L15 : Depression

State five psychological symptoms of depression ?

•Continuous low mood or sadness

•Feeling hopeless and helpless

•Having low self-esteem

•Feeling tearful

•Feeling guilt-ridden

•Feeling irritable and intolerant of others

•Having no motivation or interest in things

•Finding it difficult to make decisions

•Not getting any enjoyment out of life

•Feeling anxious or worried

•Having suicidal thoughts or thoughts of harming yourself

What are the physical symptoms of depression?

•Moving or speaking more slowly than usual

•Changes in appetite or weight (usually decreased, but sometimes increased)

•Constipation

•Unexplained aches and pains

•Lack of energy

•Low sex drive (loss of libido)

•Disturbed sleep - for example, finding it difficult to fall asleep at night or waking up very early in the morning

What are the social symptoms of depression ?

•Avoiding contact with friends and taking part in fewer social activities

•Neglecting your hobbies and interests

•Having difficulties in your home, work or family life

Why is diagnosis difficult ?

•A wide variety of symptoms can be reported

•Difficult to differentiate normal mood fluctuations from depression

•No single objective test to establish diagnosis(no biomarker)

Based on interview

What diagnostic criteria are used to classify depression ?

•Diagnostic Statistical Manual (DSM 5)

Produced by the American Psychiatric Association

•International Classification of Diseases (ICD 11)

Produced by the World Health Organisation

How long does it take for diagnostic criteria to update ?

10 years

What does a patient need to get a classification of depression DSM-5 ?

Diagnosis Criteria: Five (or more) symptoms must be present during the same 2-week period.

Functional Change: Symptoms must represent a change from previous functioning.

Key Symptom Requirement: At least one of the symptoms must be either:

(1) Depressed mood, or

(2) Loss of interest or pleasure (anhedonia).

What is the exclusion criteria for classification of depression DSM-5?

- The episode is not attributable to the physiological effects of a substance or to another medical condition

- The occurrence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders

- There has never been a manic episode or a hypomanic episode.

What is the criteria need for a patient to be classified with depression ICD 11 ?

Diagnostic Timeframe: Symptoms must be present most of the day, nearly every day, for at least 2 weeks

Number of Symptoms: At least five characteristic symptoms must be present concurrently.

Affective Symptom Requirement: At least one symptom from the affective cluster (e.g., depressed mood or loss of interest/pleasure) must be included.

Relative to Baseline: Symptoms must be assessed relative to the individual's typical functioning.

What are the characteristics of the affective cluster ?

Affective cluster

- Depressed mood as reported by the individual (e.g. feeling down, sad) or as observed (e.g. tearful, defeated appearance

(Note: in children and adolescents depressed mood can manifest as irritability.)

- Markedly diminished interest or pleasure in activities, especially those normally found to be enjoyable to the individual (Note: this may include a reduction in sexual desire.)

What are the characteristics of the cognitive-behavioural cluster ?

•Reduced ability to concentrate and sustain attention on tasks, or marked indecisiveness

•Beliefs of low self-worth or excessive and inappropriate guilt that may be manifestly delusional (Note: this item should not be considered present if guilt or self-reproach is exclusively about being depressed.)

•Hopelessness about the future

•Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation (with or without a specific plan), or evidence of attempted suicide

What are the three clusters of the ICD 11 classification ?

- Affective cluster

- Cognitive- behavioural cluster

- Neurovegetive cluster

What are the characteristics of the neurovegetative cluster ?

•Significantly disrupted sleep (delayed sleep onset, increased frequency of waking during the night, or early morning awakening) or excessive sleep

•Significant change in appetite (diminished or increased) or significant weight change (gain or loss)

•Psychomotor agitation or retardation (observable by others, not merely subjective feelings of restlessness or being slowed down)

•Reduced energy, fatigue or marked tiredness following the expenditure of only a minimum of effort

What is the exclusion criteria of an ICD 11 classification of depression ?

Not Bereavement: Symptoms are not better explained by grief or bereavement.

Not Due to Medical/Substance Cause: Not caused by a medical condition (e.g. brain tumor) or substances/medications (including withdrawal).

