Over the past few years since this course was first developed, there have been some exciting development in the pharmacological treatment of depression. Much of this centers around the refinement in the use and application of existing medications, as well as some other changes in the conceptualization of treatment. Furthermore, there have also been some new product developments.

A new class of antidepressants, called Serotonin Modulator and Stimulators, or alternatively just Serotonin Modulators, was introduced in 2013. Two drugs are generally considered to fall into this class: vortioxetine (brand name Trintellix) and Vilazodone (brand name Viibryd). However, vilazodone may also be couched under the term serotonin partial agonist/reuptake inhibitor (SPARI). 

These medications were developed because there are a number of serotonin receptor sites - perhaps 15 in all - and not all of these sites appear to be positively affected by the typical SSRI medications. These medications also serve as antagonists for some of the receptor sites where some of the negative side-effects of the SSRI medications are generated. In theory, at least, this could increase the tolerability of these medications for some people. 

Because these medications have been on the marketplace for a relatively brief period of time, it may be a little too early to discern their actual effectiveness in representing improvements over the SSRIs. 

A more interesting development, albeit with significant complications, is the use of medications that target NDMA receptor sites. One of the new medications still in clinical trials, called Esketamine, is a derivative of Ketamine, a drug that was originally used as a veterinary tranquilizer and then popularized as a club or street drug. The other medication, called ALKS5461, is an opioid derivative. 

Both of these medications are designed to address the amount of glutamate in the brain. Because higher concentrations of glutamate in the brain correlate with depression, the theory is that drugs that target NDMA receptor sites might regulate the presence of this chemical and reduce depression. 

Because both of these substances carry a risk for dependence, they will be introduced into the marketplace with great caution. Certainly in light of the opioid crisis that has been occurring in the past decade, ALKS5461 will be scrutinized very carefully indeed.

Psychiatrists will then be left with the responsibility of determining how or whether to use them and under what conditions. Still, research in these areas demonstrate that efforts to find better options to address depression continue. 

However, alongside news of these improvements, there has also been a great deal of information presented in the media about the potential risks of suicide connected with the use of antidepressants. It may be helpful to address this issue here.

The concerns about increased risk of suicide related to antidepressant use have received much attention in the press in 2004 specifically as a follow-up to publications in the United Kingdom describing potential increases in suicidal intent and ideation. The study made specific mention of concerns of this nature in children and younger patients with the use of SSRI medications, and in particular, Paxil. Within hours of the news release, the offices of many psychiatrists were inundated with calls from parents and mental health professionals.

Because mental health clinicians are likely to be involved in the debate that will get generated from this kind of new information, it may be helpful to address the many aspects of this in some detail here. This will include a recommendation to view all new information as provisional, and a recommendation to integrate the new information with a clear sense of perspective.

A recent discussion was broadcast on a radio program regarding the evils of psychotropic medications. The discussion pointed out that antipsychotics like Thorazine and Stelazine made people "crazy". The speaker neglected to mention that medications like Stelazine and Thorazine are primarily used in people who seek medical help with the psychosis already present. The use of medication was not the cause of the problem; the use of antipsychotics was part of responding to the problem. The speaker correctly saw a correlation between the two elements of this equation, but got cause and effect exactly backwards. This is a common error in judgment by parties who do not look clearly at the relationship between things.

Further in the radio discussion, the speaker went on to make the same error in causation with regard to the use of antidepressants. It was mentioned that people who took Prozac often committed suicide. Again, the speaker neglected to mention that people who are depressed and potentially suicidal will seek out medical intervention that may include the use of antidepressants. Therefore, it would be reasonable to expect some degree of overlap between the population of people that commits suicide as an effect of their depression and the population that takes Prozac to try to treat their depression.

Over and above the current focus on this issue, there has always been this risk related to treating patients with depressive illness. The original norepinephrine reuptake inhibitors, the imipramine class medications, can take as long as a month to generate an effective therapeutic response for depressive symptoms.

However, patients who lacked the motivation and energy to function often experienced some increase in energy on these medications prior to the reductions in the feelings of hopelessness and helplessness that accompanied their depression. This could create a window of vulnerability in which low-affect patients now had increased energy with which they could pursue suicidal actions. Since two weeks worth of this kind of antidepressant could serve as a lethal dose by disrupting cardiac rhythm, this created a dangerous scenario.

The speed and relative safety of the newer antidepressants represents an improvement in this situation, not a regression. It is true, however, that the advent of the SSRI medications and the safety that was presumed to accompany them may have created a certain degree of complacency on the part of prescribing clinicians. The United Kingdom study may be useful in creating a reminder to remain ever vigilant against this complacency.

In reference to earlier materials from this course, SSRI medications should probably be used infrequently with children. While serotonin reuptake inhibitors are wonderfully effective in the removal of anxiety in adults, in children that loss of anxiety can have a disinhibiting effect, not unlike the disinhibiting effects of alcohol. This aspect of SSRI use does have some relevance with concerns about suicidal ideation in children.

