Depression

Diagnosis of Psychiatric Diseases

• Largely based on classification which is based on categorisation of symptoms —> describing something you have or haven’t got.

• Manuals used to categorize symptoms:

  • DSM-5 (diagnostic Statistical Manual)

  • ICD-11 (international classification of Diseases)

• Improved diagnosis but lacks pathophysiological definition

• These diagnostic manuals don’t consider broad overlap in psychiatric conditions

• As it doesn’t define pathophysiology gives no suggestions on how to treat the symptoms therapeutically

Dimensions of diagnosis

• May be contribution to the disorder throughout your development —> difficult to pinpoint exactly when you’re classified as having this disorder

• Psychosocial environment can also drive certain behavioural traits in some disorders such as depression and bipolar disorder.

• Some clinical syndromes will differ between the prominent causing factors, E.g mental retardation has a large neurodevelopmental contribution, smaller psychosocial contribution

• Genetic determinants of some disorders that are more fixed than others. Those where neurodevelopment is more crucial for the development of the disorder have a larger genetic determinant

• Its not that none of these disorders have no genetic component, but some are just very difficult to pin down

• No simple biological underpinning for the complex spectrum of disorders but understanding it can lead to better mitigation strategies

how should we treat these people - research domain criteria

• Suggesting that biological interactions between genetics, environment and neurodevelopment can be used to better describe behavioural domains:

  • Negative valence – behaviours which apply aversiveness

  • Positive valence – overindulgence E.g: addiction

  • Cognitive systems – how you think E.g: affected in anxiety

  • Systems for Social Process – E.g: if youre depressed might isolate yourself

  • Arousal/Regulatory systems – ability to be activated appropriately affected by a condition

  • Sensorymotor systems – ability to move and express body language

• These behavioural domains come together to better understand the psychiatric condition

• the theory is that if people are distilled into categories it leads to better diagnosis

depression

• pathophysiology of mood

• defines as a protracted bad mood - a sustained period of bad mood where you no longer react well to the environment and it affects those around you

• difficult to use inclusion exclusion criteria as its such a human condition —> diagnosis diffuse, often based on personality traits

Diagnostic criteria

• primary indicators:

  • persistant sadness or low mood

  • loss of interest of pleasure (anhedonia)

  • fatugue or low energy most days most of the time

• persists for more than 2 weeks

• Associated symptoms

  • Disturbed sleep

  • Poor concentration or indecisiveness

  • Low self-confidence

  • Poor or increased appetite – hypo/hyperphagic

  • Suicidal thoughts or acts

  • Agitation or slowing of movements

  • Guilt or self-blame

• Diagnosis of disease based on primary indicators + persistence of disease + associated symptoms.

why would evolution drive us to become depressed?

• Mood reflects a change in behavioural state, low mood associated with negative thought

• Aversiveness is a strong reinforcer to modify behaviour associated with focus and concentration

• Modifies your brain state so you can focus on something

• Selective evolutionary advantage

• But if you over focus on a negative event, which happens during depression, it causes a debilitative focus

• however, a dysfunction in either the pathways which control focus or the modulation of these pathways will lead to a depressed state

what causes depression

• a complex interplay between

  • genetics —> about 30-50% genetic and involved in predisposition and expression of depression

  • environment

  • sex differences —> about twice as prominent in women

  • defines environment genetic interaction —> genes not isolated from their environment and have a complex interaction with their biochemical and epigentic pathways

3 theories for the biological basis of depression

1. dysregulation of the hippocampus and Hypothalamic Pituitary Adrenal (HPA) axis

2. impairment of neurotrophic mechanisms 

3. impairment of brain reward pathways 

stress

• depression often describes as a stress related disorder —> evidence of depression occur in some context of stress 

• depression in most people is caused by interactions between a genetic predisposition and some environmental factors —> “it is sensible to think not of  single cause but rather of a combination of those factors that make an individual vulnerable and the external events that can trigger a depressive episode”

