Best Medications for Depression, Part Deux (That Means Two in French)

In our previous post, we (meaning me, myself, and I) looked at antidepressants for two seconds and then looked at: 

• how bipolar can look like "regular" unipolar depression 
• how antidepressants can make bipolar depression worse 
• how antidepressants can induce rapid cycling in people with bipolar 
• how antidepressants can triple the number of days per year that someone with bipolar ends up being depressed 
• how it can be challenging to recognize bipolar 
• how people who have had manic episodes may not even know it
• how people who have had manic or hypomanic episodes may know it but be reluctant to admit it
• how some people may mistakenly think they are bipolar and tell you they are "manic" when it is not so
• how sometimes those people who seem to be mistakenly claim to be bipolar might actually be partially bipolar or on the "bipolar spectrum" after all 
• how this is all a pretty big issue since between a third and half of the people seeking help for "depression" actually have bipolar disorder 
• how most people with bipolar who seek treatment when depressed go unrecognized as bipolar 
• how the median person with bipolar sees several doctors or other practitioners many times and up to eight to ten years of mental health treatment on average before being correctly identified as bipolar 
• how most practitioners misdiagnose most of the people who actually have bipolar disorder with just depression 
• how new practitioners starting out may be very confident in their ability to do so even though many other doctors who have gone before them have a very poor track record overall of accurately recognizing bipolar disorder
• zero text in bullet points, whatsoever 
• and took a lot more words than here to explain it all than used here in this post. 

Today, we will get around to talking about What Are The Best Medications For Depression, as the title promises (and as the title of the last blog post seemed to promise as well.) 

And the answer is ...

... It depends. 

Dang it! 

Can't things just be simple? 

Well, we already looked at how simply giving antidepressants to someone with "depression" can be a huge minefield and actually make them much sicker, depending on factors that are pretty hard to figure out and that most of the pros fail to figure out in a timely way most of the time. 

First, you need to decide if your "medication" will be a pill, or a therapy, or something else. The standard antidepressants that most doctors will prescribe first and that most authorities recommend to try first, are the SSRIs. These are the largest class of newer antidepressants that includes Prozac, Zoloft, Lexapro, and several others. (For the uninitiated, SSRI stands for selective serotonin reuptake inhibiter, which is a name so long that not even doctors and scientific types like saying it, thus the much catchier "SSRI." Serotonin is one of the main neurotransmitters that our brain uses in its work of regulating our mood.) (For the initiated, my apologies for the parentheses and for the unnecessary explanations.) (For everybody, my apologies for so many parentheses.) 

As good modern Westerners, we are often quick to run to a pill to fix our problems. Ah, Westerners. (The rest of the world shakes its head sadly.) 

But there are several ways that are shown by research to improve mood just as much as antidepressant medications do. (Wait for the angry mob of conspiring pharma companies come and try to burn down my blog for preaching the truth.) 

What? As good as meds? Well ... yes, for depression. But not as good for making money. Meds are much better for that. Not money for you or me of course, we are talking about money for the big pharmaceutical companies who probably don't care if you live or die as long as they can make a buck off of you. (Just look at insulin, which has been around "forever" and whose discoverers literally sold the patent to it for ONE DOLLAR so that it would be forever affordable to all humans. It's pretty dirt cheap to produce, and yet they sell it for a few hundred dollars a bottle, while the average person with diabetes needs multiple bottles per month, and will get sick and die considerably sooner if they don't pony up the cash ((my apologies to non-native English readers: that means, "find enough money")) to pay for it. Sounds pretty much like the mafia: You will pay us whatever we ask, or you will die. Simply because we can get away with it.)

So here are the non-pharmacological "medications" that work as well as SSRIs: 

None!

Just kidding. There are some. Drum roll please.  

Exercise! 

Getting sunshine! 

Skipping a night of sleep! (This one sounds like a bad joke, but believe me or not, right now I am not badly joking. At least not in this paragraph.) 

