Information About Antidepressants

How antidepressants were developed

The 1950s saw the advent of the first antidepressants, revolutionary because there were few treatments available at the time.  Interestingly, it was the accidental discoveries in unrelated fields of medicine that brought this about. Infectious disease researchers developing a new drug for tuberculosis, isoniazid, (still used today) realized that a slightly altered version of the drug, known as iproniazid, produced unexpected positive behavioral effects in patients.  Hospital patients tested on this drug reported their spirits lifted, were ‘dancing in the hall’ and showed a reversal of depressive symptoms.  In the same time period, surgeons developing new sedating agents discovered 2 important psychiatric medications:  One was chlorpromazine, a drug that was the first antipsychotic, and with a chemical modification to it, the drug imipramine, which would become an important antidepressant.   What iproniazid and imipramine had in common was that they both enhanced levels of monoamines, a class of chemicals that comprise some neurotransmitters, messengers used by brain cells to communicate with each other.  That realization gave birth to the “monoamine hypothesis”,,  the theory that increasing levels of monoamine neurotransmitters leads to relief of depression.
Fast forward 60 years and most antidepressants have been engineered based on the monoamine hypothesis.    Older antidepressants, like the tricyclic antidepressants and the monoamine oxidase inhibitors, increase a multiple number of these neurotransmitters, like dopamine, norepinephrine, and serotonin.  The newer generation of antidepressants arriving in the 1980’s, harkened a new era,  when the  benign side effects of these new drugs shifted the treatment of mood disorders. from the severely afflicted to millions more patients worldwide with milder symptoms.

Uses For Antidepressants

Given their broad utility, antidepressants are the first line treatments for multiple conditions, especially depression of different kinds and recurrent anxiety. Most patients (up to 95%) with depression have significant anxiety as well, so antidepressants are the best ongoing treatment for both issues. Another significant condition for which antidepressants are useful is obsessive condition.The other medications generally used to treat anxiety are the benzodiazepines, such as Xanax and Klonopin, generally recommended for short-term use of symptoms, days and weeks at a time, not for long term use over months and years, partially due to their habit forming nature. The other reason they are not used long term is probably a deeper one having to do with our understanding of depression and anxiety in general. Benzodiazepines relieve the actual sensation of anxiety, the rapid heart rate, the uncomfortable, nagging worries, the shortness of breath, the dread, while not changing the perception of the threat. Antidepressants change the perception of things being out of control, the irrational thoughts that shape how one experiences a negative experience. This is only the case with anxiety, but with depression in general, since depression is shaped by a self-confirmatory collection of negative thoughts that reinforce each other. How antidepressants do this is only beginning to be understood.
Although depression and anxiety are usually intertwined, isolated situations exist in which the patient suffers from anxiety specifically and not much depression. In such situations, a medication called Buspar may occasionally be used as a chronic medication. I will discuss Buspar later, but more as an augmentation strategy to improve a standing antidepressants. The other major condition for which antidepressants are used is obsessive compulsive disorder, or OCD. OCD manifests as obsessions and/or compulsions. Obsessions are intrusive thoughts, images, or impulses that are experienced as unreasonable and foreign by the patient and difficult to control. Compulsions are actions, rituals, behaviors, or thoughts that the patient performs consciously to relieve the tension caused by these obsessions. Compulsions can also occur on their own without a specific obsession. Although OCD is not as common as depression and anxiety, there are often elements of obsessiveness and compulsiveness in those conditions, taking the form of rumination, and dwelling on negative thoughts that constrict behavior, such as jumping to the worst-case scenario.
There is one notable exception to the rule that antidepressants are used for different types of depression. In the case of depression in the setting of a patient with bipolar disorder, antidepressants are often not the first line treatment, and if used will need to be combined with a mood stabilizer or a medication with mood-stabilizing properties, such as an antipsychotic. This is because traditional antidepressants used on their own can trigger symptoms of mania in a bipolar patient. From here on out in this article, the use of antidepressants will be discussed for the condition of unipolar depression and depression mixed with anxiety onl (not for depression in bipolar disorder or for obsessive compulsive disorder).