1. Dysregulation of the hippocampus and hypothalamic pituitary adrenal axis

HPA axis 

• HPA axis is the brains main mechanism of responding to acute and prolonged stress 

• neurons in the paraventricular nucleus (PVN) of teh hypothalmus secrete corticotrophin releasing factor (CRF) which stimulates the release of adrenocorticotrophin (ACTH) from the anterior pituitary 

• ACTH then stimulates synthesis and release of glucocorticoids (cortisol) from the adrenal cortex 

• this is controlled by negative feedback by the hippocampus (has an inhibiotry influence on hypothalamic CRF cotaining neurons via polysynaptic circuits) and the amygdala which exerts a direct excitatory influence 

Stress’ impact on depression

• sustained elevated levels of glucocorticoids (seen under prolonged stress) may damage CA3 pyrimidal (hippocampal) neurons —> reduced dendritic branching, loss of dendritic spines, loss of synapses and decreased communication between regions of the brain 

• elevated cortisol also causes the reduction of formation of new granule cell neurons in the adult hippocampal dentate gyrus

• due to the nature of the damage of the hippocampus it prevents it from carrying out the inhibitory role in controlling cortisol levels via the HPA axis —> resulting in further increased circulating cortisol and further hippocampal damage 

• impaired hippocampal function may also contribute to some of the cognitive abnormalities observed in depression 

1. Dysregulation of the hippocampus and hypothalamic pituitary adrenal axis - evidence

Evidence 

• abnormal activation of the HPA axis is observed in half of individuals with depression and these abnormalities can be corrected by antidepressant treatment 

• hypersecretion of CRF in depressed patients as seen in CSF

• striking evidence between centrally administered CRF and depression symptoms: decreased appetite, increased arousal and vigilence, increased heart rate and blood pressure 

limitations 

• unknown whether HPA axis abnormalities are a primary cause of depression or are secondary to some other cause 

• however, a strong case can be made for its role in generating certain symptoms and the impact of the course of disease 

future treatment potentials 

• CRF1 receptor antagonists exert clear antidepressant like effects in several stress based rodent models 

• glucocortecoid receptor antagonists such as mifepristone may be useful in treating some cases of depression

2. impairment of neurotrophic mechanisms

Hypothesis

• neurotrophic factors theory states that a deficiency in neurotrophic support may contribute to the hippocampal pathology during the development of depression 

• possible that antidepressant induced upregulation of BDNF could help repair some of the stress-induced damage to hippocampal neurons and protect vulnerable neurons from further damage.

• antidepressant induction is at least partly mediated by CREB TF 

• BDNF reported to enchance synaptic plasticity in the hippocampus and so increased BDNF induced by antidepressants may promote hippocampal function and also explain why antidepressant response is delayed.

2. Impairment of neurotrophic mechanisms - evidence 

Evidence

• acute and chronic stress decreases BDNF (brain derived neurotrophic factor) expression in the dentate gyrus and pyramidal cell layer of the hippocampus in rodents 

• chronic (but not acute) administration of virtually all classes of antidepressants increase hippocampal BDNF levels in humans 

• adminstering BDNF or a related neurotrophin causes antidepressant like effects in the forced swim test 

Limitations 

• mice lacking BDNF die shortly after birth and so cant test what happens in mice with no BDNF

• since BDNF is mediated by CREB its unclear whether the increase in CREB causes the antidepressant effects or whether its the increase in BDNF

Future treatment 

• suggests that agents that promote BDNF may be clinically effective antidepressants 

Role of CREB

Role of CREB

• considerable evidence that the BDNF gene is induced by CREB

• supported by the fact that all major classes of antidepressants increase CREB expression

Evidence for this 

• increased CREB activity in the hippocampal dentate gyrus (via viral vector encoding CREB) exerts an antidepressant like effect in the forced swim test 

• reason that CREB is likely to produce antidepressant effects because it upregulated cAMP. clinical observation that rolipram (a type 4 phosphodiesterase inhibitor) would be expected to increase cAMP levels and exerts antidepressant effects. 

