Antidepressant Medications


Hello and welcome
to lecture number 12 in our continuing series on
drugs and human behavior. Today we’re going to talk about
antidepressant medications. I want to preface this
discussion with the caveat that I think it’s really
important to carefully evaluate, whether or not these
medications are for a patient or for yourself or
for a family member, they’re certainly not
without controversy and they’re certainly
not without side effects. That being, said depression
is something that is treatable and early intervention
oftentimes appears to be an important
part of limited treatment. These drugs are not,
I don’t think, meant to be taken for lifetimes. They should be taken for
brief periods of time and then stepped off under the
supervision of a physician. Their benefits, or
potential benefits, really are related to
the ways in which they affect and can mitigate the
effects of stress on the brain. And that’s one of the biggest
problems with depression, as it seems to oftentimes
be triggered by stress. And so if someone’s going
through a high stress time period, it’s potentially
a reasonable medication to add to try to buffer
the effects of that stress. Research still needs to be
continued in these areas, and, again, I think it’s
something– everyone should consider what’s the best
option for themselves and their loved ones and not
simply take pills because they seem to be the magic answer. I think these are things to be
considered and thought about. So what we’re going to talk
about today is talk about sort of what the hope for
antidepressant drugs, or the claims about their
use, are and then we’ll introduce depression, talk
about the pathophysiology of depression, do a
quick introduction to the types of
antidepressants we’re going to be talking about. Then we’ll break it down to
sort of three different classes, the early antidepressant
medications, which include the tricyclics,
the monoamine oxidase inhibitors and what are
called atypical antidepressant medications. Talk about selective
serotonin reuptake inhibitors, which is the primary class
of antidepressant treatment currently. And then talk about some
dual action antidepressants, some of which work for
depression, some of which work for other
things, but all fall into the selective
serotonin reuptake inhibitor or norepinephrine
reuptake inhibitor category. Finally, summarize
some of the efficacy of antidepressant medications
and talk a little bit about what’s in
store for the future. So here’s what
antidepressant drugs we hope do, is, first of all,
to alleviate the signs, symptoms, and
distress associated with clinical depression. So not just the sadness,
but the anxiety, even pain can be
involved in depression. So it’s a pretty difficult
thing to live with. Certainly plenty of people
are at risk for depression. Women seem to be at greater
risk for depression, but certainly men are at
risk for depression as well. Obviously, the ultimate
problem with depression is it could lead to suicide. Men are far more likely to
successfully commit suicide and are at the
greatest risk for that. And it’s certainly
an area where we need to be paying more attention. The number of US veterans
committing suicide every year is beyond epidemic proportions. So we need to
start to understand how to treat depression
and how to prevent it in the first place. So antidepressant drugs are
to alleviate depression, but also to relieve anxiety,
either as a single diagnosis or as part of comorbid
anxiety depression situation, to try to improve
the lives of persons with debilitating depression and
to repair the neuronal damage associated with depression. And that’s one of the things
we’re going to talk quite a bit about and I think,
for me, that’s one of the benefits
of some of these drugs is they have the potential
to try to stave off some of the damage caused by
depression and by high periods of stress. So here’s the biggest
thing about depression is these drugs are
effective for some people, but mostly for
severe depression. These drugs are not for the
mildly sad, slightly depressed. They’re probably not going
to help those people. But some exercise, some
cognitive behavioral therapy is probably really best
for that class of people. These drugs are for
the severely depressed. So if you look at the blue
circles in this graph, and you can see the blue line. The HDRS score is a
depression inventory. The vertical axis is showing
how much they’ve changed and how much they’ve improved. What you can see
is for those that have an HDRS score