Exercise is a great one that if you are able to have the discipline to do it, it lifts your mood pretty effectively, and most of the "side effects" are positive. (A psychiatrist friend of mine once told me when I mentioned this concept to him, "I can't even motivate myself to exercise. How am I ever going to motivate my patients to do it?")

Getting sunshine refers to light therapy. Most practitioners, if they recommend it at all, usually suggest using a special light that you purchase and sit in front of for certain lengths of time. A special light works, but many times you can just go outside more and get the light that way without blowing $100 on a lamp and then spending a bunch of time sitting right in front of it with it only a foot away from your face. 

Skipping a night's sleep is honestly pretty counterintuitive to my simple (OK, I'm feigning humility there) mind. If I skipped a night of sleep I am pretty sure that I would be pretty darn irritable. I'm not sure though because I've always crashed out before I get that far. But researchers have shown repeatedly that getting people to stay up all night and through the next day and not sleeping again until bedtime the following night actually boosts mood pretty much immediately and has an effect that can last for weeks. Of course, how are you going to charge for that though. Or, as a practitioner you might get stuck staying up with them all night to fully do the procedure, so not very time-efficient for the doctor. So, it is not brought up much as an option for patients. It works though so you should know about it and recommend it to appropriate persons. 

I think it is worthwhile to bring these options up to your patients. Some patients will like them, many may not, but plenty of patients will appreciate you being willing to think outside of the (pill) box. 

There are some more alternative treatments for depression as well but I will cover them elsewhere. 

Now on to the meds themselves ... 

Best Medications for Depression. Or, a Tangent on Antidepressants and Bipolar Disorder

What meds are best for depression. Antidepressants, right?

Well, maybe. But only if the depression is pretty severe. Mild and moderate depression does not really separate from placebo vs. standard antidepressants. 

Also, what if the person actually has bipolar depression, rather than "regular" unipolar depression. If you give that person antidepressants, you will likely make their depression worse, not better. Wait - it gets worse! You might actually make their depression better ... for awhile. They might seem to respond and get better. So much better. In fact, they might get better than good. They might go into a hypomanic or manic phase and cause damage to their life, livelihood, and relationships. 

Or they might get somewhat better, and be really grateful for the antidepressant. But after awhile, they may shift into a bipolar mixed episode. That is, they might develop a mixture of both depressed and manic features at the same time. This feels pretty horrible to live through, which is reflected in the substantially elevated suicide risk that mixed episodes pose. 

Or maybe you give the depressed person an antidepressant and they feel better. They feel better for several months even. But after awhile, they start to cycle. What's that? Their mood starts going up and down, alternating between depressed and non-depressed more frequently. Sometimes it seems like the antidepressant helps, and sometimes it seems like it doesn't. You should probably increase the antidepressant then, right?

Actually, the correct (more helpful) treatment is to stop the antidepressant in this case. But not stop suddenly. Stopping suddenly can make the person get much more depressed very quickly. You should taper the medication down slowly over a couple of months to let their body gradually readjust to the change in medication levels. 

When a person with underlying bipolar disorder takes an antidepressant, and begins mood cycling, it's not just that their mood starts to go up and down. It may start to do so more quickly, more frequently, and more severely. It may be transformed from "normal" bipolar condition into "rapid-cycling" bipolar. This is a worsening of the person's overall condition and can be lasting or permanent. 

If the person goes into rapid cycling, which is actually a pretty common thing which happens when people with bipolar condition take antidepressants, they end up being depressed for more total time. In fact, some studies suggest that rapid cyclers end up being depressed a full three times as many days of the year as do non-rapid cyclers! Talk about iatrogenic conditions! (For our readers used to normal English rather than technical medical terms, iatrogenic means a condition caused by medical treatment.)

So, it's kind of a big deal to make sure that the person does not have bipolar disorder. But that's pretty easy, right? And bipolar disorder is super uncommon, right? 

Well, not really, and no, not really. 

