Symptoms of Depression
- Guilty Feelings
- Early morning wakening
- Reduced appetite
The theory behind depression is an inadequate concentration of norepinephrine or serotonin in the junctional space which is leading to depression.
Let’s think of a sympathetic neural fiber. If we look at a postganglionic fiber and we have electrical stimulation going down, it’s hitting the neural vesicles which contain norepinephrine. The norepinephrine is then released in the junctional space and it’s going to hit the receptors. For example, if you have a heart and the beta-1 receptors are activated, it speeds up the heart. This cannot go on indefinitely so the body has to do something to stop this. The primary mechanism is to stop it using reuptake. So the norepinephrine goes right back to the vesicles. The other mechanism is to use an enzyme called MAO (monoamine oxidase) that will destroy the norepinephrine.
Given what you just read above, what could we do to increase the concentration of norepinephrine?
1. We could block reuptake and/or
2. We could inhibit the MAO enzyme using MAO inhibitors (MAOI).
Endogenous versus Exogenous Depression
Endogenous means the depression is within the person. Endogenous depression is treated with drugs. Exogenous means something outside their body causing depression, such as a death of a loved one. For exogenous we say that time is the healer.
Everybody will have one bout of endogenous depression. For 90% of people, within a few weeks it’s gone on its own. So those people will not seek therapy and it will go away on its own. For the other 10% it may be a single bout or one of many more to come. If they are manic or bipolar, lifelong therapy is required because the bouts are constant.
- Block reuptake of norepinephrine (NERI)
- Block reuptake of serotonin (SSRI)
- Block mono-amine oxidase enzyme (MAOI)
1. Onset of Action is 2-3 weeks.
The problem with these therapeutic options is that the onset of action takes 2 to 3 weeks. If the SSRI doesn’t work, you try a NERI and if it still doesn’t work, then you try the one that inhibits the reuptake of both. There’s no science behind it. It’s a complete guessing game that’s more of an art than a science that could take a VERY long time because you have to give 2-3 weeks for each drug.
If we finally find something that works, then we have to titrate the drug to find the right dose. So you’re not only trying to figure out what the biochemical problem is, but you have to try many different drugs within a class and then when you figure out a drug you have to refine the dosage. So this is a problem.
2. Sedating. This is a general good thing because one of the symptoms of depression is waking up early.
3. Anticholinergic Properties: Dry mouth, blurred vision, urinary retention, constipation.
4. Arrhythmogenic Properties. One of the properties of these drugs is that they could cause a fatal cardiac arrhythmia. This is a fatal symptom and if someone is acutely depressed and suicidal, they’re not going to get a 90-day supply of the drug.
- Endogenous Depression
- Enuresis: There has been a little use of enuresis which is bedwetting. Because of the anticholinergic properties, it could have some properties.
We have 3 classes, the tricyclic antidepressants, which interfere and block norepi reuptake. Another class of antidepressants block serotonin reuptake. And another which does both. So the question is, if a person has depression, how do I know what’s their true biochemical cause? Is it the lack of serotonin or norepinephrine? There is no blood test for this, so it must be trial and error. The other possibility is that it’s BOTH so we need to block the reuptake of both serotonin and norepinephrine. The fourth class, not listed below, is the MAOI which are one of the most dangerous drugs. There’s a lot of drug/drug interaction and food interactions with them.
Tricyclic Antidepressants (Norepinephrine Reuptake Inhibitor; NERI; NRI)
These commonly end with -amine, and -tripyline.
Amitriptyline (Elavil) – p.o. – Probably the most sedating of the antidepressants, so it’s useful for sleep.
Bupropion (Wellbutrin) – p.o. – It’s an antidepressant but can also be used for somebody who is addicted to cigarettes.
Clomipramine (Anafranil) – p.o – Also used for obsessive compulsive behavior.
Doxepin (Sinequan, Adapin) – p.o.
Imipramine (Tofranil) – p.o.
Nortriptyline (Aventyl) – p.o.
Protriptyline (Vivactil) – p.o.
Trimipramine (Surmontil) – p.o.
Serotonin Reuptake Inhibitor (SSRI)
These have been around for a little over 20 years and have been a godsend. Before this we only had the tricyclic antidepressants and there was a large population that wasn’t getting a benefit from the tricyclic cause they didn’t have a norepinephrine imbalance.
Fluoxetine (Prozac, Serafam) – p.o. – This was the first SSRI. Ironically not too long after Prozac came out, family members of individuals that committed suicide under this drug, were subsequently put on Prozac. Was it the drug that caused the suicide or were they going to do it anyway? We weren’t sure but the other problem was that millions of people said this drug works for me and they didn’t want it removed. Do you cater to the ones who lost loved ones or cater to the ones it works for? The FDA decided that the drug stays. All antidepressants have a label on there that if you give this drug to people under 25 or teenagers, the chance of suicide is increased.
Paroxetine (Paxil) – p.o.
Sertraline (Zoloft) – p.o
Citalopram (Celexa) – p.o.
Escitalopram (Lexapro) – p.o.
Norepinephrine and Serotonin Reuptake Inhibitors
Duloxetine (Cymbalta) – p.o.
Venlafaxine (Effexor, Effexor XR) – p.o.
Trazodone (Desyrel) – p.o.