Depression

Why is depression more prevalent in women than in men?

1. Men are less likely to seek help compared to women, resulting in higher suicide rates and lower "reported" cases

2. Depression is often masked by somatic complaints in men, such as pain

3. Hormonal differences

4. Differences in stress response

5. Sexual differences between brain areas

What is the DSM-5 criteria for major depressive disorder?

Patient exhibits 5 or more of the following symptoms for more than 2 years

-Anhedonia (Inability to feel pleasure)

-Weight/Appetite Changes

-Insomnia/Hypersomnia

-Psychomotor agitation/retardation

-Fatigue

-Feelings of worthlessness and guilt

-Diminished ability to think

-Thought of death/suicidal ideation

What are common comorbidities associated with depression?

-Diabetes

-Heart disease

-Autoimmune

-Pain

What is dysthymia?

Type of depressive disorder that has the same symptoms as major depressive disorder, however, the symptoms are less intense, and last for the majority of the day on most days (more persistent)

What are types of depressive disorders?

-Major depressive disorder

-Dysthymia (Persistent depressive disorder)

-Disruptive mood dysregulation disorder

-Premenstrual dysphoric disorder

-Depressive disorder due to another medical condition or due to substance use

What are risk factors for depression?

-Childhood emotional, physical, and sexual abuse

-Prior episode of depression

-Family history of depressive disorder

-Lack of social support

-Stressful life event

-Current substance abuse

-Economic difficulties

What is the general etiology of depression?

Thought to be a multi-factorial, dynamic interplay amongst:

-Genetic predisposition

-Environment

-Life history

-Development

-Biological challenges

In short, it is influenced by genes and the environment

Which two polymorphisms are linked to etiology of depression?

Short allele of serotonin transporter gene (serotonin synthesis)

Met allele of BDNF coding gene (BDNF synthesis)

What general genes are linked to the etiology of depression?

Genes responsible for:

-Metabolism of NTs

-Metabolism of NT receptors

-Number and types of neurons

-Neuronal synaptic connections

-Intracellular transduction of neuronal signals

-Speed with which these can change in response to environmental stressors

What is a pattern in family heritability in the etiology depression?

Depression is common amongst first degree relatives of those who have depression

How is the short allele involved in the etiology of depression?

Inheriting the short allele of the serotonin transporter gene results in the slowing down of synthesis of serotonin transporters. This causes serotonin dysregulation, reducing the speed in which neurons can adapt to changes, which has implications in increased incidences of depression

What is the role of BDNF?

Stands for brain derived neurotropic factor

Responsible for birth, survival and maturation of brain cells during development. Important for neuronal cell growth and synaptic changes via interactions with serotonin

Implicated in delirium, depression, and other psychiatric disorders

What is the relationship between BDNF and serotonin?

BDNF activates DNA binding factors that stimulate transcription of genes involved in serotonin function, such as tryptophan hydrolase and serotonin synthesizing enzymes, influencing the serotonin system's ability to adapt and change

Activation of serotonin receptors causes increased expression of the BDNF factor gene, resulting in increased BDNF.

This cyclic relationship results in neuronal outgrowth involving synapse formation, survival of serotonin neurons, innervation of multiple brain regions

How does BDNF influence the serotonin system?

BDNF activates DNA binding factors that stimulate transcription of genes involved in serotonin function, such as tryptophan hydrolase and serotonin synthesizing enzymes, influencing the serotonin system's ability to adapt and change

How does serotonin influence BDNF expression?

BDNF activates genes involved in serotonin function, increasing serotonin levels. Once serotonin receptors are activated, the BDNF factor gene is expressed, resulting in increased BDNF

What evidences support that BDNF is implicated in the pathophysiology of depression?

1. Patients with symptomatic depression will have lower BDNF activity in the hippocampus and the prefrontal cortex

2. Patients with depression express lower BDNF serum levels - although note that BDNF serum levels is usually not used for the diagnosis of depression

3. Patients with the Met allele

What are two alleles of the BDNF factor gene that are linked to depression?

1. Val allele (normal)

2. Met allele -> results in lower BDNF transport and secretion

What is the Met allele of the BDNF factor gene?

Expression of Met allele instead of Val allele results in alterations in intracellular transportation and secretion of BDNF

Expression of the Met allele specifically leads to

-Small hippocampus at birth

-Hippocampal hypoactivity at rest

-Hippocampal hyperactivation in learning

-Poor hippocampus-dependent memory function

How does alterations of the neocortex and hippocampus result in the clinical manifestations of depression?

