Major Depressive Disorder Treatment Overview

Major Depressive Disorder (MDD) Treatment

• MDD Symptoms: Sadness, helplessness, worthlessness, impaired sleep, impaired concentration, anhedonia, physical pain. Multiple symptoms must significantly impact daily life.
• Stress Circuit (HPA Axis): The amygdala detects stress, alerting the hypothalamus. The hypothalamus signals the pituitary to release ACTH, which triggers the adrenal glands to release cortisol and adrenaline (activating hormones). This occurs in the sympathetic nervous system (SNS).
• Depressed Brain Differences: High cortisol levels negatively impact brain cells (reducing plasticity). There are chemical differences, including low levels of brain-derived neurotrophic factor (BDNF) in the blood, which is correlated with depression. Inflammation is also a factor, with high inflammation correlating with MDD.
• Neurology of Depressed Brain: Structural differences exist with decreased BDNF, increased cortisol. Decreased dendritic branching is found in the prefrontal cortex, hippocampus, and amygdala, reducing volume and plasticity. The hippocampus also experiences decreased neurogenesis (new cell birth).
• Antidepressant Treatment Normalizes: The above mentioned structural and chemical differences are often normalized by proper treatment.

Antidepressants

• Electroconvulsive Therapy (ECT): Induces seizures via electricity to "reboot" the brain. Fast-acting and effective but short-lived effect, time-consuming treatment, and memory loss are potential issues.
• Tricyclics (TCAs): E.g., imipramine (Tofranil). Block the reuptake of serotonin and norepinephrine, but also block other receptors (acetylcholine, histamine, epinephrine), leading to potential side effects such as confusion, memory issues, sedation, and cardiotoxicity in overdose. Active metabolites can add 4+ days to the effect, especially in the elderly.
• Monoamine Oxidase Inhibitors (MAOIs): E.g., selegiline (Emsam). Originally for tuberculosis, they inhibit the action of MAO (irreversibly or reversibly). MAO metabolizes tyramine so dietary restrictions are crucial and combined with adrenaline-like drugs could be very harmful.
• Selective Serotonin Reuptake Inhibitors (SSRIs): Inhibit serotonin reuptake minimally affecting other monoamine transporters and post-synaptic 5-HT receptors. Potential side effects include "serotonin syndrome" (cognitive issues, ANS dysfunction, neuromuscular problems, agitation, sexual dysfunction, SSRI discontinuation syndrome).
• Dual-Action Antidepressants: Target serotonin and norepinephrine reuptake to minimize side effects found in older antidepressants. E.g., Venlafaxine (Effexor), Duloxetine (Cymbalta).

Pain & Opioids

• Pain Pathways: Pain signals travel from free nerve endings to the spinal cord, thalamus, and eventually the somatosensory cortex. A different pathway involves these signals reaching the hippocampus, amygdala, and cingulate cortex, processing emotions and implications of pain.
• Anti-Pain Pathways: The brain has descending anti-pain pathways originating in the midbrain, which use serotonin and norepinephrine to block pain signals. Opioids enhance this effect.
• Opiates, Opioids and Sources: Opiates (morphine, codeine) are extracted from opium, derived from the opium poppy. Opioids are endogenous ligands that bind opioid receptors (e.g., endorphins, enkephalins, dynorphins). The term "opioid" is now broadly used to encompass synthetic and natural drugs targeting these receptors.
• Opioid Receptors: Opioid receptors (mu, kappa, delta) are metabotropic; with natural/endogenous ligands like endorphins, enkephalins, dynorphins and exogenous ligands like morphine, naloxone, salvinorin A, and others.
• Opioid Drugs:
  • Pure Agonists (mu): e.g., morphine, codeine, heroin, methadone.
  • Mu Antagonists: Naloxone (Narcan), Naltrexone (ReVia, Trexan) to reverse overdose and manage addiction.
  • Partial Mu Agonists: Buprenorphine (Subutex), Tramadol. Limit respiratory depression and abuse potential, but some cautioning side effects remain.
  • Mixed Agonist-Antagonists: e.g., Pentazocine (Talwin): Less commonly used as dysphoria is a concern.
  • Suboxone: Buprenorphine + naloxone. Naloxone is inactive orally, but becomes active if crushed and injected.

Sleep and Insomnia

• Wakefulness Control: Wakefulness depends on a balance between excitatory chemicals (glutamate, acetylcholine, dopamine, norepinephrine, orexin, histamine) and inhibitory chemicals (GABA, melatonin, adenosine).
• Neural Wakefulness Centers: The reticular formation (glutamate), basal forebrain (acetylcholine), and locus coeruleus (norepinephrine) are involved in wakefulness. The Hypothalamus is also important.
• Sleep-Wake Regulation in Hypothalamus: Cell loss in specific hypothalamic areas is linked to sleep disorders (enchephalitis and fatal familial insomnia). The hypothalamus releases histamine and orexin to regulate wakefulness.
• Circadian Rhythm: The suprachiasmatic nucleus (SCN) regulates the release of melatonin from the pineal gland.
• Caffeine: An adenosine receptor antagonist. Adenosine usually suppresses activity of other chemicals, caffeine counteracts adenosine activity.
• Sleep Stages: Sleep stages 3 and 4 are slow-wave sleep, more rhythmic EEG activity. REM sleep is tied to body temperature.
• Insomnia: High comorbidity with anxiety and has multiple factors influencing the onset, maintenance, and termination of sleep.
• Sleep Aids: Many OTC aids are antihistamines while other prescription aids (e.g., Zolpidem, Zaleplon, Eszopiclone) are non-benzodiazepine receptor agonists.
• Ramelteon: Melatonin agonist with questionable efficacy as sleep aid.
• Orexin Receptor Antagonists: E.g., Suvorexant (Belsomra). Prevent activation of arousal systems, potentially helping sleep.

