Prozac and Beyond-The Synthetic Antidepressants

Beginning in the 1950s, scientists developed a number of synthetic drugs for the treatment of depression, which represented a major step forward at the time. Prior to these discoveries, conventional psychiatrists were limited to psychotherapy, able only to listen and talk to their patients, trying to clarify and resolve the underlying psychological factors of depression. While these methods remain vital parts of psychiatric treatment, the invention of new drugs ushered in a promising new era.

There are three principal types of antidepressant medications: the tricyclic drugs, the monoamine oxidase inhibitors (MAOIs), and the selective serotonin re-uptake inhibitors (SSRIs). There are also three drugs that are chemically distinct from these types and each other:

Wellbutrin, Desyrel, and Effexor. Classes differ in their mechanisms of action and side effects. However, they all have several things in common. They are effective in reducing depressive symptoms in 60 to 80 percent of the persons who use them. They also take from a month to six weeks to produce their full effects, although there can be side effects and changes in mood can occur much sooner.

In this chapter, I’ll discuss the different classes of drugs before taking a closer look at the issue of side effects.

The Tricyclics

The tricyclic drugs were the first antidepressant medications. They dominated the market for more than twenty years, and are still used today, though less frequently. They work by desensitizing a receptor in the neuron that absorbs the neurotransmitters norepinephrine and dopamine into the cells. This results in higher levels of these two chemicals in the synapse, and consequent improvements in mood.

The first one in this category was imipramine hydrochloride (Tofranil). More recent additions to this group include amitriptyline hydrochloride (Elavil, Limbitrol, Endep), desipramine hydrochloride (Norpramin), doxepin hydrochloride (Adapin, Sinequan), nortriptyline hydrochloride (Pamelor, Aventyl), and protriptyline hydrochloride (Vivactil).

A serious problem with the tricyclics is their level of side effects, particularly in patients over age sixty-five. They interfere with the body’s control of blood pressure, which can lead to dizziness and even fainting spells. The drowsiness they produce makes it hazardous to drive. Some patients experience arrhythmias, or irregularities in heartbeat, as well. Additional side effects include sedation, dry mouth, blurred vision, confusion, weight gain, flulike symptoms, sweating, rashes, nausea, constipation or diarrhea, difficulty with urination, impotence or impaired erection in men, inhibited orgasm in women, nightmares, and anxiety.

Due to these effects, tricyclics are not usually prescribed, except when cost is a consideration, since they are considerably cheaper than the SSRIs. Because the tricyclics are an older class of drug, their patents have already run out, and the generic brands are more competitively priced. Some doctors will prescribe either doxepin or desipramine to be taken at bedtime in order to counter the insomnia that often occurs with Prozac.

The Monoamine Oxidase Inhibitors

The monoamine oxidase inhibitors, or MAOIs, have a different mechanism of action than the other antidepressants. They work by reducing the quantity of the enzyme MAO within the synapse. The function of the enzyme is to help transport neurotransmitters, particularly norepinephrine, into the neurons. When MAO is inhibited, there is a greater supply of neurotransmitters in the synapse. This usually results in a reduction of depressive symptoms. The MAOIs seem to be particularly effective for atypical depression, in which depression is accompanied by oversleeping, overeating, and anxiety. This class of antidepressant includes phenelzine sulfate (Nardil) and tranylcypromine sulfate (Parnate).

While the MAOIs have fewer side effects than the tricyclic drugs, they can still cause problems in some individuals. Some common side effects include insomnia, impotence and other sexual dysfunction, dizziness, weight gain, and water retention. They can also produce a dangerous elevation in blood pressure, if the patient consumes substances containing the amino acid tyramine. These foods include all cheeses except cottage cheese and cream cheese, all forms of alcohol, pickled or smoked meats or fish, liver, sausage, salami, yeast, and fava beans. Persons taking MAOIs also need to watch their consumption of yogurt, sour cream, tomatoes, spinach, eggplant, avocado, soy sauce, raisins, plums, and bananas. Certain over-the-counter remedies, such as decongestants and antihistamines, must also be avoided. Needless to say, these restrictions put a crimp in most people’s diets, so psychiatrists are less likely to prescribe them.

Because it was originally believed that St. John’s wort worked through MAO inhibition, current sources on the herb still list the MAOI food restrictions. However, it is now quite clear that St. John’s wort does not have this effect, and the warnings are unnecessary.

