Antidepressants – A Primer

Antidepressants – A Primer

Antidepressants have come a long way. Our understanding of the biological and neurological bases for depression has expanded vastly, and the number of treatment options have increased and improved so that they can be better targeted towards individual symptoms. Public knowledge has not kept pace; thanks to poor science education and journalism and the dissemination of false information by special interests, people understand much less about depression and its treatment than they should.


This is not “the blues,” it’s not caused by a bad life situation, and it doesn’t go away by itself. It is not a single type of disorder, but several types, each with its own set of symptoms and needing different types of treatment. It often comes along with other problems that further complicate treatment. Major Depressive Disorder symptoms include (my notes in italics)

1. Feelings of sadness or unhappiness for no apparent reason, which will often get worse rather than better if the sufferer is reminded of the reasons he/she should be happy.

2. Irritability or frustration, even over small matters because each tiny failure or setback reminds the sufferer of his/her overall inability to succeed at anything.

3. Loss of interest or pleasure in normal activities because what’s the point? Why even bother? Nobody cares whether I do it or not, it’s not going to change the world, it’s not going to last, and I’m probably going to mess it up anyway like I always do.

4. Reduced sex drive I’m so fat/ugly/unattractive who would want to? My lover/spouse only says he/she wants to to make me feel better, not because of any real desire. . .

5. Insomnia or excessive sleeping I can’t sleep because I can’t stop thinking about how awful I am and how terrible my life is, or I need to sleep all the time so I don’t have to think about how awful I am and how terrible my life is.

6. Changes in appetite — depression often causes decreased appetite and weight loss, but in some people it causes increased cravings for food and weight gain eating for pleasure decreases because you don’t “deserve” or appreciate pleasure, comfort eating becomes a form of self-medication, and when people express concern over your change in weight, you know it’s because they’re disgusted at the sight of you, not because they care.

7. Agitation or restlessness — for example, pacing, hand-wringing or an inability to sit still just like an animal in a cage, who knows there’s something wrong about being in that cage, knows there’s a way out of the cage, but can’t figure out how to escape or why he wants to.

8. Irritability or angry outbursts Don’t remind me of my failure. Don’t interrupt me when I’m reminding myself of my failure. Don’t try to tell me I’m not a failure.

9. Slowed thinking, speaking or body movements shutting down and shutting out the world is a defense mechanism.

10. Indecisiveness, distractibility and decreased concentration It’s hard to be decisive or focused when you know you’re probably going to make the wrong decision and mess up everything you do.

11. Fatigue, tiredness and loss of energy — even small tasks may seem to require a lot of effort See 2, 3, 8, 10.

12. Feelings of worthlessness or guilt, fixating on past failures or blaming yourself when things aren’t going right You should be sensing a pattern here. . .

13.Trouble thinking, concentrating, making decisions and remembering things a side effect of trying to stop thinking about how awful you are, concentrating on how you’ve ruined your life, expecting that all your decisions will be the wrong ones, and shutting out memories.

14. Frequent thoughts of death, dying or suicide In the deepest depression, with extreme apathy and certainty of your potential for failure, these thoughts may take the form of wishing for something to happen to you rather than actively considering suicide.

15. Crying spells for no apparent reason There may be a reason, but it will have nothing to do with where the sufferer is, whom he/she is with, or what is happening or being talked about at the time. Depressive thoughts intrude without prompting.

16. Unexplained physical problems, such as back pain or headaches When you spend a significant amount of time thinking about what’s wrong with you and what’s wrong with your life, it’s not a big step to start thinking about what’s wrong with your body – making it worse by focusing on it as well as by not doing anything that will help it.


Right now, what we know is from animal studies, clinical trials, and patient experiences. Not perfect by any means, but better than what we had in the past. But the view that depression is caused by a shortage of serotonin has led to a lot of misconceptions about treatment – including amazing marketing opportunities for supplement manufacturers. To say that serotonin is the “feel good” neurochemical, that dopamine is the “reward” neurochemical and norepinephrine is the “fight or flight” neurochemical is only scratching the surface of their functions, and ignores the fact that these three work in concert with one another, as well as with other neurotransmitters to regulate mood and emotions.

And to say that a treatment “works on” a neurotransmitter ignores the fact that there are many different synapses that manufacture slightly different versions of it and process it slightly different ways. A look at the number of different 5-HT receptors for serotonin should give you some idea of how complex this is. Same thing with dopamine receptors, and norepinephrine receptors – which can be activated by adrenergic dopaminergic, histaminergic, and catecholaminergic activity.