Other antidepressants: Tricyclic antidepressants and Monoamine Oxidase Inhibitors

When SSRIs, Wellbutrin, Buspar, SNRIs, and Remeron are not options, then it is time to consider other medications. Although accompanied by greater side effects and specific risks, older antidepressants like the tricyclic antidepressants and the monoamine oxidase inhibitors are still around for a reason. They can be effective sometimes when other medications are not.
Like the SNRI’s, the tricyclic antidepressants enhance brain levels of serotonin and epinephrine and have similar side effects. However, they also have additional side effects, including cardiac side effects that are potentially serious and side effects related to blocking the effect of certain acetylcholine and histamine receptors. “Anti-cholinergic” side effects are ones involving increased heart rate, dry mouth, mild haziness in concentration, constipation, urinary retention. Antihistamine side effects include drowsiness and haziness. They also can anti-adrenergic (blocking receptors that bind to adrenaline) receptors, causing orthostatic hypotension, which is the drop in blood pressure that occurs when someone stands up. This is increase the risk of falling in patients who have a pre-existing risk, such as the elderly.
Monoamine oxidase inhibitors (MAOIs) enhance levels of serotonin, norepinephrine, and dopamine, not through reuptake inhibition, but by inhibiting the enzymes that naturally break-down these chemicals in the brain. These enzymes are known as monoamine oxidases, and are thought to be the antidepressant of choice with a specific type of depressive profile, atypical depression. These patients often experience hypersomnolence rather than the insomnia of typical depression, increased appetite rather than decreased, something known as “leaden paralysis”, characterized by a heavy feeling in the limbs, and hypersensitivity to perceived rejection from others. The MAOIs have gotten out of favor for the most part because of dietary restrictions that are required to be followed while on them. Hard cheeses, meats, soy products, any rotting food (or refrigerated too long), draft beer need to be avoided as they contain tyramine, a substance that accumulates in these foods. Tyramine acts as a “pressor” or chemical that increases blood pressure. In a patient not on MAOIs, the body breaks down tyramine continuously via the monoamine oxidase produced in the body. With the enzyme inhibited, though, tyramine builds up, causing the blood pressure to rise to potentially catastrophic levels . There are medications to quickly alleviate the elevation in blood pressure, which often is heralded by a severe headache, so some patients carry emergency medications and know to head to their nearest emergency room if warranted. Side effects of the MAOIs include rapid heart rate, dizziness, nausea, insomnia or oversedation (depending on the specific MAOI). There has been in the past few years a resurgence in use of the MAOIs as they have been found to be selected patients and past dietary restrictions have been seen to be overly restrictions (e.g. restrictions on eating bananas or raspberries)

Time to effect of antidepressants

Antidepressants provide at least some relief to 2/3 of patients who try them. In half of these patients, there is relief of most symptoms, while in the other half there is only some limited relief. It is still a mystery as to who responds and who does not. Generally, antidepressants require at least 4-6 weeks to have a significant effect, and the full effect can take up to 8 weeks. The explanation for this is that the antidepressant effect is a secondary effect of the changes in the levels of chemicals such as serotonin in the brain, the same effects that explain why the monoamine hypothesis does not explain the whole story for why antidepressants work. These “downstream” changes involve structural changes, like rebuilding neuronal networks in the hippocampus, increasing connections between brain cells, and enhancements in neurotrophic (growth enhancing) factors that promote normalization of functioning in neurons. The hippocampus is a part of the brain responsible for registering new memories; this helps explain why in severe depression, there is a often impairment of cognition, including with short term memory.

The Serotonin Reuptake Inhibitors

The largest class of antidepressants, the serotonin reuptake inhibitors, or SSRIs, is also the main medication used for treating depression and anxiety. Prior to the 1980’s the only antidepressants that existed, like the tricyclic antidepressants and the MAOIs, had many side effects and were easily lethal in overdose and could worsen cardiac arrhythmias. In comparison, the SSRIs have relatively benign side effects. Although the biological underpinnings of depression have not been clarified, low serotonin levels do appear to be tied to some troubling aspects of depression, such as impulsivity, suicidality, self-harm, and to impaired ability to socialize. The term serotonin reuptake inhibitor refers to the fact that nerve endings naturally secrete serotonin and uptake and “reuptake” them in their recycling of the chemical. By inhibiting their reuptake, SSRIs increase the level of serotonin in the brain.