Future directions 

• rolipram still poorly tolerated by humans due to its side effects 

• but the cloning of numerous subtypes of type 4 phosphodiesterases and their specificity for regions of the brain hold promise for future development of more selective antidepressants with fewer side effects

3. impairment of brain reward pathways

Hypothesis

• previously all research on depression has focused on the hippocampus, more recent research suggesting subcortical structures such as the amygdala, Nacc, hypothalamus have a role in causing symptoms such as regulation of motivation, sleep, apetite etc. 

• VTA neurons innervate the Nac as well as several other limbic structures. The Nac and its input from the VTA plays a crucial role in reward 

• stress causes CREB mediated transcription in the Nacc. Increased CREB in this brain region decreases an animals sensitivity to several types of aversive stimuli including anxiogenic and nociceptive stimuli. Decreased CREB in this brain region causes increased sensitivity to these stimuli. —> suggests that CREB in the Nacc controls behavioural responsiveness to emotional stimuli

• the increase in CREB seen after stress of drug exposure may be responsible for the emotional numbing or anhedonia seen in some forms of depression.

3. impairment of brain reward pathways - evidence 

Evidence 

• this would explain why mice deficient in CREB show overall normal responses to antidepressants in certain behavioural tests

• the amygdala (which is innervated by VTA neurons) appears to use the same cAMP and CREB pathway to promote the formation of both fear aversive and rewarding associations. Stress decreases the expression of BDNF in the amygdala.

• Abnormal responses to pleasurable stimuli and symptoms of anxiety and fear are observed in depressed patients.

impact of depression on brain function

• Symptomologies associated with discrete brain regions

• Broad symptomology associated with diffuse and discrete parts of the brain and so underlining it is challenging

• Distributed disruption of brain function —> communication across the brain is disrupted in a depression

why is depression hard to study - animal models/ learned helplessness

• lack of animal models as many of the core symptoms of depression cannot be easily measured in laboratory animals 

• lack of known depression vulnerability genes means that genetic causes of depression cannot be replicated in animals 

• another weakness is that available animal models of depression utilize normal mice whereas depression probably requires a genetic vulnerability in most cases 

• medications required are active in the animals after acute administration while their clinical efficacy requires chronic administration 

Forced swim test 

• a behavioural experiment we can use to measure depression in rodent models

• place a rat in a tank of water and measure the amount of time it will try and climb out before it floats on its back and gives up

• a reduction in immobility and an increased time trying to escape is considered an antidepressant effect.

current treatments for depression - monoamine theory

Monoamine theory

• Two serendipitous observations put monoamines at the front of depression research - thought that depression is associated with an inappropriate level of neurotransmitter in the synaptic cleft – specifically biogenic amines:

  • Dopamine

  • Serotonin

  • Noradrenaline

• Had the idea that if we were able to elevate the levels of biogenic amines in the synaptic cleft it could cure depression. There were two drugs elevated the levels of monoamines in the synaptic cleft and have been at the forefront of depression research:

Iproniazid

• Trials for TB and patients experiences elevated mood

• Major target was inhibition of the mitochondrial enzyme monoamine oxidase

• Mitochondrial enzyme oxidises the neuroactive form of monoamines into the neuroinactive form

• Inhibition increased the bioavailability of neuroactive monoamine

Imipramine

• A tricyclic antidepressant

• Used in trials as an antipsychotic drugs and there was an indication to improve mood