above 25, there’s pretty marked improvement with
these drugs for the most part. Obviously, not all of
them, but certainly, we start to see a pretty great
separation between placebo and the antidepressants
at that point. So it starts to separate
out at the greater the level of depression. And so the higher the level
of depression, the more likely these drugs are to work. But these drugs are not
effective for somebody who has a mild case of depression. So what is depression? Well depression, or major
depressive disorder, is a chronic, recurring,
and potentially life threatening illness. 4.5% of the total
worldwide burden of disease in disability
adjusted life years is caused by depression. 70% of psychiatric
hospitalization and 40% of suicides
are depression related. This is a really severe disease. About 9% to 10% of
the US population suffers from
depression each year. 10% of men and
about 25% of women will experience depression
in their lifetime. And only about a
fifth of those cases are adequately
treated every year. So we’ve got to do more
to treat these cases, find out what the
best treatments are. And again, I want to
make it very clear, these drugs are potentially
useful for many people, but not everyone and there are certainly
alternatives available. So I think this is a
conversation to have, for sure. So what are the
characteristics of depression? It’s an affective disorder with
alterations of emotion or mood, substantial
decreases in interest in pleasurable activities
or am inability to even express pleasure. Oftentimes, sleep
difficulties, clear fatigue or loss of
energy, feelings of worthlessness
or excessive guilt and possible thoughts
of death or suicide. From the Diagnostic
and Statistical Manual of Mental Disorder,
the symptoms are as follows. You have to have five or more
of these symptoms present during the same two week
period and represent a change and at least one of the symptoms
is depressed mood or loss of interest or pleasure. So depressed mood most of
the day, nearly every day, as indicated by either
subjective report or other report, markedly
diminished interest or pleasure in all or most all of
activities, significant weight loss when not dieting
or significant weight gain, insomnia or
hypersomnia nearly every day, psychomotor agitation or
retardation nearly every day, fatigue or loss of energy
nearly everyday, feelings of worthlessness or
excessive or inappropriate guilt, diminished ability
to think or concentrate or indecisiveness
nearly every day, recurrent thoughts of death–
not just fear of dying, but thoughts of death–
recurrent suicidal ideation without a specific plan
or a suicide attempt or specific plan for
committing suicide. These symptoms must cause
clinically significant distress or impairment. And the episode is
not attributable to the physiological
effects of substance use or some other
medical condition. So these are the symptoms
associated with depression and you can see why they can
be incredibly disruptive– the loss of the
ability to concentrate, inability to sleep,
fatigue– all of these are associated with depression. One of the important things
to understand about depression is it’s also associated with
increased levels of cortisol. And cortisol is
a steroid hormone that is particularly
damaging to parts of the brain, particularly
the hippocampus and so we’re going to
talk about the potential for antidepressants
to help stave off the effects of that
increase in cortisol. We know that depression
is often caused by some sort of high or
sudden stress occurrence. So it’s oftentimes a trigger
for manic depressive disorder. So what is causing depression? That is, what is the underlying
pathophysiology of depression? Well the classic
theory of depression is simply that it’s a deficiency
involving neurotransmitters– in particular, serotonin,
norephinephrine, and or dopamine. And the idea was that
if we could restore to normal the mood
state by prolonging the presence of these
neurotransmitters in the synapse, we
can treat depression. So that was the idea, that
we could increase mood by increasing
neurotransmitter levels. The delay in clinical
antidepressant effect, according to this
classic theory, was due to changes in
receptor sensitivity, caused by chronic increase
of neurotransmitter synaptic levels. There has to be a change
in receptor sensitivity, according to this view. Well this is the classic theory. It’s just simply a disruption
of neurotransmission. But what we really
think is going on is a disruption in what’s
called neurogenesis. So this is the neurogenic
