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ADM8283 - SECTION 7: THE DUAL EFFECT ANTIDEPRESSANTS

 

Along with the advent of SSRIs, there has been the development of newer agents that combine the effects of both norepinephrine (NRIs) and serotonergic (SRIs) actions. This group includes Effexor, Serzone, and Remeron. These represent dual effect antidepressants, the next group we will look at.

There have been prior medications with this combination of effects. Anafranil, a TCA, had effects on both the norepinephrine and serotonergic systems, but with a number of unpleasant side-effects, as is the case with the TCAs. With the newer group of agents, scientists have been able to affect both of these neurotransmitter systems, but without as many negative side effects.

This newer group of agents seems to do a better job in decreasing the negative side effects of medications that affect the SRI and NRI systems, while maintaining the benefits.

We will also include in this group one other medication, Wellbutrin, that is a dual effect antidepressant, but which affects different neurotransmitter systems. We will look at that in some detail, as well as our more traditional dual effect medications. First, though, let's look at our summary pages for all these antidepressants.

                         

                                    Effexor Summary Page


Trade Name: Effexor (1997)....................Chemical Name: Venlafaxine
Antidepressant type: NRI/SRI......... Usual Dosage: 75-375 mg/qd
Pill sizes and types: Shield shaped, peach colored tablets, 37.5 and 75 mg.
How it Works: Inhibits serotonin and norepinephrine reuptake. Also has some effects on inhibiting dopamine reuptake.
Most Common Uses: Clients with major depressive disorder.
When Effexor is used as opposed to other medications: May be useful with depression with concurrent panic disorder. Especially effective with melancholic depression, i.e. very severe depressions. If TCAs or Remeron don't work or can't be tolerated by patients with very severe depression, Effexor is likely to be the next medication to be tried.
Side-effects: May cause insomnia. Agitation is very common side-effect. May cause drowsiness. Impaired ejaculation, nausea, GI distress, constipation, dry mouth, dizziness, anxiety, blurred vision, and anorexia are also possible side-effects.
Contraindications and cautions in use: Not to be taken with MAO medications. Must not be added to medication regimen until other contraindicated medications have cleared metabolically, and other contraindicated medications should not be added until this has cleared system. Use has been associated with sustained hypertension. Dosage adjustment is necessary in clients with liver or kidney damage. It has not been established whether it is safe to take this medication during pregnancy. Use during lactation is contraindicated. Withdrawal should be administered gradually.
Comments: This medication is often used by psychiatrists after other NRIs or SRIs have shown to be ineffective. Finding the proper dosage is a problem. At lower doses, the SRI effects are predominate. At higher doses, the NRI effects are predominate. There can be a fair amount of agitation associated with use of this medication. Withdrawal from this medication is very difficult.

 

                                 Serzone Summary Page


Trade Name: Serzone (1994)....................Chemical Name: Nefazodone
Antidepressant type: SRI/NRI......... Usual Dosage: 100-600 mg/qd
Pill sizes and types: Hexagonal, flat-faced, beveled edged pills: 100 mg. - White; 150 mg. - Peach; 200 mg. - light yellow.
How it Works: Inhibits serotonin reuptake and blocks serotonin type 2 (5HT2) receptors, and has some effects on NRI systems.
Most Common Uses: Clients with depression that includes insomnia.
When Serzone is used as opposed to other medications: Best use may ultimately be as a sleep aid, due to its ability to create sedation. Otherwise, this is a medication of last resort, to be used only when nothing else has worked.
Side-effects: May cause drowsiness. Dry mouth, blurred vision, dizziness, decreased libido, dry skin, neck pain, cough, amblyopia, nausea, anorexia and constipation are also possible side-effects. May cause lowering of blood pressure. Increased risk of seizures. May cause increased hostility. In clients with bi-polar disorder, may precipitate manic phase.
Contraindications and cautions in use: Not to be taken with MAO medications. Must not be added to medication regimen until other contraindicated medications have cleared metabolically, and other contraindicated medications should not be added until this has cleared system. Priapism (erectile problem) is a possibility, and clients who experience long-duration erections should be carefully watched. Should be administered carefully with clients with history of seizure disorder. Rare but serious liver problems have been noted in patients taking this medication. Should not be taken in combination with Cisapride or Pimozide. It has not been established whether it is safe to take this medication during pregnancy, or safe for children to take. Use during lactation is contraindicated.
Comments: Best use may be as sleep aid, rather than as a first choice for addressing depression. The effectiveness of Serzone in long-term use for depression has not been shown.