Causes "cognitive" aspects of depression

-Memory impairments

-Feelings of hopelessness

Linked to lower BDNF caused by Met allele expression

What is the neurobiological theory of depression?

Depression is caused by a deficiency and/or dysregulation of neurotransmitters in the CNS

Primarily dopamine, norepinephrine, and serotonin are implicated

What is the general role of norepinephrine in mental illnesses (Source, Effects and Implications)

Source

Derived from dopamine, originates from locus ceruleus in the brain stem

Effects and Implications

Can be excitatory in inhibitory, depending on the region of the brain

Noradrenergic pathways are located in the cerebral cortex, limbic system, and the brain stem

Underactivity of these pathways is thought to be involved in depression

What is the general role of serotonin in mental illnesses (Source, Effects and Implications)

Source

Derived from tryptophan, originates from the raphe nucleus in the brain steam

Effects and Implications

Involved in the regulation of attention and complex cognitive functions

Serotonin pathways are located in the cerebral cortex, limbic system, and brain stem

Underactivity of these pathways is thought to be involved in depression and OCD

What are the 5 steps in neurotransmission between 2 neurons?

1. The neurotransmitter is synthesized by the presynaptic neuron

2. The neurotransmitter is stored in synaptic vesicles

3. The neurotransmitter is released in the synapse upon stimulation by an action potential in the presynaptic neuron

4. The neurotransmitter binds to the postsynaptic neuron to exert and excitatory or inhibitory effect. Some of the neurotransmitters bind back to the presynaptic neuron to inhibit release of the neurotransmitter from the presynaptic neuron

5. The neurotransmitter is removed from the synapse, either through reuptake by the presynaptic neuron, diffusion out of the synapse, or enzyme breakdown

What are 3 methods in which a neurotransmitter can be removed from the synapse?

1. Reuptake by presynaptic neuron

2. Diffusion out of the synapse

3. Breakdown by enzyme

What is the role of serotonin in the pathophysiology of depression?

Lower serotonin levels causes depression, however, depression also causes lower serotonin levels, therefore, it is unclear which one causes which

Studies have shown that decreased oral administration of tryptophan, a precursor of serotonin, results in depression relapse in individuals with a history of depression, however, those with a lack of Hx of depression do not experience depression in these conditions, demonstrating the link between genetic and environmental influences in the etiology of depression

What is the role of dopamine in the pathophysiology of depression?

Lower dopamine levels are linked to increased incidence of depression

Parkinson's disease, which is linked to lower levels of dopamine in the substantia niagra, is a risk factor for depression

How is Parkinson's disease linked to depression?

Parkinson's disease is a movement disorder characterized by lower levels of dopamine in the substantia niagra.

Parkinson's disease serves as a risk factor of depression as depression is also linked to lower dopamine levels

What is the role of the prefrontal cortex?

Most evolved region of the brain

Responsible for emotions, advanced thinking processes, voluntary motor and sensory functions, speech, memory,

Forms extensive connections with deeper areas of the brain

What happens to the prefrontal cortex in depression?

Lower BDNF, serotonin, norepinephrine, and dopamine levels results in decreased activity in the prefrontal cortex. This leads to pruning of the unused neuronal pathways, decreasing gray matter volume in the cortex

What is gray matter?

Parts of the nervous system that consists of the neuronal cell bodies, dendrites, unmyelinated axons, axon terminals, and neuroglia

Gray matter is significantly lower in the prefrontal cortex in patients with depression

What is white matter?

Parts of the nervous system mostly consisting of myelinated axons. Myelin acts as an electrical insulation to increase the speed of nerve conduction

What is an MRI?

Diagnostic tool used to find structural abnormalities in the brain. Can be used to distinguish white and gray matter in the brain

What is a PET scan?

Diagnostic tool where a radioactive substance is administered as a drug. Used to study neurotransmitter activity or concentration in the brain

What is the role of the temporal lobe?

Responsible for integrating and interpreting somatic, visual, and auditory information as well as recognition of the familiar, and interpretation of social contexts, such as interpreting emotions and responding with socially appropriate level of emotionality and language

It also plays a role in "fine-tuning" emotion and contains part of the limbic system responsible for emotions

What happens to the temporal lobe in depression?