In general, the SSRIs are all thought to be about equally effective, so the initial choosing of an antidepressant often involves thinking about their side effects and what antidepressants the patient has responded to in the past.

The side effects of the SSRIs can be divided into the ones that occur at the start of treatment and the ones that show up a few months later. Initial side effects, usually lasting for a few weeks, include mild tiredness, jitteriness, more frequent awakenings at night, loss of appetite, sleepiness during the day, “brain fog”, “haziness”, or diminished alertness, a type of uncomfortable restlessness called akathisia, sweating, and transient headaches. The biggest factors that seem to determine how difficult the initial period is are individual sensitivity and the how high and quickly the medication is titrated when starting the medication. “Starting low and going slow” during the first few weeks is probably the best way to minimize side effects. The initial side effects, although short-lived, can sometimes be uncomfortable and occasionally unbearable, leading to discontinuation. Rarely, they can lead to such discomfort that new thoughts of suicide can occur; this occurs more often in patients under age 25.
The side effects that come with chronic treatment, after 2-3 months, include emotional flatness, sexual side effects and weight gain. Emotional flatness, which patients describe as a limiting of the highs and lows of life, is an unfortunate side effect of lessening emotional pain. Sexual side effects present as a greater difficulty in achieving orgasm and over time as a loss of libido and interest in feeling sexual altogether. Weight gain, which some meta-analyses have estimated to be about 2 lb’s on average, occurs for unknown reasons but may be related to desensitization of certain serotonin receptors that influence appetite. In my personal experience, I have had some patients reporting 10-15 lb weight gain, but for most patients it seemed to be 5 lb’s or less.

Augmentation with other medications: second generation antipsychotics, lithium, thyroid hormone, stimulants