 

                                  Remeron Summary Page


Trade Name: Remeron (1996)....................Chemical Name: Mirtazapine
Antidepressant type: SRI/NRI......... Usual Dosage: 15-60 mg/qd
Pill sizes and types: Dissolvable wafer; film coated tablets: scored 15 or 30 mg.; unscored 45 mg.
How it Works: Enhances serotonic receptors and enhances central serotonin and norepinephrine activity. Most Common Uses: Clients with endogenous depression, especially with concurrent insomnia.
When Remeron is used as opposed to other medications: May be especially useful for clients with depression and concurrent insomnia, and for depression with anxiety. This may be the best of the new dual effect medications, and a best choice for use with severe depressions.
Side-effects: Abnormal dreams, constipation, dry mouth, dizziness, increased appetite, weight gain, drowsiness are possible side effects. Can increase cholesterol.
Contraindications and cautions in use: Not to be taken with MAO medications. Must not be added to medication regimen until other contraindicated medications have cleared metabolically, and other contraindicated medications should not be added until this has cleared system. Should be used with caution for patients with active liver or kidney disease. Should not be taken in combination with alcohol. Rare incidence of leukopenia. It has not been established whether it is safe to take this medication during pregnancy. Use during lactation is contraindicated.
Comments: Weight gain can be difficult side effect for clients concerned about weight and appearance. This medication is sometimes used to block SSRI side-effects. Due to overall effectiveness and relatively good side-effects profile, this may represent one of the best choices for patients with severe depression.

 

                                    Wellbutrin Summary Page


Trade Name: Wellbutrin (1996).............................Chemical Name: buproprion
Antidepressant type: Aminoketone......... Usual Dosage: 150-450 mg/qd
Pill sizes and types: Round, bi-convex tablets: 75 mg. - Yellow-gold; 100 mg. - Red.
How it Works: The exact effects of this medication are not clearly understood. It is a blocker, although more weakly than TCAs, of neuronal uptake of serotonin and norepinephrine, and also inhibits neuronal uptake of dopamine. It also has a CNS stimulant effect.
Most Common Uses: Clients with depression, particularly those who are sleeping too much. Also useful for patients with depression with psychotic features, and patients with depression and mild ADD.
When Wellbutrin is used as opposed to other medications: With patients who have mild ADD with depression. With patients with depression with psychotic features where no sleep disturbance is noted.
Side-effects: Increased risk of seizures. Increased restlessness, anxiety, insomnia, headaches. Altered weight and appetite.
Contraindications and cautions in use: Not to be taken by clients with seizure disorders. Not to be taken with MAO medications. Must not be added to medication regimen until other contraindicated medications have cleared metabolically, and other contraindicated medications should not be added until this has cleared system. Because of increased seizure risk, alcohol should be used sparingly, or not at all, concurrently with this medication, as alcohol lowers seizure threshold. Not tolerated well by patients with panic disorder. It has not been established whether it is safe to take this medication during pregnancy. Use of this medication during lactation is contraindicated.
Comments: Because of potential for seizures, this medication should be taken in three time per day dosages, with no single dose greater than 150 mg. This medication is also used for smoking cessation under the trade name, Zyban. This medication is often used as an adjunct to SSRIs and other antidepressants to increase their effects, and to diminish sexual side-effects of SSRIs. This medication also appears to be helpful in reducing cravings in patients with addictions.

 

Effexor is the prototypical example of the group of dual effect antidepressants. Effexor works largely as a reuptake inhibitor of both serotonin and norepinephrine. It therefore should offer reductions in both anxiety-based depression and more severe, traditional clinical depressions.

Given that the profiles of patients treated with chemicals working primarily on the norepinephrine systems are different that those patients who respond to serotonergic medications, how does one decide to utilize Effexor? In truth, this medication and the others in this category represent what is called the "shotgun approach" to treatment.