The most reliable evidence we have so far is that the problem of neurochemically-induced depression comes not from a lack of these neurotransmitters, but from our brains’ inefficient use of them. All these different synapses come in pairs. One produces the chemical, shoots it into the synaptic gap, where the other gobbles it up. When the receiving synapse is “full,” it closes up shop. Any of the chemical that’s left is reabsorbed and does nothing – it gets recycled into something else or excreted. So creating more of a chemical is going to make no difference in mood. Antidepressants target one or more of particular types of receiving synapses to open them up to more of the specific neurotransmitter so that they accept more of the chemical that is already produced rather than leaving it in the synaptic gap to go to waste.

Because antidepressants have an affinity not only for a particular neurochemical, but also for a limited number of the different types of synapses that process that chemical, they can all have a different effect on a person with MDD. As well, over time, the difference in absorption of the targeted chemical will cause secondary and tertiary differences in how other related neurochemicals are processed. This is one of the reasons why it can take 6-8 weeks before depression is relieved, and several months before side effects resolve and the long-term balance is achieved.


There is never a shortage of people claiming that antidepressants are a Big Pharma Conspiracy, that MDD is a myth or can be cured by diet or supplements or exercise or thinking happy thoughts. The problem is that these claims are based upon false information or a lack of understanding or, sometimes, willful ignorance. James Coyne addresses the problems with the reports that antidepressants are no more effective than placebo here and here.

Antidepressants take a while to work. If you use studies that span only 2-4 weeks, you will get results no better than placebo because the medications show little effect before the 6-8 week mark. Antidepressants work on people whose brains are not properly processing one or more neurotransmitter, so if you test them on people who are not depressed, have situational depression, or are otherwise not suffering from the depression the medication is designed to treat, results will be no better than placebo. If you are using a medication that is not appropriate for the symptoms that are exhibited, the results will be no better than placebo (and in some cases, might result in a worsening of symptoms.)

But if a person with MDD is appropriately evaluated and treated by an experienced professional, the results are so statistically different from placebo that there is no question whatsoever that they work. Which leads me to my last point. . .


I hope I’ve conveyed some of the complexity of the treatment of MDD. The NIMH has a brochure on medications for mental health that provides not only a basic background, but an introductory picture of the wide variety of treatments available, and how they can be used. It’s a consumer guide, and it’s the tip of the iceberg as far as symptoms and treatments go. As I said earlier, depression is complicated by type, by co-existing (co-morbid) conditions, and by the variety of neurochemicals and synapses that are involved.

A primary care physician might luck out and give you something that’s “safe and effective” and you’re good to go. A clinic psychiatrist will have a better working knowledge, but might be limited in what he/she is allowed to prescribe, or might treat too limited a type of clientele to have a wider experience that would help in diagnosing more complex cases or overcoming negative side effects or unresponsiveness to their most commonly prescribed medications. If the option is available to you, the best place to start is with a board certified private psychiatrist – and if you have a known co-morbid condition like ADHD or autism, or already know that you are bipolar, you can look for a doctor with specialization in those, as well. He/she will also be much more aware of food and drug interactions and make you aware of them up front – and assuage your fears about those horrible black box warnings.

Regardless, you need to advocate for yourself. You need to know that if a medication hasn’t produced significant improvement after 8 weeks, you need to explain coherently to the doctor what effect it is having on you and why you feel it isn’t working – not only to state your case that you want to try something different, but also so that the doctor can use your reaction to help determine which medication might work better. (If it helps, keep a log from day to day of changes you notice.) You need to realize that just because Lexapro didn’t work doesn’t mean that Celexa won’t either – that just because Effexor wasn’t right doesn’t mean you shouldn’t try Cymbalta – and even though Aplenzin is supposed to be newer and better, maybe you’d improve more on Wellbutrin. Sometimes, even, you’ll find that a particular generic brand works better for you than another (or even a name brand) even though the active ingredients appear to be identical.

You will need to compromise on side effects (some are worth dealing with simply because the medication works so well) and accept that the medication alone is not going to solve everything or make you happy all the time. But that list of symptoms above, along with the feelings behind them that I tacked on, will go away or diminish to the point that they’re manageable and proportional to reality. If the medication doesn’t do that, it’s not because medication doesn’t work; it’s because you need a different medication. There are a lot out there that you never even heard of, so don’t settle.

I hope that you’ve found this interesting and helpful. Leave me questions in the comments if you have them.