Augmenting with medications that may be antidepressants or antianxiety medications, but possibly not. This ability to add to the effectiveness of an antidepressant is augmentation.
Wellbutrin and Buspar were mentioned earlier. In addition to possibly relieving chronic side effects, they can sometimes improve the chances of a mildly effective SSRI being more effective (each is also used as a sole medication for some patients).
Serotonin enhancing antidepressants: SNRIs, Remeron, TCAs, even MAOIs, be mixed and matched. The main side effects to be monitored when doing this are i) liver enzyme interactions: some of these medications are metabolized (broken down) by liver enzymes that are inhibited by newer antidepressants, causing the blood levels of older ones like the TCAs to possibly rise to dangerous levels ii)
Second generation antipsychotic medications, or SGAs. These medications are named for their use in treating psychotic disorders; however they have found usefulness for treating anxiety and depression as well. Like the SSRI’s, they are offshoots of older medications first used in the 1950’s, in this case the first generation antipsychotics, drugs such as haloperidol and fluphenazine. Like the first antidepressants, the FGAs were discovered serendipitously in the course of testing drugs used for other indications. The understanding of their chemical activity would drive the “dopamine blockage hypothesis” of treating psychosis. In short, delusions and hallucinations, which form the elements of psychosis, originate from aberrant signals traveling along specific neural pathways that use dopamine as a neurotransmitter. By blocking the dopamine receptors there, antipsychotics are able to inhibit psychotic thought processes. However, just as TCA’s and MAOIs had heavy side effects limiting their use, so did the first generation antipsychotics: most prominent of these were severe movement disorders and impaired cognition. Over the past 3 decades, however, a new generation of antipsychotics have been developed with reduced motor effects, leading to a greater acceptance of their use, similar to what happened with the SSRIs. The SGA, or second generation antipsychotics, have fewer movement and cognitive side effects but also enhancement in mood. These new drugs modulate not only dopamine signals in the brain but also serotonin signals. As a result, they found a use for a new population of patients who did not necessarily have psychotic symptoms. In conjunction with antidepressants, they were found to increase their efficacy of the antidepressant for an unresponsive patient. One reason they are thought to be particularly effective is that they modulate 2 particular serotonin receptors in a unique way. They increase the signal strength through the 5HT-1a receptor mentioned earlier, thought to be responsible for largely responsible for the antidepressant and antianxiety effects of serotonin-enhancing medications. They also inhibit signals through the 5HT-2a receptor, thought to be a receptor that counteracts the effects of 5HT-1a. This one-two punch is thought to allow SGAs to work quickly, sometimes within 1-2 weeks, to relieve depression and anxiety. As one can imagine, this makes SGAs particularly useful in urgent cases of depression. Often, SGAs and benzodiazepines are used in the initially stages of severe anxiety and depression. Dose titrations are simple with SGAs since they are used at lower doses than are used when treating as a psychotic disorder like schizophrenia. However, caution needs to be heeded. Although they have fewer motor effects, they are not the FGA’s because they increase the risk of a “metabolic syndrome”: hyperlipidemia (high triglycerides and LDL cholesterol) diabetes, and high blood pressure.
Lithium: There is a solid body of evidence supporting lithium as an effective and generally well tolerated augmentation medication. Of all the adjunctive medications, lithium is the most extensively studied and may also reduce the long-term risk of suicide. The manner in which lithium augmentation is effective is unclear but has been hypothesized to be due to sensitisation of serotonin receptors. Other neurotransmitter systems such as noradrenergic transmission and other messenger systems have also been theorized. Lithium plasma concentrations are drawn to achieve therapeutic levels (0.4 to 1 mmol/L). Side effects include nausea, diarrhoea, abdominal pain, muscle weakness and fine tremor. The interval before full response to adjunctive lithium is said to be in the range of several days to 6 weeks. The main concern over chronic treatment with lithium is that thyroid and kidney function be monitored at least yearly. In a small percentage of patients, usually bipolar patients, who require higher doses of lithium, there will be a decline in functioning of these 2 body systems. While this often does not cause a pragmatic issue with the majority of patients, even the ones who show a decline, the biggest concern is with a small number of patients who eventually go on to develop renal failure and require dialysis. It is unclear who will have that complication, but it often is associated with patients who have been exposed to high levels, e.g. In older patients who do not drink enough fluids and become dehydrated.
Thyroid hormone:Thyroid hormone supplementation, even in patients with normal thyroid function, may increase the effectiveness of antidepressant medication treatment, whether used as an augmentation agent (445, 446) or in combination with an antidepressant from the outset of therapy (447). The dose typically used for this purpose is 25 mcg/day of triiodothyronine, in- creased to 50 mcg/day if the response is inadequate after about a week. The duration of treatment required has not been well studied. The risk in patients without a pre-existing cardiac condition is fairly low.
Stimulants: Many clinicians find that augmentation of antidepressants with low doses of stimulants such as methylphenidate or dextroamphetamine may help improve otherwise suboptimally responsive depression, although not all clinical trials have shown benefits from this strategy. What stimulants can do is restore functionality to patients, allowing them to mobilize and complete tasks that would otherwise hang over them and cause them further stress if left undone. They may also lead to patients becoming involved in social or therapeutic activities that can improve mood. Stimulants can worsen or exacerbate cardiac problems and can be addictive in certain patients, so a history of addictive disorders and a cardiac history should be ruled out..

A brief roadmap of getting onto an antidepressant

A roadmap: The time frames indicated are approximate and not set in stone.

If the initial 3 weeks of a patient’s being on an antidepressant are tolerable, meaning that side effects are mild and the dose is able to reach at least half of the recommended middle-of-the-road dose, then I allow the patient to stay at a comfortable dose for the 4-6 weeks it takes to see a response. If the patient is extremely sensitive at 3 weeks, then I may keep them at a lower dose or switch to another medication. At 6 weeks at the highest dose with tolerable side effects or optimum response, it is time to assess whether they need to have their medication switched or to modify their treatment in another way. If there is remission (meaning diminution of most his/her symptoms) then I keep patients on the medications at least 6 months, barring significant side effects. If there is little improvement, I would adding another medication to optimize the effect or switch to another antidepressant.

Making the decision to take an antidepressant

When patients seek treatment for emotional or mental problems, it often comes after a long delay, after patients have had repeated episodes of feeling distraught and out of control. It can be years. Unlike the denial associated with having physical symptoms, associated with the fear of finding out that there is something serious going on, the denial with mental conditions triggers a deeper denial about there being anything wrong with oneself. We accept our reactions to the world to be rational, attributing cause of symptoms to external factors. As an example, if our heart races and we feel fear after hearing something critical from another person, our immediate instinct is that they are threatening to us and not on our side. Sometimes a person can live that way for years, feeling misunderstood and menaced by others. If insight later comes, it is a chance for the perpetual chain of misunderstanding to be broken. It often takes the form of a vague sense of recognition after the fact that our reactions were inappropriate or excessive and that the anxiety was self-generated, albeit triggered by hearing something.

