Naturally, individuals who are depressed and who consult with a psychiatrist for their depression want to know how their psychiatrist can help them with their depression. Traditionally, in the field of psychiatry, treatment has been delivered through two major modalities: psychotherapy (talk therapy) and pharmacotherapy (medication). This paradigm applies to the treatment of major depressive disorder as well; the best-studied treatments for major depressive disorder are, in fact, medications and various forms of psychotherapy. Other treatments for major depressive disorder include exercise, light treatment (for major depressive disorder with a seasonal component) and electro-convulsive therapy (E.C.T.). Novel approaches that directly stimulate the nervous system are also being studied.

But, the basic treatment approach for most individuals with depression today is administration of psychotherapy alone, medication alone or the combination of psychotherapy and medication.

Treatment of major depressive disorder has two basic goals: 1) to help individuals recover from their current episode of major depression as quickly as possible and return to their baseline level of functioning and 2) to minimize the risk of subsequent episodes. Because major depressive disorder, in most individuals who suffer from the illness, is a chronic, recurrent illness, it is very important for psychiatrists to discuss with patients how best to prevent subsequent episodes.

Sometimes, the recommendation of psychotherapy alone is made if someone is:

1. experiencing a first episode of depression and it happens to be a mild major depressive episode that has clear situational triggers

OR

2. if someone is ambivalent about or opposed to the use of medications.

Psychotherapy for Major Depressive Disorder

Normally, in my practice, I recommend that individuals in either of these two situations pursue a form of psychotherapy called cognitive-behavioral therapy (CBT), as it has the most scientific evidence to support its use in the treatment of a major depressive disorder. The theoretical underpinnings of CBT for the treatment of depression are easy for most individuals to grasp. The basic idea is that how we feel (mood) is affected by what we think (cognitions) and how we behave (behavior). So, if therapeutic interventions can be directed at the level of an individual's thoughts and behaviors, mood should be affected in a positive direction. The basic work of CBT for major depressive disorder can often be accomplished in 12 to 20 sessions.

Another form of psychotherapy that has been shown to be effective for major depressive disorder is interpersonal psychotherapy (IPT). In this type of therapy, the individual's relationships and historical patterns in relationships are analyzed, to see how they could be contributing to the major depressive disorder. By working with a therapist in IPT, the depressed individual can begin to make changes in important relationships in his life that would, then, promote recovery from the major depressive episode.

Anti-depressant Medications

When someone is in a major depressive episode and there is no evidence from the clinical history that he could have a bipolar disorder (especially the "harder" forms of a bipolar spectrum mood disorder - bipolar I and bipolar II), conventional anti-depressant medications can often be recommended. Nowadays, the most widely prescribed conventional anti-depressant medications for the treatment of major depressive disorder are the selective-serotonin reuptake inhibitors (SSRIs), selective serotonin-norephinephrine reuptake inhibitors (SNRIs) and an agent called buproprion (brand name Wellbutrin).

These newer medications have largely replaced the use of older conventional anti-depressant medications, including the tricyclic antidepressants and the monoamine oxidase inhibitors, not because they are any more effective, necessarily, but because they are generally better tolerated, in terms of side-effects, much less lethal in overdose, and less likely to cause serious interactions with other medications.

Currently, the SSRI anti-depressants comprise 6 different medications:

1. fluoxetine (brand name Prozac)
2. paroxetine (brand name Paxil)
3. sertraline (brand name Zoloft)
4. fluvoxamine (brand name Luvox)
5. citalopram (brand name Celexa)
6. escitalopram (brand name Lexapro)

The SNRIs include:

1. venlafaxine (brand name Effexor)
2. duloxetine (brand name Cymbalta)

Anti-depressant medications come with side-effects, certain other risks, and benefits, and they generally have a delayed onset of action. Furthermore, not all anti-depressants may be effective for a particular individual's major depressive episode; sometimes, a psychiatrist and a patient will have to go through a trial and error process in order to find one that works reasonably well. Unfortunately, at this time, there are no routinely used tests (e.g. blood markers or functional imaging studies of the brain) that can help us predict which anti-depressant medication a particular individual will respond to. However, there is interest in developing this kind of test and some experimental methodologies are used by some clinicians and research groups with varying success.

In general, 70% of individuals with major depressive disorder who try 1-4 medication interventions will achieve full remission of depressive symptoms. About 50% will achieve full remission after 2 medication interventions. Certain individuals, however, with major depressive disorder do not respond effectively to conventional anti-depressant medications and they are deemed, then, to have "treatment-refractory major depressive disorder."

In my practice, I almost always start individuals on a lower dose of anti-depressant medication than typically recommended by the drug manufacturer and titrate up gradually to a therapeutic dose. With this approach, I find that patients are often better able to tolerate the initial side-effects and, consequently, stick with the medications. The major factor under an individual's control in determining whether an anti-depressant medication will work for him or not (apart from substance abuse) is taking the medication for an adequate period of time at a therapeutic dose.

