Comprehensive Study Notes on Ketamine, Anxiety, and Benzodiazepines

Ketamine as a Therapeutic Drug

• Ketamine is used recreationally, but it also has therapeutic potential for different reasons.
• It has been used as an anesthetic for surgeries on people and animals.
• Lower doses (sub-anesthetic) are now being investigated for treating major depressive disorder.
• Some patients in trials experienced a rapid lifting of the "fog of depression" within hours of ketamine injection, unlike typical antidepressants.
• SSRI antidepressants take 4-6 weeks to work and are effective for some but not all individuals.
• Ketamine's immediate effects are different from the long-term readjustment/healing that SSRIs may provide.
• The mechanism of action is still under investigation.
• Clinical trials involve multiple doses per week (e.g., every other day) for a few weeks (2-3 weeks).
• Patients often experience a remission from depression for several months after the treatment course.
• Ketamine isn't a cure, as patients may relapse into depression.
• Psychiatrists and psychologists are researching optimal therapy courses, side effects, and the overall potential of ketamine as a therapy.
• Ketamine might become a primary treatment, potentially replacing SSRIs in the future, but this is uncertain due to the early stage of research.
• Research in rats and mice indicates that ketamine injections can reverse depression-like symptoms within three hours.
• Changes in the activity of the anterior cingulate cortex were observed.
• Over a longer term (12-24 hours), structural changes and new connections were found in the anterior cingulate cortex.
• The anterior cingulate cortex in humans has subdivisions involved in activating or suppressing the stress response.
• The exact equivalency between rodent and human cortex regions is uncertain.
• Ketamine may have a profound effect on remodeling the prefrontal cortex, which controls the stress response, leading to a quicker effect than traditional antidepressants.

Long-Term Effects and Side Effects of Ketamine Use

• Recreational ketamine use has known long-term effects that can be studied.

• Significant negative side effects exist:

  • Memory and cognitive problems are common due to ketamine blocking NMDA receptors, which are essential for making new memories in the hippocampus.
  • Memory problems are possibly reversible if NMDA receptor blockage is stopped, allowing new memories to form.
  • Kidney damage: Regular ketamine use can cause irreversible kidney damage.
  • This was not a problem when ketamine was used as a one-off anesthetic.
  • Regular use is toxic to the abdomen, kidneys, bladder, and possibly the gut, causing cramps.
  • These are serious medical side effects.

• If ketamine becomes a common antidepressant, these side effects need close monitoring.

• Addiction:

  • Ketamine is likely addictive.
  • Tolerance develops, causing physical addictiveness and withdrawal symptoms upon cessation.
  • Withdrawal symptoms include psychotic features like hallucinations.
  • NMDA receptor antagonists affect dopamine release in the nucleus accumbens and can be psychologically addictive.
  • The conclusion is that ketamine would likely be psychologically addictive, though specific studies are limited compared to drugs like cocaine.

• Legality:

  • Ketamine is a class B drug, meaning possession, distribution, or sale is illegal without clinical or veterinary purposes.

• Psychoactive Effects:

  • Antidepressant doses of ketamine do have psychoactive effects.
  • Patients don't lose consciousness but experience altered perceptions.
  • This is why patients are kept under observation after ketamine administration.
  • Similar trials are being conducted with hallucinogenic drugs like LSD for depression, showing promising results.

K Cramps

• K cramps, or ketamine-induced cramps, are pain experienced in the abdomen caused by ketamine use.

Ketamine as an Anesthetic

• Ketamine as an anesthetic may still have side effects.
• Higher doses used in anesthesia are likely to cause stronger side effects during that time.
• Clinicians must balance the benefits of using ketamine with its potential side effects.

Psychotic Features & Withdrawal

• The reason for psychotic features during withdrawal isn't fully understood but involves the body compensating for the drug's effects.

Anxiety and Anxiolytic Drugs

• Anxiety disorders are characterized by extreme worry and fears that cause chronic stress.
• They are frequently comorbid with depression.
• While everyone experiences anxiety, an anxiety disorder involves long-term, unremitting, and debilitating anxiousness.
• Diagnosis criteria include symptoms lasting more than six months.
• Anxiety disorders are more common in women than men, though the reasons for this are varied (societal, biological, genetic, hormonal, etc.).
• About a third of people may be diagnosed with anxiety.

Treatments for Anxiety Disorders

• Talking therapies are effective, but access is limited due to high demand.
• Exposure therapies can help with specific phobias (e.g., arachnophobia, agoraphobia).
• Virtual environments are used in exposure therapy, such as at universities for people with autism in social situations.
• Drug treatments are common, including SSRIs and beta blockers.

Benzodiazepines as Treatment

• Benzodiazepines are sedatives and anxiolytics.

• They reduce anxiety and can be used as sleeping pills to treat insomnia.

• Examples: Valium, Xanax, Librium, Klonopin, Rohypnol.