In an ideal world, you could just ask a person, have you ever been awake for four straight days or more, when you weren't on drugs? Yes? Bipolar. No? Not bipolar. 

Ever since Seth tricked Osiris into laying down in that coffin and thus unleashed chaos into this world, it has been more complicated than that to diagnose bipolar. 

Bipolar One is one form of bipolar. It is the "classic" form of bipolar - bipolar in its clearest manifestation. Surely anyone who has had a manic episode in the past would know so and be immediately straightforward about it, right? Well, actually, the person might legitimately NOT remember ever having a manic episode. 

That is from state-dependent amnesia, much like in Charlie Chaplin's classic 1931 movie City Lights. If you are under 95 years old and have not seen the movie, the main character (Charlie) saves the life of a megamillionaire. The megamillionaire is then extremely grateful and lavishes gifts on Charlie whenever he sees him - as long as he (the rich guy) is very drunk. But when the rich guy is sober, he does not remember Charlie whatsoever and just runs him off. The rich guy's memory is state-dependent. 

Many times people with bipolar disorder literally cannot remember what happened during their manic episode. It can be like getting so drunk that your friends have to tell you what you did at the party last night. If you do not have people around you to tell you what you did, you might not have even any way to know what happened. 

Or, if they have "bipolar two," characterized by hypomanic episodes that are less intense than the full manic episodes of bipolar I, they may simply enjoy the high of the elevated mood. One person I interviewed recently reluctantly admitted that she has had manic or hypomanic episodes in the past but she is not interested in treating them, as she enjoys them. Her only concern is the times of depression. Thankfully she had enough trust in me (just barely) to admit this - many others choose to withhold this information. 

Another problem with diagnosing bipolar when a patient comes to you reporting depression is false positives. Sometimes (pretty frequently actually) you will meet people who will immediately tell you that they are "bpolar." "Oh yes, I have bipolar moments all the time. Just yesterday I had three manic episodes." This, of course, is a highly different definition of "manic episode" than is used in the DSM-5. "True" manic episodes need to last at least four days straight, among other diagnostic criteria. What these patients refer to is "mood lability," or mood that changes rapidly or is otherwise unstable on a moment-to-moment or hour-to-hour basis. Or they may have a good mood for a few days when something good happens and get somewhat slap-happy (a highly technical medical term.) This false self-identification is especially common with people who come from a particularly low level of formal education or have a low socioeconomic status. 

But! Sometimes people who mistakenly report these very non-bipolar "bipolar" characteristics to you actually DO have bipolar condition. It may be bipolar I, bipolar II, or bipolar NOS (not otherwise specified.) In bipolar NOS, a person may have some characteristics of bipolar, but does not meet full criteria. That is, they do not have enough symptoms to be technically considered to have "bipolar." And yet, as most mental conditions exist on a spectrum, it is not as simple as an on-off switch - they have bipolar, or they do not. Maybe they are somewhat bipolar. Their mood goes up and down. They experience significant irritability. Sometimes their thoughts seem like they are racing and they get distracted very easily. They get excited and become more prone to make risky and poor decisions that get them into trouble. And a lot of times they are just down in the dumps, feeling like life is meaningless and with no desire to do anything, even get out of bed. Maybe they meet criteria during those times for major depressive disorder (MDD). Maybe they don't check off the required symptoms on the checklist to "qualify for MDD, either. What about them?

Unfortunately, the condition that this group of persons has is not clearly defined in the DSM-5. That is not to say that this "condition" is uncommon. It is actually pretty common to find in a psychiatrist's (or other mental health prescriber's) office; it's just not currently dealt with in the DSM. 

So what do we do with people who are not quite bipolar I or II, and not fully MDD? Well, this is a very controversial subject, but the majority of consensus opinions by expert psychiatrists is, the more bipolar characteristics that a person has, the less likely antidepressants are able to help. If only a tiny bit of "bipolarity," antidepressants are more likely to help. But the more bipolarity that a person's mood symptoms suggest, the more you should try to avoid prescribing them antidepressants, and the more likely that antidepressants will end up harming them in the short or long run. 

