psychiatric disorders cbns 106

Schizophrenia symptoms

can be positive and negative

• Positive: Delusions, Hallucinations, Disorganized speech

• Negative: Flat affect, reduced speech, lack of initiative

what do VMAT inhibitors do?

alleviate symptoms of schizophrenia

• reserpine

What is VMAT

is the transporter that loads neurotransmitters into vesicles (Dopamine, Serotonin, Norepinephrine

what does Reserpine do?

block VMAT and reduces NT concentration in the synapse.

This reduction alleviates symptoms of Schizophrenia but can have side effects like sedation, Parkinson’s symptoms, and depression

How does D2 antagonists help with schizophrenia?

they alleviate symptoms by blocking D2 receptors and positive symptoms

• ex. Chlorpromazine

• more specific than reserpine

Clozapine

second generation antipsychotic that can treat schizophrenia symptoms

• targets D2 and 5HT2A

generalized anxiety disorder symptoms

• Excessive anxiety

• fatigue

• restlessness

• impaired concentration

• irritability

• difficulty sleeping

Everyone has generalized anxiety disorder

False! everyone gets anxiety but it becomes a disorder when it disrupts daily lives

What can be used to treat general anxiety disorder?

• antidepressants (first line of treatment)

• benzodiazepines

how do benzodiazepines work?

they alleviate acute symptoms of anxiety

• bind to GABA-A receptors and increase frequency of opening

• GABA-B receptor agonists are also used medically for things like spasticity and narcolepsy

what are emotions

short-lived, related to objects or events, and more intense than moods

what’s a mood

longer-lived, not necessarily related to objects orvevents, and less intense than

emotions

• depends on summed emotions over time and the valence (positive or negative) depends on the relation between mood and your affective happiness line

affective happiness line

average of affective experiences over time. how one generally feels most of the time

what is arousal

A state of heightened physiological and psychological alertness that increases attention

• follows the inverted U of performance

what is general arousal

the difference between feeling awake or sleepy

inverted U of performance

Low arousal or stress leads to low performance whereas arousal or stress levels that are too high also reduce performance.

• There is a sweet spot for maximal performance!

mood disorders

can occur over a range of arousal levels from high to low

• Mania and depression are associated with particular symptoms and bipolar disorder cycles between both

how are genes and mood disorders related?

Many genes have been associated with psychiatric disorders.

• They are often correlated with other issues as well, for instance, Schizophrenia often goes with Bipolar disorder and Anxiety disorders often go with Major Depression

symptoms of depression

• Changes in sleep and appetite

• fatigue

• low motivation for sex or other activities

• thoughts of self-harm or suicide

• feeling worthless

• physical pain

- Depression is common, comes in several flavors, and is on the rise

how did COVID affect anxiety and depression in the population?

pandemic stress increased both anxiety and depression

history of antidepressants

• WW2 pharmacy revolution

• Trofranil created in 1950s

• Iproniazid (monoamine oxidase inhibitor) made

• monoamine threory of depression

• 1970s: SSRIs discovered

• serotonin theory of depression

WW2 pharm revolution

A shift from small scale to industrial scale production of drugs like penicillin; paved the way for modern biotech and pharma companies

Trofranil (tricyclic anti-depressants, TCA)

made in 1950s

• was being tested for Schizophrenia when it was discovered to have antidepressant effects

  • severe side-effects and risks of lethal overdoses!

  • used as third- or fourth-line treatments

Iproniazid (Monoamine Oxidase Inhibitor)

• was being tested for tuberculosis but induced euphoria and high energy in patients

  • severe side-effects and risks of lethal overdoses!

  • used as third- or fourth-line treatments

Monoamine theory of depression

Depression may be due to low levels of monoamines

serotonin theory of depression

Depression may be due to low levels of serotonin

SSRIs: Selective Serotonin Reuptake Inhibitors

block reuptake of serotonin

• have fewer side effects and work as first line treatments

SNRIs: Serotonin-norepinephrine Reuptake Inhibitors

block reuptake of both serotonin and norepinephrine

• have fewer side effects and work as first line treatments

MAOIs: Monoamine oxidase inhibitors

inhibit the enzyme that breaks down monoamines

MAOIs, TCAs, SSRIs, and SNRIs all…

target broad neurotransmitter systems

do antidepressants work?

• Studies show that antidepressants improve symptoms in 20 out of 100 people

• Drugs also prevented relapses in 27 out of 100 people (Great if it works!!, not so much if you are treatment resistant)

antidepressant (SSRI) side effects

• nausea, diarrhea, sweating, tremor, decreased libido, decreased appetite, weight gain, dependency on medication, sleep problems

They can also lead to withdrawal following cessation

treatment resistance

SSRIs have long time to take effect and a host of negative side-effects during short- and long-term use

where is depression in the brain?

it is hard to say, as they target serotonin circuits, which are widespread across the brain.

• Broadly targeting serotonin could target depression circuits, but also have opposing effects

• Some 5HT receptors are inhibitory and some excitatory, this can lead to negative side-effects

Treating psychiatric disorders this way is like pouring oil all over your engine and hoping some gets where it needs to go!

Stress/ HPA axis

The hypothalamic-pituitary-adrenal (HPA) axis is activated in stress

what is stress in the body?

Stress can arise from social, economic,

dietary, sleep, or medical conditions

- Glucocorticoids like cortisol are released in stress along with adrenaline (epinephrine) (fight or flight)

- Chronic, high levels of cortisol reduce BDNF expression!

how are stress and depression related?

depression increases stress

- Chronic stress increases adrenalin and corticosteroids

- These increases carry risks to the cardiovascular system (sympathetic activation)

- Risks to sugar metabolism and diet

- Reduced BDNF signaling leads to depression and increased risk of other neurological disorders

- Depression also increases stress and it becomes a negative cycle

history of antidepressants

1990s: Treatment resistant patients were prevalent and there was a lack of new drugs

- 2000: Ketamine (a potent anesthetic) was found to rapidly reduce depression symptoms through a glutamate burst leading to a host of new therapeutic targets

• For example, new FDA approved drugs like dextromethorphan and esketamine target glutamate signaling

• These offer hope for treatment resistant depression

ketamine as depression treatment

low doses Ketamine preferentially blocks NMDA receptors in GABAergic inhibitory neurons

- This results in more glutamate release and more LTP

• The effects of Ketamine are complex but a major hypothesis focuses on increasing BDNF and neuroplasticity

plasticity theory of depression

Traditional antidepressants likely take a long time to work (if they work) due to slow induction of increased BDNF and increased plasticity

- Increased monoamines in the synapse activate receptors that change gene expression

By rapidly increasing BDNF and plasticity through Ketamine administration (or similar NMDA antagonists) the effect is faster and more efficient (in theory)

new treatments for depression

• Ketamine

• Video Games?

• Psilocybin

• Transcranial Magnetic Stimulation (TMS)

Psilocybin for depression

47% of treatment resistant patients had reduced depression 5 weeks after a single dose

- Microdosing is not generally effective, and some people have severe negative reactions

- Studies like this also give us information on specific brain regions!

Trans Cranial Magnetic Stimulation

- Applied magnetic pulses through the skull activate large regions of the brain

- This activation is thought to boost activity across the brain and reduce symptoms of depression

low activity theory of depression

stepped care models for treatment

Cases of depression and anxiety should be taken seriously.

- Care should match the intensity of diagnosis

- Stepped care starts with monitoring and education and escalates through higher intensity forms of medication and therapy

depression treatment

- Aside from medical interventions, do things that enhance positive feelings

- Life is busy, stressful, and tiring sometimes, please take care of yourself