Educating individuals about the delayed onset of therapeutic action of conventional anti-depressant medications sets their expectations at a place where they are, therefore, less likely to abandon the course of treatment for lack of immediate effect.

Difficulty of Weaning Off Anti-Depressant Medications

One other piece of information that I try to convey to my patients is that by making a decision to take an anti-depressant now, they may be unwittingly making a decision to be on an anti-depressant indefinitely. This situation is especially the case, I believe, with individuals with chronic or recurrent major depressive disorder, but it may also apply to individuals with other kinds of depressive disorders, including Dysthymic Disorder and Recurrent Brief Depressive Disorder (RBD).

Why this is the case is not entirely clear to me, but what I have observed in my practice, time and time again, is the conundrum of someone who has responded well to an anti-depressant medication, is in remission from depression and wants to get off medication either because of certain side-effects (usually weight gain or sexual side-effects of one kind or another) or for philosophical reasons (e.g. not liking the idea of being on a medication forever).

Normally, if someone in my practice is intent on getting off his medication, I recommend that he get off the medication as gradually as possible. If the individual is agreeable to such a slow weaning off process, I might recommend decreasing the dose of the anti-depressant by 20% to 30% of the therapeutic dose for that individual for 3-6 months before making another dose reduction. This strategy avoids the pitfall of acute anti-depressant withdrawal precipitating major mood or anxiety symptoms, as withdrawal-related mood and anxiety symptoms typically resolve after several weeks, at the longest, with this schedule of dose reduction. If, after 3-6 months, the individual is feeling no worse, then I might recommend reducing the dose by another 20% to 30% of the original therapeutic dose.

For many individuals with recurrent major depressive disorder or recurrent brief depressive disorder, somewhere along this weaning off process, they experience significant enough depressive symptoms that they no longer want to continue with the weaning off process. Often, they experience again what it was they were trying to get rid off in the first place and decide that they do not want to experience those symptoms again if they can help it. Sometimes, having relief from significant depression for the first time in their lives (due to the effect of anti-depressant medication) the contrast between feeling well and feeling depressed is magnified in their minds. Sometimes, in fact, it's the case that anti-depressant medications bring individuals with depression to a place they have never been to before, in terms of stability of mood, emotional resilience and overall functioning.

So, one idea of why individuals have a hard time getting off anti-depressant medications, if they have responded to them well, is that they come to appreciate just how much of a difference the medication makes in their lives, in terms of preventing depressive symptoms, improving emotional resilience and overall functioning.

Another idea is that when someone does respond well to anti-depressant medication and experiences a new level of being depression-free, he is able to take on more than he was able to previously. That's to say, he is able to take on additional responsibilities in his life (e.g. a romantic relationship, an increase in responsibilities at work, etc.) without those responsibilities overwhelming him and precipitating depression. Weaning off medication, then, having taken on these additional responsibilities, he is unable to cope with the stresses of these additional responsibilities and, depression follows.

A third idea is that being on anti-depressant medication for long periods of time sensitizes individuals to depression by some other mechanism (e.g. a neurobiological mechanism), so that when they try to wean off medication, depression almost certainly follows. Furthermore, the severity of the depression may be worse than anything they previously experienced, so that they are especially desperate to feel the kind of relief they experienced on anti-depressant medication again.

In any case, because I have observed this phenomenon (i.e. not being able to successfully wean off an anti-depressant) enough times in my practice, I make it a point nowadays to warn individuals of this distinct possibility when they make the decision to try an anti-depressant.

Loss of Efficacy of Anti-Depressant Medications

Anti-depressant medications can also lose efficacy over time. In other words, a dose of medication that is effective at keeping an individual with major depression symptom-free for a period of time no longer works (without there being any obvious change in the level of psychological stress in the individual's life). Sometimes, the length of time is as short as several months. Other times, anti-depressant medications can afford several years - or longer - of remission from major depressive symptoms.

Side-Effects of Anti-Depressant Medications

SSRI and SNRI medications produce characteristic side-effects early on and later in the course of treatment. Usually, the "early" side-effects of these medications subside over a period of several weeks to a month or so. Not everyone experiences each of the typical side-effects, but most people will feel some side-effects from these medications early on. Later, however, it usually feels to them that they are taking a sugar pill, in the sense that they do not appreciate any immediate or moment-to-moment side-effects associated with the medication (e.g. dry mouth, sedation, dizziness/lightheadedness, etc.). Their bodies seem to acclimate to the early side-effects, in other words.