Not a Mixed Episode: Does not meet criteria for a mixed mood episode. (manic depression)

Functional Impairment: Causes significant impairment in personal, social, educational, or occupational functioning — or requires major effort to maintain functioning.

What are the two types of depression ?

Unipolar and bipolar depression

State the characteristics of unipolar depression?

Mood swings in one direction

What type of depression is the most common ?

Unipolar

What are the majority of unipolar depression cases caused by ?

-75% cases reactive (induced by environmental causes)

-25% cases endogenous (genetic)

Name three types of unipolar depression ?

-Depressive disorder

- Dysthymic depressive disorder

- Major depressive disorder

What is bipolar depression?

- Oscillation between depression and mania

- Less common

- Strong hereditary tendency

What is bipolar depression a major cause of ?

A major cause of premature death and disability

What are the comorbidities associated with depression?

- Illness (chronic especially chronic pain)

- Neurological disease (stroke,drug abuse)

- Suicidal ideation (•20% of depressed individuals will attempt suicide

•10% of severe depressives will commit suicide)

- Anxiety(depression with anxiety or anxiety with depression)(manifest more severe symptoms)(less responsive to treatment)(higher risk of suicide)

What neurochemical changes are seen in depression?

1) Depressed functional levels of NA and 5HT

2) Altered activity of HPA axis, increased levels of cortisol, and reduced cortisol-mediated feedback control of CRH and corticotrophin

3) Reduced functional BDNF (poss malfunction of TrkB receptor)

4)Elevated glutamate levels

What genetic attributes increase the incidence of depression ?

Inheritance = First degree relatives of patients: 30%

Monozygotic twins = 40-50%

Sex = affects twice as many females as males

What does it mean for there to be a shared genetic risk between forms ?

If you are related to a patient with bipolar depression you have a higher lifetime risk of having major depression or bipolar depression

State two genes for which there is evidence of a link to depression ?

1) HTR2A = 5-hydroxytryptamine receptor 2A

2) GRIK4 = kainic-acid-type glutamate receptor KA1

What are GWAS studies ?

Screening of the entire genome to find the genetic associations of depression

- Identified 44 risk variants and refine the genetic architecture of major depression

What are the environmental factors that can cause depression ?

- Loss of loved ones

- Environmental factors = loud noise, work stress

- Social isolation

- Co morbidties

What are two possible reasons why the age of onset has decreased in recent years?

1) Life might be getting more stressful

2) Better depression diagnosis

What is the gene and environment interactions in depression ?

The more depression-inducing factors an individual has (e.g loss, stress, social isolation ) => the increased prevalence of the S(short allele) genotype of the 5HT transporter

Does the increased number of depression inducing life factors impact the l genotype of the 5HT transporter ?

The number of life events does not matter for the l(long allele) genotype

What is the difference in developing depression for people with the s and l genotype 5HT transporter ?

S genotype = more sensitive to life events causing depression

L genotype = consistent risk of depression throughout their life

Why may the different alleles lead to differences in the incidence of developing depression?

The alleles may lead to different levels of transcription of the 5HT transporter

(so genetic variation modulates the response of individuals to stress)

What are the brain regions associated with depression ?

- Amygdala

- Ventrolateral prefrontal cortex

- Dorsolateral prefronatal cortex

- Medial prefrontal cortex

- Striatal regions (ventral striatum)

- Hippocampus

- HPA axis

What is the key brain region in depression and why ?

Amygdala

- Responsible for fear and anxiety

- Communicates readily with midbrain where monoaminergic neurons are found

- Associated with emotions and recalling emotionally charged memory

What does the prefrontal cortex do ?

Decision making - planning and anticipation

What is the role of the striatal regions (ventral striatum) ?

Relay

allow communication between differnt brain regions

What is the role of the thalamus ?

Relay -communication between different brain regions

Takes information from the periphery of the body into the brain (and vice versa)

What is the role of the hippocampus ?

Important in learning and memory

(recall and new experiences)

What is the role of the hypothalamus-pituitary axis ?

Release of cortisol (stress hormone)

What are the anatomical differences in the orbitofrontal cortex of depressed patients?