If the MAOIs and SSRIs are combined, there is the potential for a dangerous reaction known as the “serotonin syndrome”. Therefore, it is essential that there be at least a two-week period when switching from a MAOI to a SSRI, and a five-week period when changing from a SSRI to a MAOI. SSRIs, particularly Prozac, remain in the body for an extended period.

The Selective Serotonin Re-Uptake Inhibitors

Prozac (fluoxetine hydrochloride) was the first selective serotonin re-uptake inhibitor, or SSRI, put on the market. First introduced in 1987, it quickly became the most widely prescribed antidepressant medication ever. In fact, sales of Prozac accounted for $1.2 billion in 1995, and over 6 million Americans use it regularly. Prozac’s success has spawned other SSRIs, including Zoloft (sertraline hydrochloride) and Paxil (paroxetine hydrochloride).

How do these drugs work? In Chapter 3 of the book “The Mind, Body and Mental Health”, we saw how neurons release a neurotransmitter called serotonin into the synapses between cells. The SSRIs desensitize a receptor on the neuron that would normally absorb serotonin into the cell. As a result, there is a greater supply of serotonin in the synapse, which allows the neurons to transmit a stronger serotonin signal. Serotonin is one of the brain’s natural antidepressants, so higher serotonin levels enhance mood and bring about a reduction in depressive symptoms.

The introduction of the SSRIs was considered a major advance in the pharmaceutical treatment of depression. Prior to this time, the only synthetic drugs on the market were the tricyclic drugs and the MAOIs. These options all have a variety of side effects, and persons using the MAO inhibitors also have to follow a restricted diet. That is why the development of the SSRIs was seen as a significant breakthrough.

Developed by Eli Lilly and Company after fifteen years of clinical research, Prozac has been marketed as a highly effective solution for depressive symptoms. It has even been recommended in best-selling books as a way to develop a more “socially rewarding personality.” Yet despite all the media attention, studies show that Prozac is no more effective than St. John’s wort-or other antidepressant drugs, for that matter-in combating depression.

Prozac and the other SSRIs can exact a high price for their benefits. Prozac is considered better than the older drugs because “only” 17 percent of the people who try it have to stop because of negative experiences, compared with nearly a third (31 percent) of the patients taking the tricyclic drugs. The reported side effects of Prozac, listed in percentage of incidence, include nausea (21 percent), headaches (20 percent), anxiety and nervousness (15 percent), insomnia (14 percent), drowsiness (12 percent), diarrhea (12 percent), dry mouth (9 percent), loss of appetite (9 percent), sweating and tremors (8 percent), and rashes (3 percent). In my own practice, and in reports from others, I believe these percentages are far too low, and that the true incidence of side effects is much higher. This discrepancy is likely due to the limited time span in the initial studies (only four to six weeks), and to the relatively small number of subjects.

The SSRIs also reduce sex drive. Studies that looked specifically at sexual dysfunction found that 34 percent of all men and women using Prozac had a drop in libido or difficulty in attaining orgasm. Again, in my experience, the figure is much higher. Many patients do not mention this as a side effect for a number of reasons, including embarrassment and the fact that sex simply isn’t an issue for some people. For others, the loss of sex drive is balanced out by the reduction in depressive symptoms.

Prozac is also more likely than other antidepressants to cause restlessness and agitation. Some people have even experienced violent or destructive outbursts, and the drug’s association with suicide remains controversial.

Zoloft and Paxil are similar to Prozac in terms of their side effects. However, Paxil tends to be more sedating, making it preferable for people with anxiety or insomnia. Zoloft generally falls in between the stimulating Prozac and the sedating Paxil, but individuals will differ in their responses.

The newest SSRI is Serzone (nefazodone hydrochloride), which is especially useful in cases of agitation, anxiety, and insomnia. Side effects were mild in a 2,200 patient sample, according to a manufacturer’s pre-marketing trial. It appears to have the lowest incidence of sexual dysfunction of all the SSRIs, and also appears to be more effective in reducing suicide risk.

The Other Antidepressants

There are antidepressants that don’t fall into any of the established classes: Wellbutrin, Desyrel, and Effexor.


Wellbutrin (bupropion hydrochloride) seems to boost norepinephrine function, with no impact on serotonin levels. Chemically related to amphetamine, it usually has a more energizing effect than the other synthetic drugs. Wellbutrin does not affect the heart or libido as do antidepressants, so it is often used to treat depression in individuals who have problems in these areas. It has also proved useful in the treatment of bipolar depression and a condition known as attention deficit disorder, which is characterized by impulsive behavior and a short attention span.