Because SSRI medications are the most widely prescribed anti-depressants currently, the discussion that follows is limited to this class of medication. I normally provide my patients with the following information:

1. That it is very common to experience some side-effects early in the course of treatment, but that most of those side-effects will subside gradually over the course of 1-3 weeks
2. That the early side-effects will likely re-emerge if/when we make a dose increase
3. That late side-effects such as weight gain, emotional numbness or apathy, decreased libido and increased sleep need can occur with all of these medications

The early side-effects with these medications include:

1. A sense of dizziness or lightheadedness or some kind of funny feeling in the head
2. Headaches, particularly if someone is already vulnerable to headaches (e.g. pre-existing migraine disorder)
3. Appetite suppression with Prozac
4. Possible appetite increase with the others, including increased craving for carbohydrates (this side-effect may also appear only later in the course of treatment)
5. Sleep disturbance (usually insomnia with Prozac, but either insomnia or hypersomnia with the others)
6. Gastro-intestinal side-effects (bloating, gas, loose stools, nausea, sometimes frank diarrhea)
7. Sensory changes (e.g. feeling cold all of a sudden, for no reason, or tingling/warm sensations all over the body)
8. Increased yawning
9. Sedation (less so with Prozac, usually)
10. Sexual side-effects (inability to have an erection or get aroused, delayed orgasm, decreased sensitivity, inability to have orgasm)
11. Increased perspiration, sometimes, including "night sweats"
12. Vivid dreaming, including nightmares, sometimes

These anti-depressants can also sometimes precipitate worsening anxiety states in certain individuals (e.g. panic attacks).

More concerning side-effects that are generally infrequent include:

1. Akathisia, a sense of subjective restlessness, such that one feels the need to rock in a chair or pace about. This side-effect can be so uncomfortable sometimes that people feel as though they want to crawl out of their skin or die. Patients should generally call their psychiatrists right away if they experience this side-effect.
2. Precipitation of hypomania or mania. These are altered, "elevated" mood states that are usually seen in individuals with a bipolar spectrum mood disorder.
3. Serotonin syndrome, a potentially fatal cluster of symptoms that typically develops in the context of being on two different medications that modulate serotonin transmission in the brain (e.g. Demerol with Prozac). Symptoms can include waxing and waning level of consciousness, confusion, agitation, high temperature, and autonomic instability (rapid changes in blood pressure and pulse).

For most individuals, the early side-effects of SSRI medications will "disappear" after a few weeks and the medications are generally very well-tolerated.

Later in the course of treatment with SSRI anti-depressants, a number of phenomena can emerge:

1. Decreased overall libido, sometimes with ongoing sexual dysfunction (e.g. delayed orgasm or inability to have orgasm)
2. Weight gain (least liability with Prozac, generally speaking, and most with Paxil)
3. Emotional numbness, possibly
4. Sometimes an apathy syndrome (a feeling that nothing matters much in life, without being particularly depressed)
5. Increased sleep need (e.g. going from needing 6-8 hours of sleep per night to feel rested, to needing 8-10 hours per night)

As it turns out, some individual are exquisitely sensitive to the side-effects of these medications (either because they have a particular neurochemistry or because they are slow metabolizers of the medication or for some other reason). And other individuals feel virtually no side-effects.

Known and Potential Benefits of Anti-Depressant Medications

The known benefits of anti-depressant medications are reduction of depressive and anxious symptoms, including control of panic attacks, obsessions, compulsions, and obsessive ruminations. These benefits, in turn, usually improve the quality of an individual's life - sometimes considerably. Whether these medications can, by some mechanism, decrease overall mortality (i.e. prolong survival) in individuals with major depressive disorder remains unknown, though it seems reasonable to speculate that they might decrease overall, cumulative suicide risk. (Incidentally, in younger individuals, such as teenagers and young adults less than 24 years of age, these medications can increase suicidal thoughts and gestures on rare occasions; there has been tremendous controversy about this phenomenon, but I tend to believe that it is a real phenomenon).

Recently, a lot has been made about the association between major depressive disorder and coronary artery disease ("heart disease"). Individuals with coronary artery disease and major depressive disorder fair worse, for example, in terms of negative cardiac "events", than individuals with coronary artery disease without co-occurring major depressive disorder. So far, however, prospective data that suggest that treatment of major depressive disorder in these individuals alters the natural course of their coronary artery disease do not exist. Nevertheless, it is an exciting possibility. Certainly, the evidence seems to suggest that the physiology of major depressive disorder interacts, somehow, with the physiology of heart disease. Theoretically speaking, therefore, it's possible that treatment of major depressive disorder with conventional anti-depressant medications may improve overall mortality (i.e. prolong survival) in an individual on the basis of improved cardiac status, by "reversing" - or somehow mitigating - the physiology of major depressive disorder.