This term - the "shotgun approach" - was coined with respect to very potent antibiotics that killed broad ranges of bacteria, and not just specific groups. It means utilizing a potent chemical with potentially broad - but not necessarily very specific - effects.

The fact that Effexor does work on both neurotransmitter systems involved in depression can make it a highly effective agent. It can also expose the patient to unnecessary chemicals with side-effects. Therefore, I will personally tend to use Effexor only after appropriate trials of NRIs and SRIs have been unsuccessful. It is my sense that this approach to using this medication - and others like it - is the most common in practice.

At low doses, Effexor tends to have more of an SRI effect, whereas the NRI effect tends to kick in at doses over 200 mg. At low doses I have tended to see agitation similar to Celexa, as well as nausea and indigestion, although somewhat less severe to what is seen with Luvox.

While Effexor's "shotgun approach" is its advantage, the wide variation of dosaging is its disadvantage, in my opinion. Finding the right dosage can be problematic. Effexor can be given in doses as low as 25 to 37.5 mg. or in doses as high as 450 mg. Severe depressions do require dosages in the 300 to 450 mg. range.

Ironically, the SRI effects of the medication seem to work against the sedative effects needed for treating severe depressions in which there is initial and terminal sleep disturbance. Other side-effects include sexual dysfunction, hypertension, and headache - similar to what can be seen with the SSRIs.

More alarmingly, however, it is commonly understood that Effexor is very difficult to discontinue. One must very gradually lower the dosage and sometimes use other SSRIs to blunt the difficulties of withdrawal. Patients have noted severe dizziness, gastrointestinal distress and even disorientation. In summation, while Effexor does have a place in treating depression, it is not as easy to use as clinical practice might imply.

As a follow-up to Effexor, Wyeth released another dual effect medication called Pristiq whose molecular structure is a variation of the molecule that is the active ingredient in Effexor. Effexor went off patent in 2008 and this new medication was released in 2008. 

Reviews and sales of this new medication were not positive and the company that released it ended up not trying to get it approved in Europe. Ongoing use and evaluation of the medication may lead to new conclusions, but the drug is not used as widely as the company producing it had hoped. Below is the Summary page for Pristiq.

 

                                        Pristiq Summary Page

 

Trade Name: Pristiq (2008)....................Chemical Name: Desvenlafaxine

Antidepressant type: NRI/SRI......... Usual Dosage: 50-400 mg/qd

Pill sizes and types: Rectangular, pink-peach-orange colored tablets.

How it Works: Inhibits serotonin and norepinephrine reuptake. Also has some effects on inhibiting dopamine reuptake.

Most Common Uses: Clients with major depressive disorder.

When Pristiq is used as opposed to other medications: Pristiq is used very much in the same ways that Effexor is used, as it is derived from the molecule that comprises Effexor. However, a number of studies appear to show that it is less effective at lower doses and has more side effects than Effexor at higher doses. However, it may be useful for depression that accompanies pain and chronic pain. 

Side-effects: May cause insomnia. Agitation is very common side-effect. May cause drowsiness, decreased sex drive and impaired ejaculation. Nausea, GI distress, constipation, dry mouth, dizziness, anxiety, blurred vision, increased sweating and loss of appetite are also possible side-effects. Rare but serious side-effects include seizure, hallucinations, blurred vision, muscle rigidity, and severe skin reactions.

Contraindications and cautions in use: You should not take this medication with Effexor or if you have been shown to be allergic to Effexor. Not to be taken with MAO medications. Must not be added to medication regimen until other contraindicated medications have cleared metabolically, and other contraindicated medications should not be added until this has cleared system. Side-effects from this medication will be increased if medication is used concurrently with alcohol. Use has been associated with sustained hypertension. Dosage adjustment is necessary in clients with liver or kidney damage. This medication should not be taken during the last three months of a pregnancy. Use during lactation is generally contraindicated, but use should be discussed with your physician. Withdrawal should be administered gradually.