The main difficulty with this drug is its association with seizures. While this problem appears to be dosage related, Wellbutrin has been found to cause seizures in 1 in every 200 persons who take it. Psychiatrists tend to shy away from it for this reason, although a new timed-release version may eliminate this problem. Other side effects include restlessness, insomnia, irritability, and headache. Wellbutrin must be taken three times per day, another inconvenience, to maintain a relatively stable concentration level in the blood.


Desyrel (trazodone hydrochloride) works on the serotonin system. Rather than being used for its antidepressant effects, it is most often prescribed along with Prozac because the drowsiness Desyrel induces counteracts Prozac’s tendency to produce insomnia. Desyrel’s other side effects include headache, upset stomach, low blood pressure, dizziness, and dry mouth. In men, it can also cause a dangerous condition called priapism-painful, drug-induced erections that may not end upon discontinuing the drug. These side effects explain why Desyrel is seldom prescribed as an antidepressant.


Effexor (venlafaxine hydrochloride) is chemically similar to an antidepressant compound in chocolate known as phenylethylamine (PEA), sometimes associated with the “love effect.” It is likely that PEA raises the level of endorphins in the brain, which creates a sense of well-being. The tradition of giving chocolates on Valentine’s Day reflects our intuitive knowledge of this effect.

Effexor is able to inhibit serotonin re-uptake as effectively as Prozac, yet it also boosts norepinephrine levels much as the tricyclic drugs do. That means it provides the benefits of the tricyclic medications without producing many of their side effects. Effexor also provides benefits for nearly half of the patients who do not respond to other antidepressant drugs, a far higher response rate than for other medications.

However, some 37 percent of the patients who try Effexor report problems with nausea, and one in every five persons experience dizziness, drowsiness, or dry mouth. Sleep disturbances can occur, as well. It can also increase blood pressure, so persons with high blood pressure should avoid the drug. On the good side, it does not seem to intensify the effects of tranquilizers or alcohol. It must be taken two or three times per day due to its short half-life, and dosages should be tapered off over two weeks to avoid withdrawal symptoms of severe rebound anxiety and depression. This can be extremely disabling, and sometimes even dangerous. I have seen suicidal depression result from sudden Effexor withdrawal.

The Problem of Side Effects

Scientific studies and the personal experiences of millions of patients have given us new insight into the frequent side effects produced by synthetic antidepressants. We now know that some of these medications can cause problems in up to a third of all users, forcing some to stop treatment altogether. We have also learned that particular classes of drugs are better tolerated than others. The MAOIs, for example, have fewer side effects than the tricyclics, but still produce multiple actions within the body that are unrelated to depression. These drugs can be particularly troublesome, even life-threatening, when taken in combination with certain foods or chemicals.

The reason for these side effects is related to the nature of synthetic drugs. When we affect one system in the body, we often affect others in both a positive and negative sense. For instance, a class of drugs called beta-blockers, commonly prescribed for high blood pressure, often adversely affect the brain’s chemistry, causing depression. It simply isn’t possible to isolate the brain biochemically from the circulatory system. Medications may have a single intended action, but it is impossible for them to not affect other parts of the body. This often creates unwanted, and sometimes dangerous, side effects (see Talking Back to Prozac by Peter Breggin (ST. Martin’s). I have seen very severe toxic reactions to SSRIs-resulting in permanent damage-in susceptible individuals.

It may seem odd that drugs can produce a side effect in some individuals but not in others. Yet each of us has a unique brain and body biochemistry. For reasons that are still not totally understood, certain people respond better to one medication than another. They may have a more pronounced reduction in their depression, or not have any side effects to speak of. Another person could take the same dosage and have quite different results. Consequently, the selection of the best antidepressant medication is often a matter of an educated guess, followed by trial and error, for the psychiatrist.

For many people, particularly those who come to me for a change to St. John’s wort, the side effects they experience are so intense-or the expense is so high-that they prefer to stop synthetic medications altogether. Jan, Jeremy, and Will can all testify to this.

Jan: “I’ve suffered from dysthymia all my life. What worked for me was to drink a lot, until alcoholism stopped that dead in its tracks. Then came Prozac. It worked OK, but I couldn’t stand the side effects. Then I took Zoloft for three months, 100 milligrams a.m. and 100 milligrams p.m. It worked. It cost a lot. I am also not sure I liked the leveling off of all my emotions! So, a month ago I began substituting St. John’s wort, two tabs at night instead of the two doses of Zoloft. I’m very happy with the results. I no longer suffer debilitating PMS, either.”