Psychedelics

• Anticholinergic Drugs: E.g., scopolamine (mAch antagonist). Low doses: sedation, euphoria, amnesia. High doses: euphoria, hallucinations, excitement, tachycardia, increased body temperature, and dry mouth. Used for anesthesia.
• Serotonergic Drugs: e.g., LSD, synthesized in the 30s & 40s. Binds to 5-HT2A receptors, causing perceptual distortions (visual, auditory, space/time). Various uses over the decades have included therapy to combat psychosis.
• Serotonergic Psychedelics (other): E.g., Ololiuqui, Bufotenine, Psilocybin/Psilocin (shrooms). Alternative metabolic product of serotonin found in people with psychiatric disorders and commonly used in treatments for depression, PTSD, addiction, and end-of-life anxiety.
• Catecholamine-like/Entactogens: E.g., Mescaline (anxiety, visual distortion, tremor), MDMA (increased norepinephrine/dopamine/acetylcholine and empathy; with various potential concerns for neurotoxicity etc).
• Antiglutamatergic Drugs: E.g., PCP and ketamine (NMDA receptor antagonist). Confusion, altered perception, stupor, coma.
• Kappa Opioid Agonist: Salvinorin A (hallucinations, dysphoria).

Endocannabinoid System and Cannabis

• Endocannabinoids: Signaling molecules synthesized on-demand from arachidonic acid.
• Endocannabinoid Functions: Analgesia, sensory processing, motor coordination, memory, cognition, appetite, and the immune system.
• Endocannabinoid Receptors: CB1 (central nervous system), CB2 (periphery/immune system).
• Endocannabinoid Inactivation: Anandamide (FAAH) and 2-AG (MGL) are broken down by enzymes.
• Cannabis Components: Cannabis sativa and indica contains psychoactive Delta-9-tetrahydrocannabinol (THC) and non-psychoactive Cannabidiol (CBD), and Cannabinol (CBN).
• Medical Uses: Analgesia (Sativex), appetite stimulation (Marinol), issues influencing pain, inflammation and potential treatment of other issues like cancer and AIDS.
• Cannabis Timeline: 1964: THC identified. 1988: CB1 receptor identified. 1991: CB2 receptor identified. 1992: endocannabinoids identified (anandamide, 2-AG).
• Pharmacokinetics of THC: Half-life ~30 hours. Depot binding and metabolism can impact duration and effectiveness.

Alcohol

• Pharmacokinetics: Absorbed easily and quickly diffuses through membranes. Distributed throughout the body and crosses the blood-brain barrier.
• Metabolism: Metabolized primarily by alcohol dehydrogenase in the liver (varies between genders) into acetaldehyde, and then into acetic acid.
• Excretion: Excreted via lungs, urine, and other pathways.
• Pharmacodynamics:
  • Glutamate: Suppresses NMDA receptor function, leading to reduced glutamate release.
  • GABA: GABA agonist. Chronic use decreases GABA’s effect.
  • Opioids: Induces opioid release and subsequent dopamine release
  • Cannabinoid System: Stimulates anandamide production.
• Alcohol Tolerance: Metabolic (increased enzyme activity), pharmacodynamic (changes in receptors). Effects also apply to the behavioral changes that accompany chronic consumption.
• Alcohol Use Disorder (AUD) Pharmacotherapy: Treating withdrawal (e.g., benzodiazepines, anticonvulsants), preventing relapse (e.g., disulfiram, naltrexone), and treating comorbid disorders (e.g., depression, PTSD).

Addiction

• Opponent Process Theory: Repeated exposure to a stimulus (A process) weakens its rewarding qualities and strengthens an opposing response (B process).
• Addiction in Opponent Processes: Tolerance (A process weakening), withdrawal (B process becoming more prominent). Drug use less pleasant, withdrawal/cravings dominate.
• Brain Disease Model: Addiction stages & underlying brain circuitry.
  • Binge/intoxication: Basal ganglia (reward pathway) is activated.
  • Withdrawal: Limbic system (amygdala), stress system (HPA), negative affect.
  • Preoccupation/Anticipation: Prefrontal cortex, stress system, basal ganglia, insula (cravings).
• Pharmacotherapy of Addiction:
  • Agonist: Replace addictive drug with a similar one (e.g., methadone).
  • Partial agonist: Prevent withdrawal and cravings while minimizing drug's rewarding qualities (e.g., varenicline).
  • Antagonist: Block the drug's effect (e.g., naloxone).
  • Aversive: Induce a negative reaction (e.g., disulfiram).
  • Antidrug Vaccines: Stimulate the immune system to reduce drug entry into the brain.