theory of depression. Existing neurons are able to
repair or remodel themselves and the brain is actually
capable of making new neurons. We call this
neurogenesis and this is a brand new– within
the last 10 or 15 years– discovery about the brain. So a variety of
stimuli can actually damage neurons and
decrease neurogenesis– in particular, stress
damages hippocampal neurons. We also know that
several factors are known to repair neurons
and increase neurogenesis. Among them are
antidepressant drugs. And so the idea is that
antidepressants aren’t there to just increase
neurotransmitter levels, but actually to help repair
and increase neurogenesis and so actually get the brain
functioning better once again. So there’s been some attempt to
identify the cellular processes in the hippocampus
and the frontal cortex that are responsible for
the protective effects of antidepressants. So this is a major focus
of research in this area. One of these areas
is looking at what’s called cyclic AMP
response-element-binding protein, or CREB, which
unfortunately has nothing to do with Krebs cycle,
but it is the cyclic AMP response-element-binding
protein. This activates
genes that control the production of
protein, called brain-derived neurotrophic
factor, or BDNF. BDNF is an important factor
the has been recently talked about in a variety of
areas about its role in important normal
health and development of the nervous system. So you’ll probably hear a lot
about BDNF in other classes. So the critical
importance of BDNF is it prevents neuronal
death and protects neurons. We know that chronic
stress can reduce brain-derived
neurotrophic factor. The blood levels of BDNF are
lower in depressed patients. And so by trying to solve
this piece of the puzzle, we think we can
actually stave off some of the damage caused
by chronic depression. So here’s the basic idea. Stress, injury, or
illness may cause loss of neurons and some
reduction in neurogenesis. So this can be due to
death of a loved one, loss of a job, other
significant stress, even birth of a child,
marriage, all sorts of things can cause this kind of
stress, or even just some sort of injury, head
injury, traumatic brain injury. So antidepressants then increase
brain-derived neurotrophin factor, decrease those
glucocorticoids that are responsible for part
of that stress response, and then they increase
neurogenesis and neuronal survival. So that’s part of the puzzle. An open question is
what are the genetic and what we call epigenetic
factors in depression? So somebody’s
underlying genetics, there certainly is heritability
components of depression. And then the epigenetic
factors are, you know, has stress or substance
abuse or brain injury cause some alteration in
the genetic expression which then results in
depression or results in neuronal injury or death. Are some people more
resilient to these effects? Are they less resilient? Are they more susceptible? What are the genetic factors? And these are some really
important questions that hopefully we’ll have
the answer to sometime soon. So here’s the basic idea. Depression is a consequence
of some sort of stress event. Stress damages the brain and
weakens its ability to recover. Antidepressants then
relieve depressed mood by acting at the cellular level
to promote neuronal survival and reverse stress
induced neuronal damage. The immediate effects
of depressants is to modulate neurotransmitter
synaptic levels, but the ultimate targets
are intracellular molecules, responsible for maintenance of
neuronal health and plasticity. So the idea is to
help repair the brain. So what are these
antidepressants? Well, the tricyclic
antidepressants are so named simply because
of their chemical structure. We’ve talked about
this previously, but often the old school
way of talking about drugs was by talking about
their molecular formulas. Monoamine oxidase inhibitors
inhibit the enzyme monoamine oxidase, thereby
increasing the levels of dopamine and serotonin
in the synaptic cleft. The atypical
antidepressants, which would probably most of them
now be called dual action antidepressants. The SSRIs, or the selective
serotonin reuptake inhibitors, do exactly what they describe. They block the
reuptake of serotonin into the presynaptic neuron. Then there are dual
action antidepressants. Those primarily affect
norepinephrine and serotonin and then those that simply
affect norepinephrine reuptake inhibitors. And so these are the
different classes of drugs that we are
going to talk about. The tricyclic antidepressants–
so in this section, we’re going to talk about