Comments: This medication has been approved in the US and Canada, but has not been approved for use in Europe, and the parent company, Wyeth, withdrew its application for approval in Europe. The European committee in charge of giving approval commented that this medication appeared to be less effective than Effexor, with no advantages in terms of safety and tolerability. However, an evidence based review published by NIMH noted that "Because only a minority of patients experience remission after an initial trial of an antidepressant, and because it is not possible to know in advance which antidepressant will help a particular patient, a greater number of options can lead to better results. As one of only a limited number of SNRIs, DVS has the potential to play a significant role in improving treatment outcomes." 


Serzone is also a broad spectrum antidepressant because it works on both the SRI and NRI systems. Serzone is effective in alleviating anxiety-driven depression, as one would expect from a serotonergic agent. However, Serzone minimizes the side-effects profile of an SRI by also antagonizing certain serotonin receptors (5HTs, or Serotonin 2, to be precise). Therefore, it seems not to produce the sexual dysfunction seen in most SSRIs.

Theoretically, this SRI effect - without some of the side-effects - combined with the NRI effect found in Serzone, should make this medication ideal for addressing the kinds of problems found in people who are depressed.

Unfortunately, dosaging appears to be one of the major hurdles in utilizing this medication. The effective dose range can be anywhere from 200 to 600 mg. The difficulties in achieving the right dosage may make other medications more expedient and useful.

My experience with this medication has produced very mixed results, and I will therefore tend to use it as a second or third choice rather than my first choice. However, Serzone is similar in chemical structure to Trazodone, with similar effects, but with the added benefits of NRI effects. Therefore it may ultimately be more useful as a sleep hypnotic agent like Trazodone than as an antidepressant of first choice.

While Remeron is usually listed under the dual effects category, it is an extremely effective NRI medication. Because of this, Remeron has actually replaced the TCAs as my primary choice in treating typical clinical depression.

In a similar fashion to the TCAs, Remeron has some antihistaminic properties, and therefore has the side effects of sedation and appetite stimulation. Patients with major depression tend to present with sleep disturbance, as well as appetite reduction and weight loss. These antihistaminic side effects, therefore, can be utilized to the patient's benefit.

The dosage range of this medication is from 15 to 60 mg. at bedtime, with increased antidepressant benefits at higher doses. Ironically, at the higher doses the NRI effect tends to overwhelm the antihistamic effect, so the sedative effect, as well as the increased appetite and weight gain, tend to be less prevalent at higher doses.

While weight gain can be a positive side effect of Remeron when weight loss is a symptom of depression, it also tends to be the major problem with this medication. Particularly when treating women (who may be conscious of their weight in terms of appearance), the gain of up to 25 pounds can be considered a very negative side-effect to have in an antidepressant. This can undermine Remeron's appeal in use.

Remeron does also have an SRI effect that is quite interesting. Unlike with Effexor and Serzone, the SRI effect of Remeron is actually quite minor compared to the NRI effect. However, the SRI effects are the "icing on the cake", with the anti-anxiety action working to help with the depression in that arena.

Another reason that Remeron is one of my favorite medications for treatment of severe depression is that its serotonin selectivity has been designed to avoid sexual side-effects, as well as the agitation that is seen with less selective SSRIs.

Since Remeron's SRI effects are quite minor, it does not appear to be as effective in terms of a "shotgun approach" to depression. Patients whose depression has a greater degree of anxiety to it may not be quite as well served with this medication.

On the other hand, Remeron offers a considerable advantage over TCAs in that it has a minimal risk of cardiotoxicity. While a two week supply of TCAs can represent a lethal overdose, Remeron would require two to three months' worth of a standard dosage to approach potential lethality. There is, however, one potential side-effect Remeron does share with the TCAs - a small incidence of causing leukopenia (a reduction in white blood cells affecting the body's ability to respond to infection). Patients with repeated infections on this drug must be closely watched.

There is a relatively new medication to discuss in this category. This is Cymbalta (Duloxetine). The primary use for this medication, at least at present, is for treating pain, but this medication also has some SRI and NRI effects. We have not had as long a time to utilize this in clinical practice, however there is great promise in using Duloxetine to treat depression associated with chronic pain. Below is the summary page.

 

                               Cymbalta Summary Page

 

Trade Name: Cymbalta (2004)....................Chemical Name: Duloxetine

Antidepressant type: NRI/SRI......... Usual Dosage: 20-60 mg/qd

Pill sizes and types: Yellow-green (20 mg), blue and white (30 mg), blue and yellow-green (60 mg) capsules.