• Administration:

  • Typical benzodiazepines reach peak blood levels in about an hour due to digestive tract absorption.
  • They are lipid-soluble and cross the blood-brain barrier.

• Half-Life:

  • Different benzodiazepines have varying half-lives depending on their purpose:
  • Sleeping pills have short half-lives to avoid grogginess the next day.
  • Anxiolytics have long half-lives to maintain a steady drug concentration.
  • Half-lives range from 90 minutes to six days, including active metabolites.
  • Chemists can design drugs with active breakdown products to prolong the anxiolytic effect.

• Benzodiazepines are also known in the context of spiked drinks and date rape drugs.

• About a tenth of the class have taken benzodiazepines, probably because most have been prescribed SSRIs for their anxiety disorder.

• Drawbacks include drowsiness, memory impairment (anterograde amnesia), muscle relaxation, and mental confusion.

• They prevent the formation of new memories at the time of the event.

• Used in acute anxiety situations like anxiety attacks, where an SSRI would not be effective.

• Used for alcohol withdrawal to prevent dangerous withdrawal effects.

  • Alcoholics cannot stop alcohol consumption abruptly due to life-threatening withdrawal symptoms, which benzodiazepines can mitigate.

• Sometimes used in combination with other drugs for epilepsy treatment.

• Mechanism of Action:

  • Benzodiazepines are indirect Gaba-A receptor agonists, enhancing Gaba's effects.
  • They increase inhibition in the brain caused by Gaba, hyperpolarizing the post-synaptic membrane.

Gaba Activity and Benzodiazepines

• Gaba is present throughout the brain, especially in interneurons.
• In the cerebral cortex, increased inhibition from benzodiazepines can cause confusion and memory impairment.
• In the hippocampus, increased inhibition impairs memory formation (anterograde amnesia).
• In the spinal cord and brainstem, Gaba receptors control skeletal muscles, leading to muscle relaxation.
• In the amygdala, orbitofrontal cortex, and insula, inhabitation reduces anxiety.
• Benzodiazepines help Gaba in the VLPO inhibit the alertness and awaken side of the flip-flop, making them effective sleeping drugs.

Alcohol and Benzodiazepines: Similarities and Risks

• Alcohol is also a Gaba-A agonist.
• Due to their similar action on Gaba receptors, benzodiazepines can reduce alcohol withdrawal effects.
• Alcoholics are susceptible to benzodiazepine addiction.
• Combining alcohol and sleeping pills (benzodiazepines) is dangerous and can lead to overdose.
• Both act on Gaba receptors, causing excessive inhibition in breathing centers.
• Never combine drugs with similar effects.

Long-Term Effects and Considerations

• Long-term benzodiazepine use has side effects.
• The population most prescribed benzodiazepines long-term may be older people in retirement homes.
  • However, benzodiazepines can mimic dementia symptoms (confusion).
  • It's important for doctors and care home staff to be aware of potential misdiagnosis of dementia due to medication side effects.
• Benzodiazepines:
  • Are addictive and cause physical dependence.
  • Also have a part to play on the VTA and Nucleus accumbens which is related to psychological dependance from alcohol.
• Withdrawal symptoms can include increased anxiety, insomnia, restlessness, agitation, and irritability.
• Regular users should not abruptly stop benzodiazepines; a slow, supported taper is necessary.
• Class C drug.

Module Summary

• Lectures covered stress response and its potential link to mood disorders like depression.
• Depression may arise from chronic stress and physiological changes.
• Biomedical and clinical psychological perspectives on depression are not incompatible.
• Treatments: SSRIs and other drugs targeting monoamines.
• New potential treatments like ketamine.
• Anxiety and benzodiazepines.

Exam Preparation Guidance

• Understand drug mechanisms.
• Logical effects based on the brain systems involved.
• Focus on effects linked to demonstrated relationships.
• Half-lives (general understanding, not exact numbers).
• Focus on concepts and mechanism rather than memorizing lists of facts.

Sex Differences

• Apply an understanding of how hormones and sexual orientation play a role in affecting the brain
• Be able to search for evidence relating organizational (Prenatal androgens) and Active (CRH) role of hormones related to an anxiety
• Conceptual level rather than detailed factual level.

Understanding half life and drug design

• Design through both trial and error
• Computer based models to predict how molecules will affect the body
• Always need to do trials to test it

Combining medication

• Switching from an alcohol addiction to pills for alcoholics can be possible. Carefull monitoring is imperative

Epilepsy effects of Benzos

• Drugs are not precise, they have all sorts of effects
• If you have epilepsy, it will stop seizures to stop

Benzodiazepines and Lasting Effects

• There are lasting effects like building up tolerance, may need to be taken down again
• No permanent damage, UNLESS REALLY NEED HIGH DOSES

Set Word Limit

• 400 words each for short answer questions