the tricyclics, the MAOIs, and the atypicals
because they’re kind of an older class
of antidepressants that are prescribed far less, but
are still available and may be appropriate for some people–
almost certainly much cheaper than the
SSRIs– but they are associated with pretty
significant side effect profiles. So these tricyclics
are a class of drugs that all have this
characteristic three ring molecular core. Probably the most
well known of these is amitriptyline,
imipramine, and et cetera. These are all fairly similar
in their overall profile. The tricyclics cause two
pharmacologic actions that account for both their
therapeutic effects and most of their side effects. So they act by blocking the
presynaptic norepinephrine and serotonin reuptake
transporter proteins. So this is their
mechanism of action. This is what provides
their beneficial effects. Unfortunately, they also block
the histamine and acetylcholine receptors, which is responsible
for most of their side effects. So we get sedation and cognitive
dysfunction that might occur. The anticholinergic
actions in these drugs can be somewhere
between bothersome and incredibly toxic. The nortriptyline and
desipramine seem to be best. They seem to have the
least anticholinergic and antihistaminic properties. All tricyclic
antidepressants have three significant
clinical limitations. They have very slow
onset of action. They have significant
side effects and in overdose,
they are cardiotoxic and potentially fatal. And so providing
somebody who’s depressed with a drug that can
kill them– probably not the best course of action. Now if this is a drug
that they respond well to and they can be
trusted with them and the side effects
aren’t too bad, it’s certainly something
to think about. So some of the side effects of
these tricyclic antidepressants occur because they’re
anticholinergic and antihistaminic and
a little bit from their antiadrenergic actions. So there are certainly
cognitive and memory effects. That’s the
anticholinergic effects, the neurological effects,
cardiovascular effects, gastrointestinal effects,
sexual side effects, endocrine effects, allergic
reactions, et cetera. So what to conclude
about the tricyclics? They’re no more
efficacious than SSRIs. The potential side
effects and toxicity are certainly much greater
than SSRIs and SSRIs have a higher rate of patient
comfort and compliance. MAOIs, or monoamine oxidase
inhibitors– monoamine oxidase is an enzyme that
regulates the amount of monoamine neurotransmitters,
norepinephrine, dopamine, and serotonin in
the body and brain. Three classic MAOIs were
developed in the mid 1950s. Their use is limited by
potentially fatal interactions when taken with certain
foods and medicines. You probably all looked at
cough medicine or almost any over the counter
drug and it says do not take if you’re taking
monoamine oxidase inhibitors. So any drugs that are
adrenaline-like that might be found in a nasal spray
or anti-asthma medications or cold medicines are
potentially fatal and any foods that contain tyramine
are also potentially fatal in combination
with monoamine oxidase. Despite all that, interest
in MAOIs has remained strong. They can be as safe as SSRIs. They can work in many
patients who respond poorly to either tricyclics or
SSRIs, so they are potentially a good choice for some people. They’re particularly
effective drugs for the treatment of a
wide range of depression. So people who are
non-responders to SSRIs, these might be a good choice. The atypical
antidepressants include maprotoline and amoxapine–
the maprotoline– sorry– offers few therapeutic
advantages, can cause seizures and can be fatal in overdose. The amoxapine may produce
parkinsonian-like effects as a result of postsynaptic
dopamine receptor blockade. Not generally a first
choice and overdose can certainly be fatal. The other atypical
antidepressants I want to talk briefly about
are trazodone, clomipramine, and buproprion. Buproprion is used quite
a bit in our modern times. So trazodone is as
efficacious as the tricyclics. It has a unique mechanism. Unfortunately, it can cause
drowsiness and priapism, which is an erection that
lasts for more than four hours. It is less anticholinergic
and therefore causes less cognitive dysfunction. A new formulation
was approved in 2010 for treatment of major
depressive disorder in adults. The daytime sedation is
sometimes problematic, so it can be taken at night. Clomipramine is a tricyclic
antidepressant treatment that inhibits mainly
serotonin reuptake with some norepinephrine