How it Works: Inhibits serotonin and norepinephrine reuptake. Also has some effects on inhibiting dopamine reuptake.

Most Common Uses: Clients with depression, generalized anxiety disorder, pain from neuropathy or fibromyalgia, and clients with bone and muscle pain.

When Cymbalta is used as opposed to other medications: To treat clients who suffer from depression associated with physical and particularly chronic pain.

Side-effects: Most common side effects are nausea, somnolence, dizziness, headaches, dry mouth and insomnia. May cause decreased sex drive and impaired ejaculation. GI distress, constipation, dry mouth, increased sweating and loss of appetite are also possible side-effects. Rare but serious side-effects include blurred vision, difficulty breathing, and severe skin reactions.

Contraindications and cautions in use: Not to be taken with MAO medications. Should not be used concurrently with any CNS stimulant, due to the possibility of serotonin syndrome. Must not be added to medication regimen until other contraindicated medications have cleared metabolically, and other contraindicated medications should not be added until this has cleared system. Side-effects from this medication will be increased if medication is used concurrently with alcohol. Use has been associated with sustained hypertension. Dosage adjustment is necessary in clients with liver or kidney damage. This medication should not be taken during the last three months of a pregnancy. Use during lactation is generally contraindicated, but use should be discussed with your physician. Withdrawal should be administered gradually. Not recommended for any patients with uncontrolled narrow-range glaucoma.

Comments: This medication has been used in Europe for the treatment of urinary incontinence, but has not been approved in the US for this purpose.



I have had the opportunity to work with orthopedically injured patients in cases that involved worker's compensation. One of my close friends is a wonderful orthopedic surgeon in my town who has taken an interest in the psychological impact of injury and the effects of this psychological impact on recovery from surgery.

This relationship has afforded me the opportunity to work with several of these patients and examine how chronic pain interferes with the treatment of depression. As we have discussed earlier, insomnia is one of the hallmark presentations of depression. In chronic pain patients, it is the pain itself that interferes with the ability to sleep.

Patients unable to sleep have severe difficulty recovering from depression. Those recovering from severe injuries face this problem in a very real way. TCAs have often been used in treating headaches, as the NRI effect does appear to help with pain.

Duloxetine holds forth even greater promise in utilizing the pain mediating benefits of NRIs, while having some secondary effects on addressing the underlying depression with both NRI and SRI effects. My hope is that this medication will live up to its promise in this arena, offering a new option for chronic pain patients who are struggling with depression as a result of that pain. Duloxetine may also be helpful with urinary incontinence in women.

Finally, we come to Wellbutrin, our oddball medication in terms of classification. Research has been unable to date to determine its exact method of creating positive effects. As near as we have been able to determine, it appears to cause a dual response of neurotransmitters, but by working with the NRI system and the systems that reuptake dopamine, another important neurotransmitter with chemical effects in the brain.

This holds some very interesting implications for use of this medication. The patient who would respond well to Wellbutrin would be very similar to the patient who would respond well to Vivactal - a severely depressed patient who presents with hypersomnia (over-sleeping), as opposed to the patient who is having insomnia, or difficulties falling and/or staying asleep.

This sounds strikingly similar to the population that is treated with SSRIs. As you might recall, I stated that I was not as inclined to use SSRIs as other psychiatrists might be. You might, therefore, think that I would not use Wellbutrin very much.

Surprisingly, however, Wellbutrin turns out to be one of the medications I use the most. How can this be? This is largely because I specialize in child psychiatry, and Wellbutrin is especially effective in working with children and teenagers. There are reasons why this is so, and it will relate back to something that has already been discussed.

As described earlier, SSRIs have the effect of reducing anxiety. Like alcohol that reduces inhibitions by its anxiolytic effect, SSRIs can be extremely disinhibiting in children. This disinhibition can have the effect of reducing self-control, which is partially held in place in children through anxiety

The dopaminergic effects of Wellbutrin, on the other hand, appear to improve organization - particularly in terms of a child's ability to respond to others and respond to structure. This is a wonderful property in treating depression with psychotic features, like paranoia or hallucinations.