Lower serotonin, norepinephrine, and dopamine levels results in decreased activity and subsequent neuronal pruning in the temporal lobe, leading to decreased functioning and lower gray matter volume in the temporal lobe. It is unclear whether these changes are the result or the cause of depression as these changes revert to normal once the depression is treated

What is the role of the amygdala?

Located in the medial temporal lobe, a primitive part of the brain. It is responsible for processing information from the environment and enacting appropriate behavior. It plays a role in emotional functioning, affective responses in social settings, sexual arousal, aggression, and fear.

The amygdala specifically processes information from the temporal and occiput lobe and sends information to the hypothalamus and the rest of the limbic system

What happens to the amygdala in depression?

The amygdala receives increased blood flow and consumes more oxygen, resulting in anhedonia (decreased drive for pleasurable activities), anxiety, and reduced motivation - symptoms of depression.

An overreactive amygdala also causes changes in connectivity in the limbic system, resulting in symptoms of emotional liability, irritability, and suicidality

What is the role of the limbic system?

Primitive area of the brain responsible for regulating emotions. Processes both lower and higher brain centers to link thoughts and ANS responses to emotions

What are the parts of the limbic system?

-Hippocampus

-Parahippocampal gyrus

-Cingulate gyrus

-Amygdala

-Fornix

What is the role of the fornix in the limbic system?

A bridge like structure responsible for connecting the hippocampus and the hypothalamus

How does alterations of the hypothalamus lead to clinical manifestations of depression?

Lower norepinephrine, dopamine, and serotonin levels leads to alterations in the hypothalamus. Specifically, these alterations cause the neurovegetative symptoms of depression, which includes:

-Oversleeping/insomnia

-Appetite changes

-Fatigue

-Loss of libido

-Anhedonia

What are changes to cortisol levels in depression?

Cortisol levels in plasma and CSF are higher in patients with depression compared to those without

What are changes to CRF levels in depression?

Increased levels of CRF messenger RNA and protein are found in the limbic brain regions of patients with depression compared to those without

What are changes to the hypothalamus in the context of the stress response in depression?

There is a severely depressed negative feedback response in 1/2 of patients with depression, leading to an overproduction of CRF and cortisol

What are changes to the HPA axis in patients with depression?

The stress response activates the amygdala and norepinephrine systems, resulting in heightened vigilance and fear and resulting in an exaggerated stress response that is compounded by childhood stress.

This leads to increased norepinephrine levels, CRF levels and cortisol levels. In addition, the negative feedback loop of the HPA axis is blunted in severely depressed individuals, causing uncontrolled cortisol production

What are alterations in cortisol levels during the day in depression?

In a non-depressed individual, cortisol levels rise in the morning and are flat throughout the day. Stress also does not result in decreased BDNF levels for the non-depressed individual.

In individuals with depression, there are often erratic spikes of cortisol throughout the day

What are alterations to thyroid function in depression?

Decreased thyroid function - resulting in decreased metabolism

What is the treatment alterations of thyroid function in depression?

Thyroid replacement therapy to treat decreased thyroid function

Reverses effects of hypothyroidism and allows better response to antidepressants (better metabolism)

What are alterations to the sleep wake cycle in depression?

Issues with sleep/wake cycle is a common early sign of depression

A common pattern is for individuals with depression to reach deep sleep earlier in the cycle.

The sleep wake cycle is controlled by melatonin, which becomes dysregulated in depression

Patients with depression should always try to normalize their sleep/wake cycle as best as they can

Which hormone is responsible for regulating the sleep wake cycle?

Melatonin, a hormone produced by the pineal gland during the night, is used to regulate the sleep wake cycle and the body's circadian rhythm

Which regions of the brain are primarily influenced in depression according to the module?

Prefrontal cortex (Decreased gray matter)

Temporal lobe (Decreased gray matter)

-Limbic System-

Amygdala (Overreactive)

Hippocampus (Cognitive aspects of depression)

Hypothalamus (Neurovegetative aspects of depression)

What is circadian rhythm?

Cyclic patterns of sleep and wakefulness throughout a 24 hour day that provide a temporal organization for physiological process and behaviors to function effectively throughout the day. Examples include hormonal secretion and temperature regulation

What happens to the circadian rhythm in depression?

Depression causes circadian abnormalities in mood, sleep, temperature and hormonal secretion.

These abnormalities are usually corrected once depression is treated

What are treatments for depressed patients with sleep/wake cycle abnormalities?