potentiating effects. It’s classically indicated for
obsessive compulsive disorder and seems to be equal to
tricyclics, but again, limited by its side effects. Buproprion, which is
Welbutrin or Zyban, primarily effects the
dopamine reuptake inhibition. It certainly affects the
dopamine transporter. It has an anti-craving
action, so that’s good. It has been tried for
treatment for people who are quitting some
drugs like cocaine and it’s certainly
been approved for use for people who are
trying to quit smoking, which is what Zyban is for. It can cause anxiety,
restlessness, tremor, and insomnia. It’s used to treat depression,
attention deficit hyperactivity disorder, nicotine dependency. Unfortunately, it can
cause anxiety and seizures, but it can potentially
improve sexual function and it’s certainly not
effective for panic disorder. So next we’ll spend
some time talking about the selective serotonin
reuptake inhibitors. This is the class of
antidepressant drugs that are primarily used
at this particular time. These are all potent blockers
of the presynaptic transporter for serotonin reuptake. So they block
reuptake or inhibit the reuptake of serotonin. The degree of
blocking of reuptake for other neurotransmitters
varies greatly. These include fluoxetine,
sertraline, paroxetine, fluvoxamine, citalopram,
escitalopram. So these are all
selective serotonin number reuptake inhibitors. We’ll talk about
these individually. Prozac’s obviously the oldest
and most commonly prescribed. Paxil is often
used for treatment of generalized anxiety
disorder and panic disorder and has a pretty significant
affective blunting effect in some people. And then citalopram
and escitalopram seem to be sort of the
newer go to antidepressants in this class. There are two newer SSRIs
that are kind of too new to discuss in great detail. Vilazodone has a dual
serotonin action, doesn’t appear to have
any therapeutic advantages over other agents. Vortioxetine is a multimodal
antidepressant, which inhibits serotonin reuptake,
is an agonist to serotonin-1A, a partial agonist
to serotonin-1B and an antagonist to
5-HT3, 1D, and 7 receptors. So keep an eye out for those. They may demonstrate
some efficacy. One of the big
problems with SSRIs is they inhibit some of the
cytochrome P450 enzymes. So we get this
enzyme inhibition. So it’s an important
clinical consideration for people who are taking
other medications, things like other cytochrome
P inhibitors, hydrocodone, or birth control. All these drugs can
have some effects on– some of these drugs
can have some effects on those other
drugs so you always want to check and see what
kind of drug interactions there might be. In particular, fluoxetine, seems
to have the most significant cytochrome P inhibition
effects as does fluvoxamine. Citalopram and escitalopram
have very few cytochrome P enzyme inhibition or very little
cytochrome P enzyme inhibition. In particular, you can see
that cytochrome P450 2DG is the most
significantly affected by this class of
drugs, which is also the enzyme which is necessary
for converting hydrocodone into codine. The clinical differences
amongst these individual SSRIs appear to be minimal. They appear to be about
as equally effective and are about as effective
as older antidepressants. Importantly, SSRIs are
not fatal in overdose. There are some concerns
with SSRI therapy, which include plenty of people
who are treatment resistant and the potential for what’s
called serotonin syndrome. Potential side effects
of all these drugs include sedation, some apathy,
some sleep disturbance, possible cognitive impairment,
physiological symptoms, possible weight gain, some
have sexual side effects including inability to obtain
an erection or an inability to orgasm– which doesn’t seem
to help anyone’s depression. Some people report
it as a benefit, that is that delayed
orgasm seems to be somewhat of a benefit for some people. So keep in mind that that’s
potential side effects. People who are at risk for
bipolar disorder, these may trigger manic episodes. And certainly drugs like Paxil
have significant withdrawal effects. All these drugs contain
a black box warning about the potential
for suicidal ideation in children and
adolescents, on which we will talk about
in more detail when we get to talking about
adolescence psychopharmacology. Quick warning about serotonin
syndrome– high doses or combinations of drugs can
produce exaggerated responses to these drugs. These include altered
cognition, which can include disorientation,
confusion, hypomania, delusions, sort of