Note that the same seems to be true for people who do meet full DSM-5 criteria for MDD, but who also have some elements of bipolarity as well. If bipolar traits are significant in this person's MDD, then antidepressants are less likely to help as well. 

So anyway, here you have this person in front of you. They have pretty bad depression right now, and you are reasonably sure for now that they do not have bipolar. However, keep in mind that a good three or four out of ten of those people who show up sitting in front of you reporting depression actually have some sort of bipolar condition. Hopefully you will identify all of them. Or even most of them. The reality is that the vast majority of people with bipolar who show up for treatment depressed do NOT get diagnosed with bipolar. Most people with bipolar actually get evaluated many times by several different doctors or other practitioners over a span of 8-10 YEARS average before they eventually get their correct bipolar diagnosis. So hopefully you do way better than the vast majority of other prescribers out there, most of whom probably have substantially more experience than you do. 

Which is another way of saying, always suspect bipolar when you see someone for "regular" depression. And always be on the alert to see if someone who you are treating for depression has a poor response to their antidepressant(s). 

Read more about this in my next post, where I may get around to actually talking about the "Best Medications for Depression."

Depression Algorithm

Step One: Make sure the person meets DSM-5 criteria for depression. The research has been done on people who meet full criteria. People who partially meet criteria might respond similarly but the chances start to go down. 

Tip: If they are only one symptom away from meeting criteria, use your psychotherapy skills to try to make them feel excessively guilty about something! (If they did not already have excessive guilt.) That tips them over the edge and now they meet full criteria, and are statistically more likely to respond to the medications in the algorithm. 

Start with an antidepressant. SSRIs are popular but bupropion also works and does not cause loss of libido. So look at your patient and decide, is this someone who could use a little bit less libido? Do they seem like they are about to sexually assault someone? If yes, go with the SSRI. Do they seem like someone should really be at risk of reproducing? (Be honest.) If maybe no, go with the SSRI. Also, remember how overpopulated the planet is! Or, do they seem like they deserve a decent sex life? If yes, then prescribe the bupropion. 

If that first medication does not work, then evaluate your initial assessment (see previous paragraph) and prescribe something else. 

Prescribing Algorithms for Psych Meds

Prescribing algorithms aim to give guidance to prescribers as they choose the safest and most effective treatments for their patients. They are not hard-and-fast rules that take decision-making out of the prescription process by any means. However, they do gently push individual prescribers to take into consideration the whole body of published medical knowledge as it pertains to the person being treated. 

Each of us who prescribes medications has our own personal experiences prescribing different medications. I gave this person with bipolar disorder olanzapine during a mixed hypomanic episode and their mood leveled out pretty quickly but then they also put on 65 pounds over the following six months. I gave two people in a row ziprazidone for bipolar mood stabilization and they both stopped taking it within two months but I prescribed one of them alprazolam and they loved me and kept coming back for more for years. 

It is sort of like the old parable of the blind men who are each holding on to a different part of an elephant. One is holding onto the trunk, another on a leg, another on the tail, and another sitting on the elephant's back. Each one has a totally different set of information regarding what an "elephant" is all about. Note that each one is completely correct - they are just not able to take into consideration the knowledge and experience of the others. 

Doctors are humans who are caught in a situation somewhat like that of the blind men in the parable. They see how one person, with a unique set of characteristics - only a tiny fraction of them knowable to the doctor - and how that person seems to respond to a particular medication treating a certain condition at a certain time. Maybe the doctor has a negative experience with a medicine that is actually quite uncommon - it is only human and natural for that doctor to have greater space reserved for that negative information regarding that drug in their mind. It might be the best medicine on the planet but the doctor will be less likely to prescribe it if they have the one case out of five million with an outlying negative outcome.