Youngsters, who have not yet fully developed their executive skills - because their pre-frontal regions have not yet fully developed - are already more prone to act impulsively than are adults. Adding the disinhibiting effects of an SSRI medication may very well further predispose the child to impulsive acts, including suicidal gestures. Since children before the age of eight often do not fully understand the finality of suicide, this creates a situation that must be carefully monitored. Clearly the question of assessing the risk of suicide before and after initiating the use of SSRI medications must be kept in the forefront - and complacency must be avoided.

However, these factors must be balanced with other considerations. Since the introduction of the SSRI medications, adolescent suicide rates have been falling, and are now down to about eight per 100,000 per year. This suggests that the relationship between SSRI medications and suicide concerns contains some very positive elements that cannot be disregarded. In the end, it is important not to "throw the baby out with the bathwater". Likewise, it is important to continue to use the armament of medications in well-planned ways, always weighing the risks and rewards with clear eyes and sound judgments.

A careful and reasoned approach would suggest that in almost all cases with children receiving SSRI medications, inappropriate social behaviors should be observed during the initial phases of medication use, as they may herald disinhibition of the sort we have been describing.

In cases involving potentially suicidal adults, the speed of response created by the SSRI class of medications in fact helps to decrease the risk of a time lag between improvement in energy on the part of patients and improvements in affect. This represents an advance over earlier generations of medications and serves to reduce the risks involved in treating depression. Vigilance in these matters is still required. However, I am struck by the irony of the public response to these issues as if they had never been examined before.

The concern for medications used prematurely or with too little oversight leads to the next area of study. In 1963, Jack Dryfus, the well-known founder of the Dryfus fund, reported his experiences with Dilantin (Phenytoin) as a remedy for severe depression. During the 1980s, doctors were routinely provided with a copy of a book by Mr. Dryfus entitled, A Remarkable Medicine has been Overlooked.

Shortly after this, anti-seizure medications such as Tegretol began to be considered for use with bipolar disorder. Ultimately, another anti-seizure medication, Depakote (Valproic acid) became the first anti-seizure medication to receive an indication for the treatment of mood disorders, and in particular, bipolar disorder.

The concept was embraced in a somewhat over-enthusiastic manner, to the extent that all kinds of seizure medications were utilized – effectively or ineffectively – in the treatment of mood disorders. As noted in an earlier section, Desyrel (Trazodone) briefly became the most widely utilized antidepressant, despite its ineffectiveness. This was largely attributable to good marketing and "hype". Likewise, medications like Fenfluramine were tried to treat autism, only to discover that its use was not only ineffective, but often dangerous.

Clinicians are now using anti-seizure medications in the treatment of mood disorders and impulse disorders. Oppositional-defiant children – children who exhibit temper tantrums – are being placed on anti-seizure medications, often with very little concern for the potential long-term ramifications of such an action.

Please be aware that anti-seizure medications are frequently used in the treatment of bipolar disorder, as well as in the treatment of impulse disorders when it is clear that there is an underlying bipolar disorder. However, they should typically not be used in children who are merely difficult to manage.

This is to say that there are additional tools in the armament of medications to be utilized to address depressive problems. However, if one wants to utilize these new resources correctly, it requires a discerning eye, a willingness to conduct a thorough assessment, and the ability to resist the temptation to give in to the latest rage and the pressures of the marketplace.

As noted earlier, Depakote is indicated for the treatment of bipolar disorder.

Likewise, Trileptal and Lamictal will sometimes be used. These either have indications for the treatment of bipolar disorder, or have indications pending. Lamictal (Lamotrigine) appears to be a very effective treatment in bipolar patients who present with an episode of depression. Its effects seem to occur through its mediation on the neurotransmitter glutamine. It seems to have minimal side effects, other than the dose-related emergence of skin rashes. These rashes can be avoided if the dosage is increased gradually.

At this time, it appears that Depakote and Trileptal are more effective in responding to the mania aspects of bipolar disorder, as opposed to the depression associated with bipolar disorder. Promising research is also being done with Topamax in the treatment of mood disorders. This medication also shows some potential for creating weight loss. Clearly the utilization of anti-seizure medication in the treatment of mood disorders is something that bears watching and observation. However, at this time, these medications are typically utilized for bipolar disorders only, and these not in treating unipolar depression.

Clearly the utilization of anti-seizure medication in the treatment of mood disorders is something that bears watching and observation. However, at this time in my practice, they are utilized for bipolar disorders only. I do not use these medications in treating unipolar depression.

There are some other developments that bear mentioning here. Wellbutrin XL has been introduced and it represents a clinical improvement in the delivery system of Bupropion. When Wellbutrin was first released in its immediate release form, dosing was required two to three times daily. This delivery shortcoming was largely resolved with the introduction of Wellbutrin SR, or slow release. The introduction of the XL form of Wellbutrin now appears to be very effective in maintaining a good day long dose, and it is expected we will see a significant switch to the new XL form.