Dopaminergic response also appears to be one of the key factors that allows stimulants to be effective in treating Attention Deficit Disorders. This means that Wellbutrin, with its dopaminergic properties, can have a role in treating ADD, especially when the disorder is accompanied by mild depression.

In treating Attention Deficit Disorders, stimulants represent a simple, direct and effective way to improve focus. However, stimulants are not useful in treating the loss of self-esteem and accompanying depression that are secondary effects of the ADD client's often painful journey through life. Wellbutrin can help improve focus and - through its NRI effects - help with the depression.

During the 1980s, TCAs were thought to produce improvements in focus for people with ADD, similar to what was seen with stimulants. However, my sense is that people who are depressed or anxious also have a decrease in the ability to focus. TCAs may have improved focus through alleviating the depression and/or anxiety, without actually addressing the underlying chemistry that produces the ADD.

I personally have not seen TCAs be effective in treating uncomplicated ADD - that is, ADD without the underlying depression and anxiety. Wellbutrin, however, does work with ADD, while also being able to address symptoms of major depression.

In the treatment of major depression, dosages should be as high as 350 to 450 mg. For treating children with mild ADD and mild depression, however, dosages between 100 and 200 mg. are effective.

When Wellbutrin was first on the marketplace, it was a medication that required two to three dosages per day, due to a short half-life. The current preparation is a Wellbutrin SR (slow release) that generally allows for once a day dosaging. With patients who complain that their medication "wears off" in the afternoon, a split dosage of 150 mg. in the morning and 150 mg. in the afternoon may also be used.

The one potential side-effect that may cause concern with Wellbutrin is insomnia, as this medication tends to be invigorating. Since getting a good night's sleep is important in combating depression, this is a side-effect that must be carefully watched.

It is commonly known that Zyban, an anti-smoking medication, is Bupropion, the same medication as Wellbutrin. This implies that Wellbutrin may have some usefulness in working with addictions, and, in fact, I do use this medication in helping people discontinue other addictive substances besides tobacco. I also use it in working with patients that show some repetitive behaviors, such at trichotillomania (hair pulling), especially when the repetitive behavior is due to sensation craving, as opposed to obsessional belief.

So what are the drawbacks of this wonderful medication? We have already discussed the insomnia factor. Another side-effect that may be cause for concern is an ability to lower the seizure threshold.

Wellbutrin does not appear to cause seizure disorders, but it does make it easier for people with seizure problems to have problems more easily. People who have had multiple concussions or other neurological disorders that tend to cause seizures should not be put on Wellbutrin.

I have had two patients experience seizures while on Wellbutrin. In both cases, insomnia and lack of food also worked to lower the seizure threshold. One of the patients also lowered the seizure threshold by drinking alcohol. This was unfortunate, since Wellbutrin was very effective for both patients.

I have also observed on a number of occasions rapid heart beat, nausea and orthostatic hypertension as side effects with this medication. The rapid heart beat tends to occur within a half-hour of taking the medication. It appears to be a transient side-effect, in that it will usually clear up after two to three weeks of use. Patients should, therefore, be encouraged to tolerate this side-effect long enough to have it go away.

Wellbutrin, like Effexor, now exists in a extended release (XR) form. In their regular form, both of these medications have relatively short half-lives and may require multiple dosing.

This is important. Statistically, people taking medication in one or two doses per day have an over 90% compliance rate. This drops dramatically when a third dosage is added. The XR or SR (sustained release) form of Wellbutrin - or Effexor - have great advantages in terms of assuring compliance with treatment.

One last important fact concerning the use of Wellbutrin: it is often used in combination with an SSRI medication. Wellbutrin is thought to help combat the sexual side effects so often seen with SSRIs. In my experience, however, I have not seen this to be as beneficial as many other physicians think.

This leads to the next important consideration in this chapter on dual effect antidepressants. Clearly, if the chemistry of depression has connections to a number of different neurotransmitters, then some clients might be better served by targeting as many of the chemical systems as possible. This suggests the use of combination therapy, in which several different antidepressants may be used together.

In theory, if you can line up medications that work together and enhance each other's positive effects, you can create a medication regimen that offers improvements over the use of a single drug.