feelings of losing it, some behavioral
alterations, including agitation and restlessness,
some autonomic symptoms, including fever, chills,
sweat, diarrhea, hypertension, and tachycardia, some
neuromuscular impairment, including ataxia
and hyperreflexia. And this usually can resolve
within 24 to 48 hours, provided that they reduce whatever
amount of drug they’ve taken. One problem with
taking these drugs is they’re associated
with what’s called serotonin
discontinuation syndrome. There are six core somatic
sets of the symptoms that the acronym FINISH
will help you remember. They include flu-like symptoms,
fatigue, lethargy, myalgias, chills, and headache, insomnia,
gastrointestinal symptoms, including vomiting and diarrhea,
potential imbalance, so dizziness, vertigo, ataxia,
sensory disturbances, sensation of electrical shocks
in the arms, leg, or head, and hyperarousal,
so anxiety or agitation. I can tell you, I was
out of my antidepressant. I take escitalopram, or Lexapro,
and ran out at some point and I can tell you, the
flu-like symptoms and imbalance, all of that really
are problematic. And once I got back on them,
it resolved that issue. So I’m hoping to
eventually step off them. You have to step off these
drugs slowly or just simply power through the serotonin
discontinuation syndrome. So SSRIs and suicide– here’s
where we get some question about whether or not they
improve or don’t improve risk for suicide. You certainly get
reductions in the thoughts of death, which are an
important part of reducing risk for suicide. You see there isn’t much
reduction in suicidal ideation. I mean, there’s a little bit. And there is just
simply not much room to move the needle on
attempts or completion. It’s the same thing
with suicidal ideation. It reduces from
about 4% down to 0%, so that’s a significant
improvement, but without treatment, it gets
it almost to zero as well. So it probably
depends, of course, on the level of
depression, et cetera. But at least reducing
those thoughts of death seemed to be an
important part of this. So let’s take a look
at some specific SSRIs. Prozac, or fluoxetine, is the
first SSRI-type antidepressant and the first non-tricyclic
antidepressant that’s considered a first
line antidepressant. Has similar efficacies
to tricyclics and is often the first
to be prescribed. In fact, oftentimes,
insurance companies insist that it’s the
first to be prescribed. It has a two to
three day half life, but it has an active
metabolite that has a half life of six to 10 days. So it takes almost three
months to reach steady state. So this is one of the biggest
problems with this class of drugs, is it takes so long
to get the point that you’re taking in as much as
you’re putting back out. And so you oftentimes have to
stay on these drugs for quite a while to determine whether
or not they’re effective, which can be problematic. Side effects include serotonin
syndrome, anxiety, insomnia, and sexual dysfunction–
particularly, inability to obtain an erection. Sertraline, or Zoloft– it’s
four to five times more potent and selective than Prozac. Reaches steady state much
quicker, four to seven days, is shorter acting and
less– has a shorter acting and less active metabolite. Appears to be effective in
treating depression, dysthymia, and some anxiety disorders. It’s reportedly effective
in comorbid PTSD and alcohol dependence and has
few anticholinergic, antihistaminic, and adverse
cardiovascular effects as well as low risk of
toxicity and overdose. A pretty good
choice for those who are having a pretty
severe depression. This is a pretty
safe drug for them. Paroxetine, or Paxil–
personally, this is one of those drugs that
I think works very well for people who have very
disruptive anxiety disorders, but it would not be my first
choice for major depression because it does seem to have
some serious affective blunting in some people. So it’s FDA approved
for treating depression, obsessive compulsive
disorder, and panic disorder. It should not be used
during pregnancy at all. It seems to be more
selective than Prozac and, again, has about
a 24 hour half life. Fluvoxamine is a
derivative of fluoxetine. It’s available for treatment of
obsessive compulsive disorder. Appears to be an
effective antidepressant, but again, appears to be best
in OCD, PTSD, panic disorder, social anxiety disorder. These are off-label uses, but
they are used in those areas. Citalopram, or Celexa, it’s been
available in the US since 1998, used for treating major
depressive disorder, social phobia, obsessive