-Encourage patient to normalize sleep-wake cycle

-Promote sleep hygiene routines (decrease alcohol intake and stimulants before bed)

-Prescription of sedative medications

What are alterations to cytokines in depression?

Cytokines serve as mediators between immune and nerve cells.

Increased cytokine production, which can be exacerbated by infection and autoimmune diseases, leads to symptoms of depression, such as pain and depressive symptoms

Why are infections and autoimmune diseases risk factors for depression?

Infections and autoimmune diseases result in increased cytokine production and dysregulation, which can manifest as symptoms of depression, such as pain and depressive symptoms

What causes symptoms of pain in depression?

Serotonin modulates pain as it's pathways release pain-suppressing endorphins.

Decreased serotonin levels in depression thus lead to increased pain

Cytokine production in depression is also increased, which may lead to pain symptoms

How can environmental factors lead to depression?

Environmental factors can act as stressors that further act as triggers of the stress response and HPA axis.

The way a person interprets their environment and thinks about themselves can also induce and perpetuate depressive symptoms

What are environmental causation factors that can lead to depression?

Psychodynamic factors (Negative beliefs)

Behavioral factors (Anhedonia)

Developmental factors (Lack of parenting)

Family distress (Family dynamics)

Social Factors (Traumatic life events)

What are hormonal alterations in depression?

HPA axis dysregulation (Increased CRF + Cortisol)

Thyroid dysfunction (Decreased thyroid)

Sleep Wake Cycle and Circadian rhythm alterations (Melatonin)

Cytokine dysregulation (Increased cytokines)

Pain (Decreased serotonin + Increased cytokines)

How do psychodynamic environmental factors lead to depression?

Distorted negative beliefs of self, environment, and future induces or perpetuates depressive symptoms

How do behavioral environmental factors lead to depression?

Reduction in rewarding activities or an increase in unpleasant events can lead to depression.

Depression decreases energy and thus the chances of engaging in pleasurable activities, leading to further mood disturbances

How do developmental environmental factors lead to depression?

Loss of parent or inadequate emotional parenting can result in delays or inability to reach developmental milestones

How does family distress lead to depression?

Disruption in family dynamics, such as maladaptive circular patterns, leads to increased chances of the development of depression in family members

How do social environmental factors lead to depression?

Traumatic life events, such as a loss of an important human relationship or loss of an important role in life can lead to depression

What is the general goal of antidepressant treatment?

Increase synaptic sprouting and rewire connections which are dysregulated or pruned due to disuse (leading to neuronal atrophy and decreased neuronal volume)

Do antidepressants exert their effects immediately?

No, antidepressants take time to exert their effects - typically days to weeks - as it takes time for BDNF levels to rise back and exert synaptic sprouting effects

What are the general effects of antidepressants?

Antidepressants increase dopamine, norepinephrine, serotonin, and/or BDNF levels, which causes increased activity and nerve cell volume, resulting in increased synaptic plasticity

What is the mechanism of action and adverse effects of SSRIs?

Mechanism of action

Inhibits serotonin reuptake by the presynaptic neuron, resulting in increased serotonin in the synaptic space

Adverse Effects

Nervousness, insomnia, sexual dysfunction, weight gain

What is the mechanism of action and adverse effects of MAOIs?

Mechanism of action

Blocks degradation of serotonin, norepinephrine and dopamine by inhibiting monoamine oxidase

Adverse Effects

Orthostatic hypotension, hypertensive crisis, headache, insomnia, diarrhea

What is the mechanism of action and adverse effects of tricyclic antidepressants?

Mechanism of action

Inhibits serotonin, dopamine, and norepinephrine reuptake by the presynaptic neuron, resulting in an increase of these NTs in the synaptic space

Adverse Effects

Anticholinergic effects, sweating, sedation, orthostatic hypotension

What is the mechanism of action and adverse effects of SNRIs?

Mechanism of action

Inhibits serotonin and norepinephrine reuptake by the presynaptic neuron, resulting in an increase of these NTs in the synaptic space

Adverse Effects

Nausea, Headache, Nervousness, Hypertension

What is the mechanism of action and adverse effects of NDRIs?

Mechanism of action

Inhibits norepinephrine and dopamine reuptake by the presynaptic neuron, resulting in an increase of these NTs in the synaptic space

Adverse Effects

Increased appetite

What is the use of electroconvulsive therapy?