Scientific studies are designed, in theory, to try to give us as much relevant information as possible. They follow large numbers of patients with certain qualifying characteristics and then record their responses to those treatments using statistics. This medicine helps more people get better, on average, than taking a sugar pill. 

However, it is not realistic to expect every doctor to read through all of the published studies and meta-analyses, especially new doctors or other prescribers coming into the field today. They would have to read all of the OLD studies ever published, as long as all of the NEW studies being published every day. 

But sometimes teams of doctors and their associates get together to pore over all of the available evidence, and then try to synthesize it for the rest of us. Three studies say that A works better than B but two studies say that B works better than A, but they had possible errors in methodology and possibly the results were swayed by certain characteristics of the population being studied. 

The results of these very laborious and labor-intensive labors elaborated by these laboratory laborers...

Are ALGORITHMS. 

In algorithms, a doctor can learn from the experience of a thousand other doctors and the experiences tens of thousands of patients, without ever meeting them. 

Quetiapine was discontinued at a higher rate than the other second-generation antipsychotics when taken as a mood stabilizer. Ziprasidone caused zero weight gain but still led to slightly increased blood sugars when used to treat psychosis. Varenicline actually works better for successful smoking cessation than nicotine replacement therapy (never mind those three people I knew that got nightmares and increased psychosis). 

Dr. David Osser is one person who has been running a project for decades out of Harvard where he and others pore over published studies in order to develop prescribing algorithms for mental health conditions. He and his associates make recommendations about what medications psychiatrists should prescribe first for what conditions.

They try to show, based on published studies, which medications are likely to be the most effective, have the least side effects, and least risk of drug interactions.

They seek to give guidance not only to brand-new psychiatric prescribers, but to seasoned psychiatrists as well. It really is easy for us to make the same mistake over and over, and actually become more convinced over time about how great we are doing. 

I think of it this way: The people that I see in my day-to-day practice are the survivors. Lots of people that I used to see, I don't see any more. The people that I do see, responded well to the treatments I gave them, and kept coming back. The people that did not respond as well to the treatments I gave them, are less likely to come back. So it is easy for me to get the idea that I am doing a more effective job than I actually am. My patients are the ones who have responded well to "Dr Me." 

I personally find invaluable the work of Dr Osser and others who strive to formulate algorithms for best practice. There are many medical and psychiatric bodies which have also set out to promote best practices. Algorithms truly are about best practices - not taking away autonomy or decision-making. Algorithms provide additional information about what has been found to work in the shared body of published knowledge on the subject. 

Unfortunately, a lot of knowledge that doctors and other medical and psychiatric providers have is not included in algorithms. This is because only a tiny fraction of our experience goes into published works. The case studies which get printed sometimes are not even as good as personal experience because we miss a lot of the context and it is hard to tell if the case studies are representative or outliers. 

The other downside is that lots of the studies out there are funded by medication manufacturers who will naturally try to devise studies in a way that reflects their product in the best possible light. So we get algorithms that tend to focus more on newer, more expensive treatments like second-generation antipsychotics, which may have a higher long-term side effect profile than other, older, more benign medications that do not have the same financial backing. 

While we are on the subject, another limitation is that most studies tend to be for the short term, whereas we are treating conditions for the long term. And most studies are done on people taking only one or possibly two medications, and have no comorbid medical or psychiatric conditions. How often do you meet "ideal" patients like that in real life? Not very often. 

So there are some huge, gaping holes in the knowledge base that all these recommendations and algorithms are based on. If venlafaxine beats imipramine for psychotic depression, does that mean that duloxetine would be expected to beat clomipramine for melancholic depression? And even if it did in five patients out of ten, the only one that we care about right now is the patient sitting right in front of us. 

Still, algorithms are an invaluable tool, in part because there IS so much uncertainty in what we do. For the things that we do "know" as a profession, it is our duty to try to put into practice as much as possible, for the greatest likelihood of benefit for our patients.