SP.236 / ESG.SP236 Exploring Pharmacology Spring 2009

Transcription

1 MIT OpenCourseWare SP.236 / ESG.SP236 Exploring Pharmacology Spring 2009 For information about citing these materials or our Terms of Use, visit:

2 Mechanisms Antidepressants Serotonin, dopamine, and norepinephrine Why the latent period before efficacy? (discuss) What is depression? Discussion: Share your research Do antidepressants induce suicide? Do MAOIs deserve such a bad rap? Discussion: Are antidepressants overprescribed? Antidepressants cure everything

3 Metabolism (destruction) Reuptake

4 Increase synthesis (Levodopa, 5-HTP) Antidepressant Mechanisms Inhibit breakdown (MAOIs) Antagonism (Mirtazapine) Agonism (Pramipexole) Release (Amphetamine) Electroconvulsive therapy (Unknown mechanism) Inhibit reuptake (SSRIs, TCAs) Partial agonism (Buspirone)

5 5-HT, DA, and NE Effects of each Side effects of each When is each preferred?

6 Are antidepressants sedatives or stimulants?

7 Why the latent period? Maybe receptor populations need to change. For instance, maybe feedback mechanisms initially prevent the 5-HT level from rising, but over time those feedback mechanisms give up. Maybe it takes time for new brain cells to grow. Maybe it takes time for the drug level to build up in the bloodstream. Maybe it is psychological: Depression is learned helplessness and despair that was reinforced over years of bad experiences and anhedonia. It takes time for the brain to change gears, and learn to be optimistic.

8 About the latent period It is not universal, and it is not predictable. Sometimes it is one week, sometimes it is twelve weeks. Sometimes there is no latent period, but rather a honeymoon which quickly fades. Anxiety might improve before depression, or vice versa. OCD usually takes the longest to respond, quite probably because it takes a long time to forget old habits even after the chemicals driving them have been fixed. Side effects are almost always worst at the beginning, and improve over days or weeks.

9 What is depression?

10 Share your research

11 Antidepressants and Neurogenesis A great overview of the evidence in layman s terms: hanismintro.htm Summary: Depressed people have small hippocampi. The hippocampi shrink more as the depression progresses. The hippocampi grow larger if the depression is successfully treated by any means.

12 Antidepressants and Neurogenesis The Hypothalamic-Pituitary-Adrenal axis theory: The HPA axis releases stress hormones (cortisol) in response to stressful events. These hormones kill brain cells and ultimately lead to HPA overactivity (positive feedback)

13 Do antidepressants cause suicide? Yes, sometimes. Children and adolescents at greater risk, adults at some risk too. Untreated depression causes more suicide, and heart attacks, cancer, lost productivity, and healthcare expenses The suicide risk always comes early in treatment, so careful observation right after starting a medication might completely eliminate the risk.

14 Do antidepressants cause suicide? The numbers are very iffy, but warning doctors and patients about the suicide risk may actually cause more suicides. One thing is for sure: A very, very small percentage of the suicides in this country are caused by antidepressants. The vast majority occur in untreated individuals or antidepressant-treated individuals who have been on the same dose for a long time and were clearly incited to suicide by something more

15 Do MAOIs deserve such a bad rap?

16 Discussion: Are antidepressants overprescribed?

17 Antidepressants cure everything! Melancholic depression (not sleeping, not eating, hopelessness, guilt, shame, nothing makes you happy) Atypical depression (good things make you happy, you might eat too much, you might sleep too much) Psychomotor depression (you are so unhappy that you talk and move slowly) Agitated depression (you are so unhappy that you are frantic and edgy all the time) Bipolar depression (this is a symptom of bipolar disorder/manic depression, antidepressants are second-line medications for this disease)

18 Antidepressants cure everything! Psychotic depression (plus antipsychotics) Schizophrenia, schizoaffective disorder (psychotic people are often depressed, with very blunt emotions) PMS/PMDD Seasonal affective disorder (SAD) Posttraumatic stress disorder (PTSD) Social anxiety General anxiety Panic disorder OCD (Especially SSRIs) ADHD (certain antidepressants, atomoxetine)

19 Antidepressants cure everything! Sleep disorders (narcolepsy, especially MAOIs) Insomnia (trazodone most popular hypnotic) Fibromyalgia (diffuse pain in many body parts, perhaps caused by sleep disorder, perhaps psychogenic, probably neurological in some way) Pain (Dr. House would be on additional drugs, not just Vicodin. He would probably be on antidepressants.) Headaches Premature ejaculation (Paxil treats it) Anorgasmia (Wellbutrin treats it)

20 Antidepressants cure everything! Eating disorders (too much and too little) Irritable bowel syndrome Autism spectrum disorders Alcoholism

21 Antidepressants cure everything! Drug addiction Antidepressants help drug addicts in many ways. Many addicts are depressed or anxious. Sometimes that is why they started using drugs, or sometimes it is a consequence of the damage the drugs did to their life, friends, brain, and body. Either way, antidepressants treat depression and anxiety. Bupropion (Wellbutrin, Zyban) is good for smokers. Amineptine and nomifensine are good for cocaine addicts, they increase DA levels. Desipramine is good for PCP, ketamine, and

22 Shock therapies History: Motivation: Perhaps fever is beneficial, and syphillis patients who don t have fevers might improve if they could have a fever. 1917: Dr. Julius Wagner von Jauregg intentionally gives neurosyphillis patients malaria to cause a very high fever. He notices that if they have febrile seizures, they get less crazy and less depressed. He wins the 1927 Nobel Prize for this work.

23 Shock therapies Motivation: Maybe crazy people s brain cells are tired and need to rest. Let s induce a coma to provide that rest. 1927: Dr. Manfred J. Sakel gives schizophrenic patients insulin to induce coma, many of them are improved upon waking. Those who have seizures along with their coma improve the most.

24 Shock therapies Motivation: I ve never seen a schizophrenic epileptic, therefore the diseases must be mutually antagonistic. (This theory is dead wrong and Dr. Meduna s observations were due to coincidence) 1934: Dr. Ladislaus von Meduna gives schizophrenic patients various convulsants to induce seizure. He tried camphor, strychnine, thebaine, pilocarpine, and pentylenetetrazol (metrazol).

25 Shock therapies Motivation: Dr. Meduna s drug-induced seizures are incredibly dangerous. Let s try using electricity instead. 1937: Dr. Ugo Cerletti uses electric shocks to induce seizures in schizophrenic patients.

26 Shock therapies Over several decades: - It was noticed that shock therapy is completely ineffective for schizophrenia, but it is very effective for depression - Paralytics (including succinyl choline and vecuronium) were introduced to relax the muscles and prevent broken bones - General anesthesia was administered before the seizure to prevent panic and pain - The electric shock was applied only to one half of the head, or only to the front, to minimize memory loss