• Elevated levels of monamines

• Inhibits the reuptake of the biogenic amine

evidence in favour of the monoamine hypothesis

Drugs that increase/decrease biogenic amines cause increased wellbeing

• Tryptophan

  • The starting compound for 5HT

  • Found in Horlicks

  • Increases mood

• Reserpine

  • Prevents the reuptake of monoamines into vesicles

  • Causes depletion of biogenic amines

  • Antihypertensive with a tendency to cause depression

Measuring metabolites

• Increased levels of broken down forms of biogenic amines in the CSF, consistent with a reduction of biogenic amines in depressed patients

• Breakdown products include: 3-methyl-4-hydroxyphenylglycol and 5-hydroxy indoleacetic acid

Post mortem tissue

• Post mortem tissue of depressed brains often have a reduction in receptors for biogenic amines

• People assume that this is because of a change in genetic expression for serotonin transporter molecules but this is weakly evidenced

modulating biogenic amines 

Modulating biogenic amines in the brain

• Two drugs that have been used to treat depression based on their ability to modify biogenic amines and monamines

Imipramine

• Tricyclic antidepression 

• Blocks the transport mechanism that transports biogenic amines – all have specific transporters

  •  DAT - dopamine

  • SERT - serotonin

  • NAT – noradrenaline transporter

• Has a relatively similar Kd for all of the transporters (Kd approx. for serotonin transporter is 50nm)

Fluoxatine (Prozac)

• Tried to come up with a more specific transporter blocker

• Fluoxetine is a selective serotonin reuptake inhibitor —> very selective for the serotonin transporter (Kd approx. 1nm)

• Better selectivity in antidepressant efficacy (efficacious: produces a maximal therapeutic response)

how do transporters work 

• Transporters are secondary transporters – use sodium and chloride, in addition to the neurotransmitter to pump from the outside to the inside

• Substrate binds to the transmembrane domain

• The inhibitors, the antidepressants, bind to the substrate binding site

• Can bind to a second binding site on the membrane protein that carries the neurotransmitter

• Transmembrane protein 1 and transmembrane protein 6 come together to form a binding site – have associated sodium and chloride binding

Escitalopram

• Is a competitive inhibitor of a serotonin transporter but not only binds to the substrate binding site but also binds to an additional allosteric site

• Has increased efficacy – changes extracellular loop 4 into a closed conformation which prevents the drug from leaving the active site

• Supports the idea that 5Ht and biogenic amines important in expression of depression

other ways to elevate biogenic amines

NASSA drugs

• NaSSA (noradrenergic and specific serotonergic antidepressants) drugs change the way which you achieve elevation of monoamine and or the receptors that the signalling is being carried by

• Bind to multiple receptors which can modulate synaptic levels of biogenic amines

• Neurons have biogenic amine receptors which regulate the release of themselves

  • Nadr is released and acting as a signal to carry the signal forward but also acting on presynaptic autoreceptos which sit on the nerve terminal. But when these receptors are activated they cause the downregulation of the Nadr release

  • Nadr receptors are also found on the presynaptic terminal of serotonin neighbouring neurons (no longer autoreceptors but hereoreceptors). This causes decrease in 5HT release from the 5HT containing neurons

  • So the same receptor can discretely regulate the levels of Nadr and 5HT

• NASSA drugs block the heteroreceptos as well as the autoreceptors —> blocking a bock which causes an increase in biogenic amine release

• Also act on other receptors as agonists and antagonists to modulate the sensitivity of the neurons

• By binding to the 5HT 2 and 5HT 3 receptors it can reduce unwanted side effects which are mediated by these receptors such as: insomnia, anxiety, sexual dysfunction

summary of antidepressant drugs and their side effects

• antidepressants need to be taken for 5 weeks to determine if theyre effective

• Want to reduce side effects to increase compliance

• MAO drugs – metabolise other amino acids (tyramine specifically) and so cause a lot of side effects associated with sympathetic activation

• Select for one pathway with the hope that you get a better efficacy —> the associated selectivity seemed to reduce the side effects

antidepressant paradox 

• Can see an elevation in biogenic amines in the body almost immediately but it takes 2-6 weeks to see effect on clinical signs of depression