Other Risks Associated with Anti-Depressant Medications

Some known risks of SSRI anti-depressant medications include (apart from all the side-effects mentioned previously):

1. Increased risk for gastrointestinal bleeding in older adults who use non-steroidal anti-inflammatory medications (e.g. ibuprofen)
2. Possible decrease in bone density and increased risk for fractures in elderly individuals
3. A protracted withdrawal syndrome in very rare cases (e.g. vertigo lasting for 6 months to a year after stopping the medication)
4. Weight gain, and consequently, possible increase in risk of conditions associated with weight gain (e.g. lipid abnormalities, increased risk for diabetes, etc.)

So far, there are no data in humans to suggest that these medications increase the risk for cancers or neurodegenerative conditions (e.g. dementias). At the same time, however, these medications have only been available since 1986, when Prozac, the oldest SSRI, was first introduced to the commercial market. Their chronic administration in individuals has been a relatively recent phenomenon, therefore, and we are only at the early stages of understanding what the true, long-term risks associated with these medications are. It may turn out that they produce some ill effects or complications that can only be detected at the population level after they have been used for several more decades.

Hence, it's important for psychiatrists to periodically survey the professional literature about the risks and benefits associated with these medications and have access to up-to-date medical information.

Anti-Depressant Withdrawal Syndromes

Another risk that is associated with commonly-prescribed, conventional anti-depressant medications is anti-depressant withdrawal. As it turns out, a number of these medications can produce withdrawal symptoms after they have been used by an individual for a period of time. These withdrawal symptoms have been best characterized for SSRI and SNRI medications, but they can also occur with older medications, including the tricyclic anti-depressants and monoamine oxidase inhibitors.

Characteristics of SSRI and SNRI withdrawal include:

1. increased emotionality and emotional sensitivity
2. increased anxiety, including panic symptoms
3. increased depression, sometimes with suicidal ideation
4. physical symptoms, including nausea, vertigo, lightheadedness, headaches
5. "brain zap", described by many as an electrical sensation zapping in one's head (not necessarily painful, but uncomfortable, nevertheless)
6. fatigue and flu-like symptoms (runny nose, aches/pains)

The potential for a withdrawal syndrome among commonly-prescribed conventional anti-depressants seems to be highest for venlafaxine (Effexor) and paroxetine (Paxil). The potential to cause significant withdrawal symptoms may be related to the biological half-life of the medication and rate of clearance. Fluoxetine (Prozac), and norfluoxetine, a breakdown product and active metabolite of fluoxetine, have much longer half-lives than all the other medications in these classes and they rarely cause withdrawal symptoms. In fact, fluoxetine can be used to help manage the withdrawal symptoms associated with shorter half-life SSRI and SNRI medications.

The risk of withdrawal seems to be mitigated somewhat by a very gradual weaning off process. Even so, with paroxetine and venlafaxine, in particular, withdrawal symptoms can be present and these medications can be very difficult to get off, due to withdrawal.

For this reason, in my practice, I rarely prescribe paroxetine or venlafaxine as first-line medications for treatment of depression and anxiety disorders. The issue is not that they are not effective (sometimes, in fact, they may be particularly effective for certain individuals), but that they can be incredibly difficult to wean off. Nevertheless, I believe that they have their place in the armamentarium of medications used to treat depressive and anxiety disorders and not everyone taking these two medications will have a difficult time weaning off.

Mechanism of Action of Anti-Depressant Medication

Many patients express a desire to know how these medications work in their bodies. What I usually tell my patients is that we know certain facts about how these medications work in the brain, but that we probably don't understand nearly as much as we need to, in order to paint a complete picture of how they treat major depressive disorder and the physiology associated with this condition.

Both classes of medications (the SSRIs and SNRIs) bind to certain neurotransmitter receptors, which are expressed in differing concentrations in different regions of the brain. The SSRIs bind primarily to the serotonin transporter, blocking its action and thereby, increasing concentrations of serotonin in the spaces (synapses) between adjacent neurons. The SNRIs bind selectively to both the serotonin transporter and the norepinephrine transporter, increasing synaptic concentrations of both serotonin and norepinephrine. Effectively, then, the early physiological events in anti-depressant action include rises in the concentration of serotonin, alone, or serotonin and norepinephrine at synapses. What happens after this initial event is the subject of ongoing research and too complicated to delve into here.

Nevertheless, we do know now some important changes that happen later in the course of anti-depressant treatment. Recent research suggests that SSRI medications, for example, promote nerve cell (neuron) regeneration in a part of the brain called the hippocampus, an area that is important to both memory and mood regulation. This research also suggests that this step is crucial in the treatment of depression in an animal model, because blocking this step of neuronal regeneration with a specific agent prevents the SSRI from exerting its typical anti-depressant effect.

Researchers speculate that the stress response cascade may, over time, result in the death of certain neurons in the hippocampus, thereby producing the symptoms of depression. Administration of SSRI anti-depressants may, therefore, result in a reversal of this process.