9 - Moody Brain

chemical substances that change brain function and result in alterations, in perception, mood, consciousness and behavior

Autoreceptors: only respond to NTs from the cell, they are attached to

Heteroreceptors: only respond to NTs from adjacent cells

Psychotherapeutic agents:

licensed psychotropic drug exerting therapeutical benefit

Psychomimetics:

affects psyche wo therapeutic value —> drugs of abuse

Antipsychotics for Mania

Benzodiazepine for anxiety disorders

• -> effective but used shortly, dangerous cause induces tolerance

  —> higher dose each day

Antidepressants for unipolar depression

• 12-25% women —> 17% lifetime adjusted

• 7-15% men —> 7% lifetime adjusted

33% treatment resistant

16-20% of population suffer of depressive episode

—> expected to be biggest cause of lost life years in future (2030) because of suicide

Multicausual:

• neurobiological

• genetical

• psychosocial

• reactive

• physical

But: Very difficult and not well understood -> we only know that each of those has an effect on our neurotransmitter systems

1. Major depressed period: 5+ symptoms, including one of key symptoms

2. Sub-threshold depressive symptoms: 2-4 symptoms, may or may not include key symptoms

3. Non-depressed: 0-1 symptoms

first Antidepressants

• Reserpine:

  • 1950s, treatment for high blood pressure

  • depletes vesicles for monoamines (NTs) —> leads to depression

• Ipronazid:

  • 1951, treatment for tuberculosis

  • Blocks monoamine oxidase (NT degrading enzyme) —> elevates mood, because more dopamine etc.

changed concentration of monoamines in the synaptic cleft affects disorders

Lack —> depression

Excess —> mania

Reuptake: After release of neurotransmitters, leftover NTs are transported back into the pre-synapsis

Blocking: Transmitters are longer in the synaptic cleft —> more time for receptors to accept NTs —> increased activation of the post-synapsis

Tricyclic antidepressants

—> block reuptake pumps for norerpinephrine (NET) and Serotonin (SERT) immediately

BUT: delayed effect after weeks

Side effects:

• anticholinergic effects

• cardiovascular effects

• antihihistaminergic effects

• anticholinergic effects: blocked nose, dry mouth

• cardiovascular effects: hypotonia, arrhythmia

• antihistaminergic effects: sedation, dizziness

• Monoamine deficiency causes upregulation of post-synaptic monoamine receptors

  —> leads to increased sensitivity for NA, DA, and 5-HT

• But: too many serotonin receptors on raphe neurons (= 5-HT producers) set up a negative feedback loop —> less natural production of serotonin

• Reversal by antidepressants —> reversal of receptor up-regulation —> less receptors

1) Blocking of monoamine-oxidase —> less degradation of monoamines —> elevated mood

e.g. Moclobemide

2) ɑ2-receptors (pre-synaptic site, autoreceptors) block further release of NTs —> Inhibiting those autoreceptors leads to the continued release of NTs

e.g. Mirtazapine

3) Blocking reuptake

e.g. TCA, SSRI

A level of sedation in which a person is very relaxed but awake

Selective Serotonin Reuptake Inhibitors

e.g. Escitalopram, Fluoxetine

Inhibition of serotonin re-uptake

—> Used for Major Depressions

side effects:

• only minor anticholinergic and cardiovascular side effects

• sedative —> risk of suicide

• weight gain

• less sedation

• less anticholinergic effects

• less arrythmias

• lower risk of intoxication

e.g. Mirtazepine

—> against presynaptic a2-receptors (Mirtazepine also against 5-HT3, 5-HT2 receptors)

against: depression

side effects: fatigue (severe)

enhances effects of alcohol, benzodiazepine, …

hyperforine, minimum 3x300mg/d (Johanniskraut)

—> presumably inhibits re-uptake of NA, 5-HT, DA

against: mild depression, anxiety, nervous restlessness

side effects: Photosensibility, induction of P-glycoprotein

• 5-HT (Serotonin)

  • gastrointestinal complaints

  • sexual dysfunction

  • increased/decreased anxiety/depression (dose-dependent)

• NE (Norepinephrine)

  • sexual dysfunction

  • tremor

  • tachycardia (increased heart rate)

• mAch-receptor (Muscarinic Acetylcholine Receptor)

  • difficulaty focusing eyes

  • dry mouth

  • rapid heartbeat

• H1-receptor (Histamine Rezeptor)

  • sedative (causing drowniness or sleepiness)

• a1-Adrenorezeptor (Alpha-1 Adrenergic Receptor)

  • drop in blood pressure upon standing up

  • vertigo (dizziness)

Neuroleptics = Antipsychotics

used for disorders of thinking, perception and affect

between puberty and 30

10-30% remission (Nachlassen)

60% recurrences (Wiederauftreten)

30% stationary treatment

10-15% commit suicide

insulin- and electrical shock therapy

Positive symptoms

• symptoms that appear additional

• delusions, hallucinations

• can be treated

Negative symptoms

• apathy, anhedonia, cognitive blunting, neuroleptic dysphoria

• reduction of feelings / cognitive abilities

• present but can be less effectively treated

• genetic / organic: dopamine hypothesis

• environment: Vulnerability-Stress-Coping model —> sensitive to triggers like stress or drug abuse

• Dopamine (D2-receptor)

• Serotonin (5-HT2A receptor)

• Glutamate

• GABA

assumption: schizophrenia is due to an enhancement of dopaminergic activity (specifically in mesolimbic areas)

Pros for assumption:

• Effects of antipsychotics (AP)

  • standard AP are D2-blocker

  • Binding Affinity proportianal to effectiveness

  • risperidone / clozapine antagonises D2 / D4 receptors

• Post mortem examinations of brain of patients —> increased amount of dopamine receptors

• substances which increase DA level (cocain, amphetamine) can induce schizophrenic psychoses

Cons for assumption:

• lack of evidence for elevated dopamine metabolites

• latency of antipsychotic-induced effect (days to weeks)

• nigrostriatal

  —> coordination of movement

• mesolimbic

  —> pleasurable sensations, powerful euphoria of drugs of abuse

• mesocortical

  —> motivational, cognitive and emotional responses

• tuberoinfundibular

  —> regulates secretion of prolactin

clozapine antagonises 5HT2A receptors

serotonergic compounds (LSD) = hallucinogens

glutamate and receptors attenuated in patients

ketamin, PCP induce positive and negative symptoms

antagonists against: D4, 5HT2A, mACh, a1, H1, …