• might make patients feel worse due to the side effects but make them feel better after the antidepressant effects of the drug start to kick in

• brain structure and function as drugs are taken:

Short term

• Reduction in uptake causes an increased level of biogenic amine in extracellular fluid which can be measured by microdialysis

• More specifically increased in the raphe nuclei, locus correlius and the cortex

Medium term

• Downregulation through autoreceptors (5ht1A receptors for example) —> does this by removal from the cell surface (a homeostatic response to maintain stable levels of biogenic amines)

• Other noted changes include

  • Down regulation b2 postsynaptic receptors

  • Down regulation of a2 auto receptors

  • Down regulation of 5HT2  receptors.

  • Overall sense of a homeostatic response of pathways returns to signalling to pre-treatment levels.

Long term

• Adaptive response – plasticicity

• Two main responses

  • Neurogenesis

  • Synaptogenesis

• Useful for causing a significant changes in brain structure and is bought about by expression of growth factors such as BDNF

mode of action of 5HT

Mode of action of 5HT

• PFC connects to all the regions of the brain associated with depression

  • (dorsal raphe nucleus, locus correlius, ventral tegmental area)

• Aminal model used for the forced swim test but with an electrode in the brain – when you stimulate these regions do you bring about an antidepression effect?

• PFC projection to the dorsal raphe – this causes release of 5Ht to many parts of the brain

  • Can stimulate directly at the PFC or at nerve terminals (end of the same neurons connecting to dorsal raphe nuclei)

  • If you stimulate directly at PFC theres no antidepressant effect but if you stimulate at nerve terminals you do

  • Glutamate transmitter used between PFC neurons and DR and causes serotonin release

• this evidence proves that elevating teh levels of 5HTacts as an atidepresant 

need for better understanding of cause for depression and treatment 

• Showed that antidepressants had a lower clinical efficacy than believed

• There was no clinical efficacy relative to the placebo —> the effect of the interaction with clinicians had a positive effect on placebo group

• Antidepressants had clinical efficacy for the severely depressed individuals

• Clinical efficacy tested for 21 drugs including fluoxetine NASSA drugs and MAOIs and found good evidence for clinical efficacy

• How likely a drugs is to be correct indicated by the LOAD score. At most this is 2-3. Biological penetrance of antidepressants in population studies is clear but the effect is modest.

• You also need to consider tolerability – someone can take the drug which can have a clinical benefit but the tolerance of the drugs vary so you need to consider how tolerable the drug will be to the patient so they can take it.

• In summary antidepressants have an effect that is fair but how profound the effect is and for how long it works is not well known —> there is a requirement for improvement for this as it affects so many and can be so life changing

• There are drugs that we know have plasticity effects in the nervous system and needs to be explored if we can use them for the treatment of resistant individuals (ketamine being explored)

• Difficulty diagnosing individuals and non-compliance can be one of the challenges with research on depression

ketamine as an antidepressant 

• Ketamine is a repurposed drug which is being studies as its use as an antidepressant

• Quick in its action relative to SSRIs – beneficial for those which do not show immediate improvement

• Acts on a different receptor to SSRIs- belongs to NMDA receptor channel blockers

• Related to PCP (psychosis inducing) and MK801 (classic NMDA channel blocker)

• Block a particular receptor at central glutamatergic sysnpases (excitatory synpases)

• Usually these receptors rely on 2 types of ligand gated ion channels – both gated by gluatamte and lead to influx of sodium

  • In the case of the NMDA receptor (blocked by ketamine) it passes calcium ions which can have IC effects

  • Receptor has binding site for glutamate, glycine, ion binding site, channel blocking site (which works by plugging the hole, not preventing glutamate binding), NMDA binding

• Produces a adose depensent response –

  • at 3mg/kg used for anaesthesia and works via the block of thalamic information

  • at 1mg/kg exhibits dissociative symptoms

  • at 0.5mg/kg has the possibility to be used as an antidepressant

evidence for ketamine as an atidepressant 

• Initial experiments to test the efficacy of ketamine as antidepressants

• Double blind experiment where severely depressed individuals were first flushed out of any antidepressants they were on and tested on ketamine against other drugs that had psychoactive effects but not noted antidepressant effects. This is useful because it removes the problem of the placebo causing improvements due to the human interaction or patients knowing which drug they had been given.