compulsive disorder, and panic disorder. Has about a 33 hour
half life, which is much longer in the elderly. Same effects as all
other SSRIs, but does not include the drug interactions
because it does not inhibit the hepatic
drug-metabolizing enzymes. So this may be an
important consideration for people who
are on other drugs that you don’t want to
have interactions with. Escitalopram, or Lexapro–
this is an active isomer of citalopram. It’s twice as potent, so
you can use half the dose. Seems to be equivalent
in treating panic attacks in the elderly, but again,
careful with prescriptions for in the elderly because
of that extended half life. The dual action
antidepressants expand actions at two
different synaptic sites to improve or maintain efficacy
while limiting side effects. Nefazodone has been withdrawn,
so we won’t talk about it. Milnacipran, venlafaxine,
duloxetine, and mirtazapine are drugs that are
currently available. So let’s start with
talking about milnacipran. It blocks norepinephrine
and serotonin reuptake, blocks the NDMA-type glutamate
receptors in the spinal cord, contributing to its
analgesic action. So it is approved
only for that use. The FDA has approved this drug
for treatment of fibromyalgia, but not as an antidepressant. So it is primarily
for chronic pain. Effexor is a mixed
serotonin-norepinephrine 5-HT and norepinephrine
reuptake inhibitor. It’s not anticholinergic
or antihistaminic, has little to no cognitive
dysfunction or sedation, but can cause increase
in blood pressure. And there is a
longer acting version of this for treatment of
generalized anxiety disorder. Pristiq was approved in
2008 for the treatment of major depressive disorder
has an 11 our half life. There was some attempt to get
this approved for treatment of hot flashes in postmenopausal
women, but that was refused. Cymbalta appears to reduce
both depression and anxiety. Also seems to work well to
reduce the physical symptoms of pain, back ache, joint and
muscle pain, back and shoulder pain– particularly those
associated with depression. Depression does– it has like
an achey component to it. There is potential
for this to be used for pain and depression
that occur comorbidly and can be used for generalized
anxiety disorder and has a half life
of about 12 hours. Fortunately, weight gain, sexual
dysfunction, and hypertension have not been reported
as major problems with this particular drug. Remeron increases norepinephrine
and 5-HT transition via a complicated
presynaptic mechanism, causes a pretty high
histamine blockade, so it’s highly sedative. Keep in mind, when we talk
about histamine blockades, Benadryl is primarily
histamine blocker. If you think about what
Benadryl’s like to take, it makes you very
sleepy and that’s what these drugs are like. So just keep that in mind. This drug has been associated
with increases in appetite and body weight and has
pretty long half life of about 20 to 40 hours. Strattera is a drug we’ll talk
about when we talk about ADHD. It is a norepinephrine
reuptake inhibitor. It’s used for ADHD in
children and adults, has been used as an
adjunct in fibromyalgia, appears to be antidepressant
and analgesic, and has shown to be
effective in PTSD. Primarily, it’s used for
ADHD and comorbid depression. So how good are antidepressants? That is, how efficacious
are they really? Well there’s a very large
study called the STAR D study. The goal was to determine the
effectiveness of depression treatment for major
depressive disorder in primary and specialty
treatment centers. Talking about 3,000
participants at 41 clinics. About two thirds of
participants were able to achieve
remission if they did not withdraw from the study. Unfortunately, the dropout
rates were between 21% and 42%. So you have to consider
that the people who remained in the
study are probably the ones who were
getting the most out of these antidepressants. So while we’re talking
about a two thirds reduction in depression for
those that stayed in, keep in mind 20% to 40% of the
original group dropped out. So we’re probably talking about
50% efficacy rate, somewhere in there. Overall there didn’t
appear to be any that was any superior to others. One the biggest problems in
conducting studies on these is there a very large
placebo effects. We talked about this previously,
about how to design studies and one of things you have to
do is a placebo run in period. And what’s done in
those is you give people placebo for a first time period
and anybody who gets better is dropped from the
study because you know that they’re going to