A safe and effective non-pharmacological treatment strategy used to treat depression. It is used to electrically stimulate a generalized seizure and is prescribed with general anesthetics and muscle relaxants. The patient will not feel anything during the procedure, and will not remember the procedure afterwards

What is the usual treatment regimen for electroconvulsive therapy?

Usually 6-8 treatments, with around a 2 day interval between each treatment, lasting during a 2-4 week period. Once depressive symptoms improve, antidepressants are prescribed to prevent a relapse

What is the theorized mechanism of action of electroconvulsive therapy?

5 theorized mechanisms

1. Downregulates beta-adrenergic receptors, decreasing the stress response

2. Upregulates serotonin levels

3. Increases calcium influx into the brain

4. Impacts second messenger systems, which are responsible for converting the neurotransmitter chemical signals into a physiological one, moving the nerve impulse to the next cell

5. Upregulates BDNF levels

What are adverse effects of electroconvulsive therapy?

-Invasive due to use of general anesthetics

-Risk of developing retrograde amnesia, which may be irreversible after the procedure

When is electroconvulsive therapy used for the treatment of depression?

Used when the patient is resistant to conventional treatments (antidepressants + CBT) as the procedure is invasive in nature due to use of general anesthetics and risk of developing retrograde amnesia

What are non pharmacological strategies for the treatment of depression?

1. Electroconvulsive therapy

2. Light Therapy

3. Neuronal Stimulation Techniques

-> Vagal nerve stimulation

-> Deep brain stimulation

-> Transcranial magnetic stimulation

4.Psychotherapy (Cognitive behavioral therapy)

What is phototherapy?

A non pharmacological treatment strategy for depression

Involves the use of light to increase catecholamine levels (norepi + epi) which are low in depression, and used to shift circadian rhythm to improve sleep wake cycles (melatonin)

Only effective for patients with seasonal depression

Which patients is phototherapy effective for?

Phototherapy is only effective for patients with seasonal depression

What are three neuronal stimulation techniques used for the treatment of depression?

Vagal nerve stimulation (Vagus nerve -> locus ceruleus)

Deep brain stimulation (Ventral striatum -> limbic system)

Transcranial magnetic stimulation (Dorsolateral prefrontal cortex)

When are neuronal stimulation techniques used for the treatment of depression?

Used when the patient does not respond to electro convulsant therapy and medications

What is vagal nerve stimulation?

Type of neuronal stimulation technique - a non pharmacological treatment strategy for depression

An implanted lead neck wire is used to electrically stimulate the vagus nerve, which is connected to the locus coeruleus, resulting in increased norepinephrine levels

It is approved as a treatment option in Canada

What brain area/nerve is targeted in vagal nerve stimulation?

Vagus nerve -> linked to -> Locus coeruleus (higher norepinephrine)

What is deep brain stimulation?

Type of neuronal stimulation technique - a non pharmacological treatment strategy for depression

Electrodes from an impulse generator are used to electrically stimulate the ventral striatum, which is functionally dysregulated in depression. The ventral striatum is also connected to the limbic system.

It is a treatment option still under investigation in Canada

What brain area/nerve is targeted in deep brain stimulation?

Ventral striatum -> linked to -> limbic system

What is transcranial magnetic stimulation?

Type of neuronal stimulation technique - a non pharmacological treatment strategy for depression

Electromagnetic induction and changing magnetic fields are used to electrically stimulate the dorsolateral prefrontal cortex, which results in triggering brain activity in this region. The prefrontal cortex normally has decreased volume and activity in depression

It is approved as a treatment option in Canada

What brain area/nerve is targeted in transcranial magnetic stimulation?

Dorsolateral prefrontal cortex (reduced volume and activity in depression)

What is the overall goal of psychotherapy?

A non pharmacological treatment strategy for depression

Psychotherapy is used to reduce stressors that trigger depressive episodes and includes cognitive behavioral therapy

What is the mechanism of action of psychotherapy?

Psychotherapy is use to reduce stressors, resulting in a lowered stress response. This results in normal BDNF levels, normal neurotransmitter activity normal neuroendocrine activity, and lowered neuroanatomical changes in depression

What is the 1st line treatment of depression?

Cognitive behavioral therapy paired with antidepressants is the first line treatment for mild to moderate depression. This treatment method is especially effective for patients with a history of childhood trauma or recent stress

What is cognitive behavioral therapy?

A type of psychotherapy - non pharmacological treatment option for depression

It identifies, analyzes, and challenges habitually inflexible and negative cognitions about oneself, others, and the world