Cortial thickness of the rostral and middle orbitofrontal parts is smaller

No difference in cortical thickness of caudal orbitofrontal and dorsolateral prefrontal

What is the anatomical difference in the hippocampus of depressed patients ?

Changes in the volume of hippocampal white matter (decreased volume) (white matter = axons)

What is the evidence that depression affects brain structure ?

Change in the volume of hippocampal white matter

Decreased cortical thickness in rostral and middle orbitofrontal area

What are two possible reasons why age of onset has been decreasing in recent years ?

- Is life getting more stressful

- Better at diagnosing depression - diagnosing earlier

Why does neuronal loss and decreased neurogenesis in the hippocampus affect the whole spectrum of symptoms associated with depression ?

1) Due to the critical role of where the hippocampus sits in the brain

2) Due to its association with other parts of the brain (e.g prefrontal cortex involved in working memory, cognition and important in mood)

Which area of the brain is hypoactive in the 'Default mode network' model of depression

Ventrolateral prefrontal cortex

Which drug is used to manage bipolar depression ?

Lithium

- BD is phases of mania and lithium stabilises the phases

What is the molecular target of SSRIs

Serotonin transporter

What neuronal autorecepetor is indirectly inactivated by SSRIs ?

5HT1a

What are the Subgenual and prefrontal cortex abnormalities in depression ?

- Decreased metabolism - Significant reduction in glucose consumption

- MRI data: mean gray matter volume of the subgenual anterior cingulate cortex reduced in patients with major depressive disorder and bipolar disorder

What is the Default Mode Network (DMN)?

Network of brain regions active when the brain is at wakeful rest

What is increased in the DMN of depressed individuals ?

Increased DMN connectivity(more active in the wakeful state)

(significantly altered dynamics and connectivity)

In what two areas of the brain did the DMN show increased connectivity in depressed patients?

Subgenual anteria cingulate cortex

Prefrontal cortex

What areas of the brain are hyperactive in patients with depression ?

Hippocampus

Amygdala

Subgenual cingulate

What biological changes are associated with depression and how might they affect the brain?

Depression is associated with increased levels of cortisol and pro-inflammatory cytokines (e.g., interleukin-6).

These changes may contribute to neuronal loss and structural changes in brain areas such as the hippocampus.

What is the link between genetic variations and CND connectivity?

•Amygdala-prefrontal connectivity is significantly reduced in depressed patients and carriers of the higher active MAOA risk alleles (MAOA-H).

•Reduced coupling in this circuit is linked to a longer and more severe course of disease

•Genetic variation in the MAOA gene, (enzyme which controls monoaminergic signalling) may affect the course of major depression by disrupting cortico-limbic connectivity

What is the monoamine theory of depression ?

Depression is associated with underactivity at serotonergic and noradrenergic synapses

- Antidepressant therapies increase serotonin (and sometimes other amines) in the brain

-Reduced monoamine metabolites present in CSF of depressed patients

How do we experimentally deplete 5-HT and induce depression in animal models ?

Reserpine

Name the Selective Serotonin Reuptake Inhibitors (SSRIs) ?

Citalopram

Fluoxetine

Paroxetine

What are the adverse effects of SSRIs?

Nausea, headaches, gastrointestinal problems, increased aggression, insomnia, anxiety, sexual dysfunction

Which SSRI is the most selective for serotonin reuptake ?

Citalopram

Why is it important that SSRIs are safe in overdose ?

As higher population of suicidal ideation in depressed patients

Name a tricyclic drug ?

Amitriptyline, imipramine,

What is the mechanism of action of tricyclic drugs ?

- Inhibit reuptake of amines

- Different degree of selectivity for amines between them (5-HT vs. noradrenaline)

What are the adverse effects of tricyclic drugs ?

Dry mouth, blurred vision, constipation, urinary retention, aggravation of narrow angle glaucoma, fatigue, sedation, weight gain, postural hypotension, dizziness, loss of libido, arrythmias

What receptors do tricyclic drugs have affinity for ?

•Have affinity for H1, muscarinic, α1 and α2 adrenoceptors (not selective for 5-HT)

What is the benefit of SSRI use over tricyclic drug use?