As an additional advantage, the XL form of Wellbutrin appears to reduce the risk of an important side-effect of Wellbutrin. The producers of Wellbutrin point out that Bupropion will in fact lower the seizure threshold. (Most psychotropic medications do.) The highest risk of this problem occurs with the immediate release form of the medication. The risk has been radically reduced with the SR form of the medication, and even more so with the XL.

It may also be important to state that there are instances where Wellbutrin may be used in treating patients presenting with psychotic depression. However, in researching this utilization, it appears that this runs contrary to the accepted reasoning that the dopaminergic stimulation created by Wellbutrin should be disorganizing in psychotic patients.

On the other hand, a new antipsychotic medication, Abilify (Aripiprazole) has recently been released, and it has a dual effect on dopamine. Most anti-psychotics inhibit the effects of dopamine, or are dopamine antagonists. Abilify acts selectively to be a dopamine antagonist in some neuronal pathways, while being a dopamine agonist (dopamine supporter) in other neurologic pathways. This raises the possibility that dopamine agonists like Wellbutrin may have a place in treating psychotic depression, as well. Further research will undoubtedly continue to illuminate these complicated matters.

As noted earlier in this course, Wellbutrin's safety and its dopaminergic stimulation makes this a wonderful medication in treating patients with attention deficit disorder and mild depression. Psychiatrists will often use Wellbutrin together with a stimulant medication such as Ritalin or Adderall in such patients. However, there are concerns that some patients become moderately agitated from over-stimulation.

This highlights the importance of clearly understanding a differential diagnosis between attention deficit disorder and bipolar disorders, whose manifestations can be similar, especially in young patients. In instances where over-stimulation from combined use of stimulants and Wellbutrin occurs, careful re-examination will sometimes reveal the presence of other disorders, such as bipolar disorder, as opposed to attention deficit disorder.

The important concept for the nurse or other health professional to draw from this information is to be aware of the significance of a dopamine overload from the combination of Wellbutrin and a stimulant. It will show itself in the over-stimulation of the patient, and should indicate the need to consider a diagnosis of bipolar disorder as opposed to attention deficit disorder.

On another front, the Eli Lilly Company has recently introduced one medication relevant to our discussion here, and will likely soon introduce an even more significant medication. Strattera (Atomoxetine HCL) was introduced recently as a non-stimulant medication for the treatment of attention deficit disorders. Strattera, not unlike the TCA medications, is a norepinephrine reuptake inhibitor.

During the 1980s, very early in our understanding the prevalence of attention deficit disorders, Tofranil was considered as a potential option for treating attention deficit disorders in children who could not tolerate stimulants. Tofranil, as you might recall, is a TCA antidepressant and norepinephrine reuptake inhibitor. This idea briefly ran its course and no longer appears to be in fashion.

It is sensible to consider that the use of an antidepressant in treating attention deficit disorders is related to the fact that attention deficit disordered patients often get depressed as a secondary effect of their condition. If one treats the depression, one would expect to find some improvements in concentration.

A number of psychiatrists have speculated on whether this is the reasoning behind the development of Strattera. Strattera has not proved to be as effective in the treatment of attention deficit disorders as one would have hoped (or as much as the hype and marketing would suggest). However, it may be reasonable to think that Strattera may find its rightful place in the treatment of depression, as it is a NRI medication.

Strattera seems to cause nausea and some digestive problems in certain patients, but otherwise it seems well tolerated and without severe side effects. Dosing can run from 25 mg to 120 mg daily. This medication may need to be considered for use with attention deficit disordered patients with mild depression if Wellbutrin is unsuccessful in addressing the depression.

One more interesting footnote with regard to Duloxetine (Cymbalta). Tofranil and the TCA antidepressants tend to cause urinary retention. For this reason, this class of medications has been used in the treatment of enuresis in children. Roughly half of the papers on Cymbalta, or Duloxetine, concern the use of this medication in the treatment of urinary incontinence in elderly patients. Once again it is interesting to note how the TCA medications – previously fallen out of favor – are again being reconsidered for use, with new medications being developed to take advantage of their characteristics.

This completes the course on antidepressants. Following a brief review of important issues in this chapter, you may move to the test section to complete the post-test.

Review Questions for Section VIII

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

1. What are the concerns presently in the news about SSRI medications and increased risk of suicide, and what factors weigh in for and against those concerns?
2. How are anti-seizure medications currently being used in the treatment of conditions with depression?
3. What changes in the dosing of Wellbutrin has occurred in the past couple of years, and how has this led to improvements in the use of this medication?

References, Antidepressants,

Lieberman, DZ & Massey, SH, Desvenlafaxine in major depressive disorder: an evidence-based review of its place in therapy, Core Evid. 2009; 4: 67–82.

NIMH, Antidepressant Medications for Children and Adolescents: Information for Parents and Caregivers,

NIMH, Mental Health Medications,

NIMH, Post by Former NIMH Director Thomas Insel: Antidepressants: A complicated picture,

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