaps telling, that many of these genes appear to be involved in the normal functioning of monoamine neurotransmitters in the brain.
 

Flint J, Kendler KS. The genetics of major depression. Neuron 2014; 81 (3): 484–503.

GeneCards. http://www.genecards.org/. Accessed November 2017.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition (DSM-5™). © American Psychiatric Association, 2013.

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009. 

Sullivan PF, Neale MC, Kendler KS. Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 2000; 157: 1552–1562.

1 / 8
GWAS (genome-wide association studies) of MDD
Slide information
References

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]

Psychiatric Genomics Consortium. http://www.med.unc.edu/pgc. Accessed November 2017.

MDD Working Group of the Psychiatric GWAS Consortium. A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry 2013; 18 (4): 497–511.

Flint J, Kendler KS. The genetics of major depression. Neuron 2014; 81 (3): 484–503.

Mullins N, Lewis CM. Genetics of depression: progress at last. Curr Psychiatry Rep 2017; 19 (8): 43.

 

1 / 8
Big data and the potential of personal genetics
Slide information
References

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]

Abbasi J. 23andMe, big data, and the genetics of depression. JAMA 2017; 317 (1): 14–16.

Hyde CL, Nagle MW, Tian C, et al. Identification of 15 genetic loci associated with risk of major depression in individuals of European descent. Nat Genet 2016; 48 (9): 1031–1036.

1 / 8
Environmental factors
1 / 8
Environmental factors and MDD
Slide information
References

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]

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th Edition (DSM-5™). © American Psychiatric Association, 2013.

Chapman DP, Whitfield CL, Felitti VJ, et al. Adverse childhood experiences and the risk of depressive disorders in adulthood. J Affect Disord 2004; 82 (2): 217–225. 

Kendler KS, Karkowski LM, Prescott CA. Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry 1999; 156 (6): 837–841.
 

1 / 8
Adverse childhood experiences
Slide information
References

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]

Chapman DP, Whitfield CL, Felitti VJ, et al. Adverse childhood experiences and the risk of depressive disorders in adulthood. J Affect Disord 2004; 82 (2): 217–225.

1 / 8
Stressful life events
Slide information
References

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]

  • in two of the pairs, developing MDD was associated with a single traumatic event which befell the affected twin
  • in two pairs of twins, there was a difference in occupational stressors, whereby the twin with MDD had a difficult and failure-prone career
  • in seven of the pairs, a surprisingly consistent pattern emerged which suggested that developing MDD was associated with not being in a stable, long-term, successful romantic relationship. This strengthens the idea that romantic rejection is a depressogenic life experience

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition (DSM-5™). © American Psychiatric Association, 2013.

Kendler KS, Karkowski LM, Prescott CA. Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry 1999; 156 (6): 837–841.

Lam RW, Mok H. Depression. Oxford University Press. 2008.

Kendler KS, Halberstadt LJ. The road not taken: life experiences in monozygotic twin pairs discordant for major depression. Mol Psychiatry 2013; 18 (9): 975–984.

1 / 8
The ‘four-hit’ hypothesis
Slide information
References

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]

Nedley N, Ramirez FE. Nedley depression hit hypothesis: identifying depression and its causes. Am J Lifestyle Med 2016; 10 (6): 422–428.

Country selection
We are registering that you are located in Brazil - if that's correct then please continue to Progress in Mind Brazil
You are leaving Progress in Mind
Hello
Please confirm your email
We have just sent you an email, with a confirmation link.
Before you can gain full access - you need to confirm your email.
The information on this site is exclusively intented for health care professionals.
All the information included in the Website is related to products of the local market and, therefore, directed to health professionals legally authorized to prescribe or dispense medications with professional practice. The technical information of the drugs is provided merely informative, being the responsibility of the professionals authorized to prescribe drugs and decide, in each concrete case, the most appropriate treatment to the needs of the patient.
Congress
Register for access to Progress in Mind in your country