If that patients goes to talk therapy, there may be relief; having another person witness and hear the details of our suffering allows that person to provide both support and objective reflection. Through support patients previously suffering alone in shame finds someone who validates them. Through the therapist’s reflection, patients see dysfunctional parts of themselves as foreign to the image of who they are. Change then naturally follows. Resistance to talk therapy takes different forms. There may be shame from the thought that a person must be worthless or unloveable to have to pay another person to listen to him/her. Resistance to talk therapy can also stem from the feeling of humiliation, from the belief that opening oneself up to be questioned is like an interrogation, leading to brainwashing to occur in their service of another person’s motives.

When talk therapy is not enough, when patients have gone over the same themes and subjects over and over again, patients may be advised to consider psychiatric medication. Here there is resistance again. There may be shame because the patient feels she/he can longer be helped by others, that one is so damaged that chemical alteration of who we are is necessary. There is the fear of alteration of our thoughts, fear of changing our thoughts not to a therapist’s choosing, but to a pill that can take away our feelings or sense of ourselves, leading to the fear of loss of control. We all depend on our internal self-image and our feelings as an internal compass to make decisions and take care of ourselves.

There is another sort of patient who is reluctant to try psychiatric medications, not fearing the unknown, but because they think they know what the drugs do and that it is not a good thing. They associate antidepressants with opiates and seem them as pain-relieving medications with the same numbing effects towards emotions as opiates have towards physical pain. Thus like opiates can cover up true pathology if taken irresponsibly, they see antidepressants as covering up the perception of reality. They also see antidepressants can causing dependency and drug-seeking behavior as opiates. This returns us to a previous paragraph in which I discussed how benzodiazepines treat the sensations of anxiety, while antidepressants treat the symptoms by treating the disordered thinking behind anxiety and depression. Patients think antidepressants act like benzodiazepines.

What they do not appreciate is that antidepressants, when working correctly is supposed to relieve emotional pain in more than an immediate sense. Yes, in the immediate sense, they can take away tearfulness, the pain of loss, loss of pleasure, poor sleep and appetite. Plus, they also address thoughts like helplessness and hopelessness that define a dismal world view that gives us feelings of depression. This second fact is what is unexpected and maybe counterintuitive.

Depression and other mental illnesses leave a destructive path

The statistics speak for themselves. The monoamine hypothesis was a groundbreaking discovery, allowing countless millions to change the course of their lives for the better. Six decades later after the first antidepressant, though, depression continues to be a prevalent and severe problem, being the number 2 cause of disability worldwide.

How can a pill change our world view?

Let’s take an example. A patient experiencing a romantic break-up a year ago sees their sadness about being rejected as being due to a break-up. Their idea of what a medication will do is dull the pain of a break-up. However, they do not see that the problem is larger than that, that they their world view has been skewed, that their view of the world has been altered whereby they do not think things can give them joy again, and that they will not recover from this pain in the foreseeable future because there is not someone out there who can replaced their previous loved one.

Antidepressants not only relieve the crushing pain, but also take away how salience of the negative emotions in shaping how a person sees everything, this without taking away awareness and alertness about reality. Opiates cannot do that for physical pain.

Depression and other mental illnesses leave a destructive path
The statistics speak for themselves. The monoamine hypothesis was a groundbreaking discovery, allowing countless millions to change the course of their lives for the better. Six decades later after the first antidepressant, though, depression continues to be a prevalent and severe problem, being the number 2 cause of disability worldwide.

Other antidepressant options when SSRIs do not work: SNRIs

What if augmenting with Wellbutrin or Buspar does not help the side effects enough, or if the SSRI has no positive effect to begin with, or if the idea of an SSRIs is not appealing because of the possible side effects? Other choices for treating depression are: 1) trying another SSRI, perhaps a more modern one like Viibryd or Brintellix, which has not had as much real-world use as the more established SSRi’s, but appear to have fewer sexual side effects and risk of weight gain 2) starting out with Wellbutrin first or switching to it, as it is an antidepressant in its own right, without the side effects SSRIs have, 3) switching to a medication known as an SNRI, a serotonin-norepinephrine reuptake inhibitor, a medication similar to an SSRI but which enhances levels of norepinephrine in addition to serotonin, or an SNRI-like medication named Remeron 4) switching to older classes of antidepressants that carry more risk and/or side effects but which may be more effective. These include the tricyclic antidepressants and the monoamine oxidase inhibitors, or MAOIs, and 5) augmenting an existing antidepressant with other medications that are not antidepressants or anxiolytic medications on their own and which carry additional risk factors to considers. Explained in greater depth are the options:

For a first time (or similar) patient who has not responded to an SSRI, I might try another SSRI as different SSRIs do have slightly different side effects. For example,for a patient with great difficulty getting enough sleep, I might choose paroxetine, while for another patient with concerns about excessive weight gain, I might choose fluoxetine, which tends to have a lower risk for weight gain. With the advent of new SSRIs with fewer sexual and weight gain side effects, there are more choices now. These newer SSRIs include vortioxetine and vilazodone. If the second SSRI does not yield good results, I might try one more SSRI, but usually not a fourth. One thing to keep in mind: I have had patients come to me who say they have tried many SSRIs and failed to respond. It is important to assess how long the patient tried each SSRI and how of a dose they reached before abandoning the medication. The number reason an antidepressant do not work is that patients have not been titrated to a high enough dose.
Wellbutrin may be a good choice, but can be difficult to use with an anxious patient who has depression. Because Wellbutrin increases levels of norepinephrine and dopamine, chemicals that stimulate the sympathetic nervous system, the patient may initially feel more anxious, tense, have worsened insomnia due to increases in muscle tension, blood pressure, and heart rate. Over time, these side effects tend to recede into the background, but in the beginning can worsen symptoms. The other issue is that with obsessive rumination, which often accompanies depression serotonin enhancing medications may be more effective. Obsessiveness in general and obsessive compulsive disorder also follow this trend. However, Wellbutrin may be the optimum choice for the patient who is absolutely against taking any medication that will have sexual or weight gain side effects.
SNRIs are similar to SSRIs but block the reuptake of norepinephrine in addition to serotonin. They have similar side effects to the SSRIs but have additional ones associated with norepinephrine, such as dizziness, dry mouth, constipation, increased heart rate, and increased blood pressure. Norepinephrine provides increased energy so can offset the tiredness associated with serotonin-enhancing agents. Examples include Effexor and Cymbalta. There is some evidence to show that patients on SNRI’s can show a faster response time compared to patients on SSRIs and some psychiatrists think maybe even a greater response. There is an intuitive appeal to this belief as the SNRIs increase levels of 2 chemicals in the brain versus the 1 chemical by the SSRIs. They are contraindicated in patients with uncontrolled hypertension, closed-angle glaucoma and urinary retention. Another medication that acts like an SNRI, but is technically not in this class is Remeron. Remeron also increases levels of serotonin and norepinephrine but does so not by blocking the reuptake of these neurotransmitters but by blocking the signal that tells the body there is enough of these 2 chemicals. What makes Remeron even more special, though, is the fact that it can block specific serotonin receptors that are responsible for certain side effects from serotonin. On brain cells, there are different distinct serotonin receptors that serotonin attaches to. They are known in scientific parlance by a label, 5-HTx, where 5-HT is an abbreviation for the chemical name of serotonin (5-hydroxytryptamine) and “x” is the number, sometimes with a letter, that follows it. Each of these receptors has different, multiple effects in the body, many of which may not be related to serotonin’s antidepressant effect. There is one specific receptor that has been identified being responsible for serotonin’s antidepressant effect, the 5-HT1a receptor. The 5-HT3 receptor is thought to cause nausea and gastric distress, while the 5-HT2 receptor has been the focus of the cause of sexual side effects and insomnia. By blocking these receptors, Remeron is able to achieve antidepressant effect while not causing the sexual side effects, nausea, and insomnia found upon initiating other SSRIs. However, it can cause undesirable opposite side effects, since as increased hunger and increased sleepiness. For this reason, it is often not acceptable to patients.

Hello world!

Welcome! This is the premiere of my website, designed for my patients, colleagues and others interested. My hope is that over time, the information will be a source of knowledge I’ve gained working with my generous patients, and may spark further discussion about future directions in mental health treatment.