They are not dangerous in overdose (cardiotoxicity) like tricyclic drugs

What is the comparison of selectivity TCA vs SSRI ?

•TCA more selective for NA

•SSRIs more selective for 5HT

Why is there a delay in onset of action ?

Tricyclic drugs inhibit reuptake of amines

•The immediate increase in synaptic concentration of amines may lead to activation of somatic neuronal autoreceptors (e.g. 5-HT1A type)

•The activated autoreceptors decrease firing of the neurones

•During the first weeks of treatment the autoreceptors desensitize

•The neurones will return subsequently to the normal firing rate

•The inhibition of reuptake continues, and the level of amines continues to be high, resulting in full efficacy

What is the role of monoamine oxidase (MAO)

Enz which degrades amine NT (NA, 5-HT and DA)

Name a drug that provides irreversible, non-selective inhibition of MAO?

Phenelzine, iproniazid

What is phenelzine used to treat ?

Atypical depression (with anxiety, phobia and hypochondria)

State a MAO inhibitor with increase selectivity for MAO b

Moclobemide

- provides reversible inhibition

Name a serotonin noradrenaline reuptake inhibitor (SNRI) ?

Venlafaxine

Name a noradrenaline reuptake inhibitors (NARI) ?

Reboxetine

Name a noradrenergic and specific serotonergic antidepressants (NaSSA) ?

Mirtazapine

(antagonism at 5-HT2 and alpha-2 adrenergic receptors)

Name a Serotonin antagonist and reuptake inhibitor (SARI) ?

Trazodone

(mainly antagonism at 5-HT2 receptors and serotonin reuptake inhibition

Name a condition that is due to complications with antidepressant drug use ?

Antidepressant drug discontinuation syndrome

What is antidepressant drug discontinuation syndrome ?

•after a decrease in the dose of drug taken

•an interruption of treatment or abrupt cessation of treatment;

How can antidepressant drug discontinuation syndrome be prevented ?

•it can be prevented by a very gradual discontinuation of treatment, by using a very slow tapering of the doses taken by the patient

What are the symptoms of antidepressant drug discontinuation syndrome ?

•Insomnia

•Anxiety

•Nausea

•Headaches

•Electric shock sensations

•Agitation

•Mood swings

•Diarrhoea/abdominal cramps

What is bipolar disorder ?

•A mood disorder characterized by cycles of depression, mania and hypomania

Apart from the treatment of bipolar disorder what other conditions is lithium used to treat ?

Acute mania

Drug-resistant depression

What is the pharmacology of the other mood stabilisers ?

•Carbamazepine (blocks VGSCs amd GABA R agonist)

Sodium valproate( blocks VGSC? Increase GABA levels?)

Lamotrigine (blocks VGSCs and VGCCs and 5-HT3 antagonism )

(modifies excitability and inhibition of brain via GABA R and VGSC)

What are the reasons for 2/3 patients treated for depression failing to achieve remission ?

•Under-diagnosis

•Under-treatment

•Poor treatment compliance

•50% of patients receiving an initial prescription for an antidepressant stop treatment in the first month

•Poor patient education

•Lack of follow-up

What is euthymia?

normal, tranquil mental state

Describe the phases of treatment ?

1) The individual becomes depressed

2) Response = antidepressants

3) Stays in remission or relapse (relapse can occur before or after they achieve remission)

4) Might be a reoccurrence of depression

State the mechanism of action for the use of Ketamine for depression treatment ?

NMDA receptor inhibitor- used as sedative/analgesic/drug of abuse

(Efficacious in treatment resistant depression)

What is the use of Electroconvulsive therapy for depression treatment ?

- Hitting the brain's 'restart' button

- Can induce neuroplastic changes in hippocampus and amygdala

When is Electroconvulsive therapy used ?

Only in the most severe cases where symptoms are debilitating

In what type of depression is Cognitive behavioural therapy (CBT) effective?

•Effective for mild-moderate depression

Why is CBT useful ?

Helps patient understand thoughts and behaviours

- Reframe how their thoughts influence their feelings