• Compared the treatment against these control drugs through establishment of  a baseline depression using the Montgomery-Asberg depression (quantitative scoring system done by trained clinicians)

• In the case of ketamine treatment there was a large significant reduction in depression score. Midazolam (a benzodiazepine used as control) showed a much less decrease in depression.

• Not only was there an acute antidepressant effect but sustained effect

• 50% reduction in the score which is followed up by self-reporting.

• About 15-20% of the patients on the trial reported dizziness and dissociation – implies that youre slightly outside the dose range, which is not good because shows that it might not be well tolerated.

Explaination for ketamines antidepressant effects

•  When you give ketamine to the animal, they have elevated motility in the forced swim test, indicative of an antidepressant effect

• If you block this channel with a competitive inhibitor you don’t have the same antidepressant effect

• Ketamine has biochemical effects in the brain —> elevates BDNF which looks as if its mediated through NMDA channel block

• BDNF supports antidepressant outcomes through plasticity

changes in underlying circuitry - theory of ketamines effect

• Can model this with a simple circuit made up of an excitatory pyramidal neuron and an inhibitory interneuron

• Excitatory neurons releases glutamate and inhibitory neurons which releases GABA

• Inhibitory neurons excited by excitatory neurons, resulting in a reciprocal inhibition from this neuron to the excitatory neuron.

• You can modify the balance between excitation and inhibition with pharmacological intervention

• Drugs like ketamine selectively inhibit the glutamate receptors on the inhibitory neurons —> selectively block the excitation of an inhibitory neuron, which prevents inhibition, resulting in a super stimulation

• Ketamine in a circuit could shift the balance between excitation and inhibition elevating circuit level excitation —> might explain its antidepressant effects if this occurs in the right part of the brain

other promising treatments - non drug therapies

Psilocybin

• Psychoactive drug which has good potential for antidepressant, often in conjunction with CBT

• Low toxicity

• Acts on 5HT receptor

• Allosteric modulation of serotonin signalling

• Modification of synaptic function and plasticity

Deep brain stimulation

• Stimulate regions of the brain with electrodes

• Good change you increase circuit activity and cause acute rearrangement of brain structure which may mitigate the cause of depression

• Couples with cognitive behavioural therapy

• Shown to work for people with very disabling depression

Behavioual tharapy

• Talking therapies offered to individuals presenting with depression

• Accompanied by drug therapies

• Can be looked at by brain imaging – neurochemical changes associated with it

summary/conclusions on depression

• currently no definitive cause of depression - the 3 Nestler review hypotheses are some suggestions

• may be one or a combination of these, which cause the biological basis, with other contributing factors such as genetics/environment. 

• Currently, due to a serendipitous discovery, monoamines have been placed at the forefront of treatment and research. 

• However, due to the fact these only show moderate efficacy with chronic administration (despite the fact biogenic amine levels are increased immediately) it suggests that increasing biogenic amine levels in the synaptic cleft does not produce antidepressant effects. Rather it is the long term plasticity and change in brain structure that produces the antidepressant effects shown by these drugs, and therefore supports the view of the Nestler theories that there is a deeper underlying cause affecting multiple brain structures. 

• Research on depression is difficult and has setbacks due to 

  • difficulty diagnosing patients

  • multiple factors at play causing depression

  • limitations of animal models 

  • varying severity of depression

  • difficult to quantify symptoms 

  • tolerabiliity of drugs impeding research