Jeremy: “I was on Prozac for two years and just about went broke buying it. I then switched to Wellbutrin and that was much better on my pocketbook than Prozac. I then switched to St. John’s wort, a German brand, at about $24 for sixty 300-milligram tablets. I then found out that I could get the same thing made in the States for seven dollars. That is where I am now, and I feel great! With no side effects at all!”

Will: “My wife was on Prozac. It led her to have an ‘I don’t give a damn’ attitude about important things, and to stomach distress the entire time she was on it. She then went off Prozac and started on St. John’s wort. The stomach distress went away the day she stopped Prozac. Now that she’s on her ‘wart,’ as she calls it, she is relaxed and cares about the important things in her life.”

In many cases, besides the side effects, synthetic antidepressants produce subtle emotional results: complaints of flatness, of not caring, of dulled emotional responses. St. John’s wort, in contrast, produces none of these effects. It not only counters the depressive feelings, but allows a natural brightness of emotion and sharpness of mental functioning to emerge.

That is why I prefer to use natural products such as herbs whenever possible. They have been used for thousands of years and have a much better safety record. In fact, when herbs do affect systems other than the targeted system, those extra effects are often positive in nature. Also, the multiple components in herbs are usually at a low enough concentration that they don’t affect any one area too strongly. Their healing power is due to the synergistic effects produced by the combination of components. That is the very beauty of herbs. They promote balance and healing.

To summarize the benefits of St. John’s wort when compared with synthetic antidepressants:

  • Its side effects are not nearly as severe, and far less frequent.

  • It does not have adverse effects when mixed with alcohol.

  • It is non-addictive.

  • It does not produce withdrawal symptoms when you stop taking it.

  • It does not produce habituation, or the need for increased dosages to maintain its effects.

  • Its use can easily be restarted without requiring a long buildup period.

  • It enhances sleep and dreaming.

  • It does not produce daytime sedation. In fact, it has shown experimentally to enhance alertness and driving reaction time.

  • It does not produce agitation or instability.

According to one report, overdoses yielded an annual rate of 30.1 deaths per one million prescriptions of antidepressant. No one has ever died from an overdose of St. John’s wort.

Making the Right Decision

There is a role for both herbs and drugs in psychiatric treatment. There are circumstances when one or the other is called for, and there are situations when both are needed in combination. During my years of clinical practice, I have found that herbs should be the first line of defense. Their more gentle actions are often all that is needed to resolve the imbalances leading to depression. The more concentrated synthetic medications should be reserved for those times when their benefits outweigh their costs.

Synthetic antidepressants are highly purified, chemical substances that can provide many benefits, and can be a valuable resource in the treatment of severe depression and bipolar disorder. But they all have potentially harmful side effects. This is why a prescription is required from a psychiatrist or other medical practitioner. He or she is the one who can make an educated decision as to the best choice of drug. Your role as the patient is to be good observer and reporter, and to help guide this process, before and during treatment.

So far, as I’ve said, the value of St. John’s wort has been proven only in the treatment of mild to moderate depression and seasonal affective disorder. While the herb may be an excellent adjunctive treatment for the treatment of major depression, there is not yet enough evidence to establish its usefulness as the sole medication for this disorder. I recommend that if you suffer from either major depression or bipolar disorder and want to use St. John’s wort, you do so in consultation with a psychiatrist.

If you are dissatisfied with how your doctor responds to your questions about medications or herbs, I urge you to get a second opinion. I have heard many stories about patients who, after complaining of side effects to their doctors, were ignored or brushed off with “you can’t possibly be having such side effects.”. Sometimes, doctors have even increased the dosage, which only aggravates the problem. Remember, your doctor isn’t living inside your body. Only you know how you feel. You have a right to be heard, and to have your doctor work with you on fine-tuning your medication needs.

I think you now understand why I always use St. John’s wort as my first resort. This herb may not be able to help everyone, but it is unlikely to ever hurt anyone. Its side effects are always mild and temporary, and they occur far less frequently than with the other treatments. There are further considerations to keep in mind when you take St. John’s wort. In the next chapter, I will discuss other natural supplements you can take to round out your treatment program.

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Written by Hyla Cass MD

Explore Wellness in 2021