respond only to placebo. And then you can actually get a
much better determination as to whether or not
antidepressants are effective by getting
the people who don’t respond to just the placebo. So where do we go from here? Well, we certainly need
to develop the genetics in this area. So can we use genetics
to help guide therapy? We certainly need more effective
medications with a reduced side effect burden. I think it’s really important to
be mindful of the side effects that these drugs can cause. These are not, again, not
drugs to be taken lightly. So you want to be very cautious
and think about whether or not these are for you. But again, I want to
also make it very clear, these can be very
effective for some people and certainly living with
depression is not the answer. So these are probably
better for some people than just simply
living through it. There are other alternative
treatments you can explore too, but no depression
should go untreated. I want to make that very clear. So what can genetic testing do? Well genetic testing might
be able to help us identify deficits in drug metabolism that
predict drug interactions that occur with many antidepressants. Recent interest has centered
on how genetic alterations may influence the clinical
response or a lack of response to these medications. There are plenty of people who
don’t respond at all to SSRIs and so we’re going to explore
some alternative treatments In the next set of discussions. So in the future, augmenting
agents might be used, so drugs like modafinil. It’s a nonstimulant
wakefulness-promoting drug used to combat daytime fatigue
in patients with narcolepsy. Also been shown to
improve working memory and fluid intelligence. Aromodafinil is a sort
of longer lasting isomer formulation of modafinil. Lamotrigine is an anticonvulsant
and mood stabilizer, which might help. Two atypical antipsychotics,
Abilify and Seroquel, have been demonstrated to
have antidepressant activity for, again, people who
are non-responsive. They are now approved by the
FDA for treatment of treatment resistant depression. So if you look at
placebo versus Abilify, the minimal or
non-responses came mostly in the placebo condition and
about twice as many people had a robust response to
Abilify as to placebo. And again, you start
getting increases in differences between placebo
and Abilify in the stronger responses. But again, you should also
notice that about 40% of people still did not
respond to Abilify. Ziprasidone, again,
over a period six weeks, seemed to improve
compared to placebo. There are some
natural substances that may have
antidepressant properties. Omega 3 fatty acids,
EPA, or DHA, all of these have potential
neurogenic effects. Certainly, DHA has been shown
to be an important component for neural development in kids. Folate– this is controversial
as a treatment for depression. SAM-e, its efficacy appears to
be similar to the tricyclics. St. John’s wort– careful
with St. John’s wort. Certainly, don’t
take if you’re going to take it with
other antidepressants and make sure you discuss
this with your doctor because it does have a
number of drug interactions and so be very
careful of this one. There are other options too. DHEA, or
dehydroepiandrosterone– we’re going to talk more
about that when we get to talking
about older adults, but this may be effective
in HIV-related depression. There are some studies
that demonstrate its potential efficacy for that. So what do we conclude? Well there is certainly need
for significant resources to come up with
better alternatives to investigate the genetic
and neurogenic issues in depression. Depression should
never go untreated. We just need to find
the best treatment. So we need to
certainly– we certainly need more funding in this area. The best research in
this area is always done by people who have no
skin in the game, as it were. So that is who have no
financial incentives. So this is where I
think it’s important that we get funding for
independent research. Again, there are many
nonpharmacological treatments for depression in use
and under investigation. These include things like
electroconvulsive therapy, transcranial
magnetic stimulation, electric cortical stimulation. So these are
potentially areas where we can have nonpharmacologic
interventions and these certainly
have demonstrated to be effective for people
who are non-responders. Certainly not something
to be done lightly, but a number of
people have talked about how these alternatives
have been life savers for them. So we’ll be discussing
that in our next series.