For example, Wellbutrin - due to its dopaminergic effect - may be effective as a supplement to Remeron. It may help counteract Remeron's tendency to produce sedation and cause weight gain. Moreover, it may actually enhance the overall antidepressant effects. Similarly, Provigil, a dopaminergic agent used to treat narcolepsy, appears to have some benefits when used with SSRIs that tend to lose their effectiveness over time.

Gabatril, an anti-seizure medication that works on a neurotransmitter called GABA, is sometimes used to counteract the agitation seen in the use of SSRIs, specifically the bruxism (tooth grinding) that can occur occasionally with these medications.

Here is where the note of caution comes in. We want to make sure that the cure is not worse than the problem. When working with complicated chemicals in a system as complex as the human body, we want to approach each medical decision with great care and an ample measure of humility.

There are clearly benefits, at times, to providing patients with combinations of medications to improve effects and counteract side-effects. Earlier, in discussing dual acting broad spectrum antidepressants, I hinted at the possible use of an SSRI along with an NRI like Remeron, or in combination with a TCA.

One should always, however, be cautious and skeptical, and maintain a sense that these combinations must be well thought out and specific in their purposes. A "shotgun approach" may be a useful metaphor in this field, carrying in its meaning the implication that some of the "bullets" can cause harm in ways that are not intended.

It is my personal preference in many cases to try first to use a dual acting medication, such as Effexor, instead of a combination approach. This allows the physician better control of the proportions of the different agents.

There are, however, also times when combination therapy is more appropriate. It is not possible in this training to cover all of the possible combinations in sufficient detail to make it relevant for the trainee. What is important to realize is that different physicians will have their preferences with respect to combining and using primary and adjutant medications.

The role of the mental health clinician does not necessarily include providing a second opinion on the complex neurochemistry of these decisions, which may take the clinician beyond the limits of his/her competence. It may, however, include acting as an advocate for the client to make good consumer decisions about his/her care.

This advocacy role can include providing the client with good information about choices of antidepressants, so that the client can speak with his/her psychiatrist in an informed manner. It can also include direct communication with the psychiatrist, to provide important clinical information that may help the psychiatrist do a better job in selecting the best medication.

In bringing this clinical information to the psychiatrist - with the proper degree of knowledge - it may also allow the clinician to work with the psychiatrist in assuring that the medication choices are being made for the right reasons.

As a concerned provider of medical care, my task is to help the individual client find a medication regimen that works best with his/her specific needs. Neurochemical theory, therefore, is not the end point for what choice will work best. The client's experience - whether his/her depression improves or not - is the end point. The clinician - as a good partner in care - can provide important information about the client's experience, and help the psychiatrist to make these complicated choices with a higher degree of knowledge. This is the right partnership to undertake.

While preparing this course, I examined a textbook printed in 1984. While this book was over 2000 pages, the section on antidepressants contained about 20 pages. Clearly, the nearly 20 years of development in this field have yielded some dramatic results.

I hope that during my presentation of this material I have given the trainee some sense of the historical development and changes that have occurred over these past almost two decades. I also hope that I have given the trainee some insight beyond the textbook - beyond the theoretical - and into the more pragmatic, day to day use of antidepressants, including a little sense of the thinking process that goes into making medication decisions.

Clearly the psychiatrist has many more tools at his/her disposal since I completed my formal training. There will be many more to come. Doctors and patients alike must exercise appropriate caution in assessing the next generations of agents and treatments.

At the same time, we can celebrate a little bit on the benefits of these wonderful new tools in treating depression. Working together - with all the tools at our disposal - physicians and mental health clinicians can continue in our joint responsibility for improving the well-being of the patients who come to us for help.

In our next and final section, we will look at some important recent developments in the use of antidepressants.


Review Questions for Section VII

At this point in the training, you should be able to answer the following questions:

1. What are the three major dual effect antidepressants?
2. What is duloxetine, and what is its potential in terms of treating depression?
3. What is different about Wellbutrin in terms of the way its chemistry works?
4. What major childhood problem does Wellbutrin seem to address, in addition to its uses with regard to depression?
4. What is the role of the mental health clinician in terms of addressing issues related to antidepressants with their clients?


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