1. The title of this chapter derives from a book of the same title by
David Healy (1997). Healy points out the important but
overlooked fact that depression proper (what the DSM-5 calls
Major Depressive Disorder) [American Psychiatric Association
(APA), 2013] was basically unheard of as recently as 50 years
ago. For Healy, the antidepressant era unfolded against a
backdrop of battles within the psychiatric profession (people
endorsing the medical model perspective battling those
endorsing models emphasizing a psychological perspective),
regulatory agencies such as the Food and Drug Administration
(FDA), and the pharmaceutical industry. Antidepressant
medications are among the medications most advertised directly
to consumers and evidence is mounting that this does not in fact
increase consumer knowledge about depression and
antidepressants but rather increases misperceptions like the
discredited chemical imbalance theory of depression (Park,
2013).
This chapter is divided into seven sections. Section One
provides an overview of the current impact of antidepressants
and Major Depressive Disorder. Section Two describes early
theories of antidepressant action. Section Three covers the
neurotrophic/plasticity theory of antidepressant action and other
newer findings. Section Four begins coverage of the classes of
antidepressant medications with what are called first generation
antidepressants. Section Five is devoted to selective serotonin
reuptake inhibitors (second generation antidepressants). Section
Six covers third-generation antidepressants like bupriopion and
duloxetine and experimental drugs like ketamine. Section Seven
covers important psychological, cultural, and social
perspectives on anti-depressants including the concerns about
violent behavior being correlated with antidepressant therapy.
Learning Objectives

2. • Know what the point and lifetime prevalence of Major
Depressive Disorder is.
• Understand the conditions that are often comorbid with
depression.
• Be able to articulate sex differences in reported rates of
depression.
• Know what meta-analytic studies note as the overall efficacy
of antidepressants.
A television commercial features a grimacing young man with
his face against a wall. The commercial's narrator lists several
symptoms of fear and anxiety related to Social Anxiety Disorder
(previously Social Phobia in DSM-IV). The last scene in the
commercial shows the same young man smiling, rising from a
table in a crowded room apparently to receive acclaim for some
accomplishment. The ad ends by repeating the name of the
medication and informing the viewer, “Your life is waiting.” As
we noted in , there is vigorous debate as to whether such ads are
a valuable source of information or prey on the misconceptions
many people have about such drugs being “magic potions” to
change their lives.
At this writing, antidepressants are still one of the most
advertised and prescribed psychotropic medications. Over $11
billion is spent annually for antidepressants and it is estimated
that between 17 million (Ross, 2012) and 22 million Americans
(IMS Health, 2014) take them. In the late-20th century
prescriptions for antidepressants for children increased at an
exponential rate (Bostic, Wilens, Spencer, & Biederman, 1997)
despite scant evidence to support their use for children and
growing evidence that these drugs may exacerbate symptoms
such as suicidal ideation in child and adolescents. In 2003, the
FDA issued a public health advisory about the risk of
suicidality in children taking SSRI antidepressants, which led to
the “black box warning” on antidepressants. After this point
prescription rates for children and adolescents declined (Libby
et al., 2007). About 65% of antidepressants are prescribed for
depression and about 16% for anxiety disorders (Mark, 2010).

3. In the early part of the 21st century, meta-analytic studies began
suggesting that the efficacy of anti-depressants is about the
same as the placebo, in other words 50%. The efficacy increases
as the severity of depression in the subjects increases but there
does not seem to be any difference in efficacy between the
antidepressant drugs (Del Ra, Spielmans, Fluckiger, &
Wampold, 2013; Kirsch & Low, 2013). Some chalk this up to
methodological problems (Petkova, Tarpey, Huang, & Deng,
2012) but it is clear there is a strong placebo response in studies
on antidepressants that needs further exploration.
Antidepressants are used both on and off label for numerous
disorders. When antidepressant medications were introduced in
the mid-20th century, physicians primarily used them to treat
depression. Currently, antidepressants are used to treat a variety
of disorders, including a number of anxiety disorders, impulsive
aggression, and even chronic pain. Although antidepressants
may help people with a variety of depressive symptoms, most
studies on antidepressants examine their use in treating Major
Depressive Disorder as defined by DSM-5. Thus, before
discussing the history of antidepressants, let's review Major
Depressive Disorder proper.
The 12-month prevalence of MDD is approximately 7% with
significant differences across age groups. For example, the
prevalence in 18–29 year olds is three times higher than in
people 60 years or older. It seems that male children are more
prone to depression than female children but after puberty,
females have a 1.5–3 fold higher reported rate than males
(American Psychiatric Association, 2013).
MDD is diagnosed when a person meets five criteria from a list
of nine in DSM-5. Practitioners using the International
Classification of Diseases Mental and Behavioral Disorders
(WHO, 1992) can choose from specifiers of severity based on
the number of symptoms a client has. Symptoms in both
manuals include vegetative symptoms like increase or decrease
in ability to sleep, increased or decreased eating and weight

4. changes, decreased sex drive, difficulty concentrating, and
anhedonia (loss of pleasure in things the person used to enjoy).
The depressed person may also have inappropriate guilt,
recurrent thoughts of death, fatigue most of the day, and
feelings of worthlessness. It is important to note that we have
no clear understanding of why the antidepressant drugs covered
in this chapter would directly reduce the symptoms listed. There
are different theories but we have yet to understand why people
get depressed and, when medication helps them, why it helps
them. That said though, we know that the more vegetative
symptoms a client with depression has, the better candidate they
are for an antidepressant. We should note that it is important to
add that depression is also part of the symptom profile
in many disorders including Bipolar I Disorder, Bipolar II
Disorder, Persistent Depressive Disorder (previously Dysthymia
in DSM-IV ), Schizoaffective Disorder, Cyclothymia, and
Substance Use Disorders.
Depression and anxiety, two of the most common symptom
types seen by mental health professionals, are often comorbid
(occur together) in adults as well as children. This is so much
the case that the study groups for DSM-5 considered a Mixed
Anxiety and Depression diagnosis though it did not appear in
the final draft. This highlights the importance of an accurate
diagnosis, because a client may suffer from depression with
some secondary anxiety, anxiety with some secondary
depression, or from both an anxiety disorder as well as a mood
disorder. Even when a client's symptoms fall into one diagnostic
cluster at the time of intake, such a client may later show
symptoms outside that cluster. Diagnosis is a process that
continues throughout the therapeutic relationship and goes well
beyond the limited categories of the DSM. Although we focus
mainly on depression and antidepressants in this chapter and on
anxiety and anxiolytics in , these are rather artificial
distinctions we use for instructive purposes. Just as students
must learn the “laws” of Newtonian physics before they can

5. understand the exceptions to those laws that occur in particle
physics, they must also learn how classes of medications
evolved around diagnostic categories and how market and
clinical forces exploit the permeable nature of these classes. In
the next section, we discuss theories of antidepressant action
from the medical model perspective.
When an antidepressant “works,” what does that mean
and how does it work? The drug “working” usually means is
some but not all symptoms decrease or go into remission. How
the drug works is a harder question to answer. The simple
answer is “we don't know.” We have theories but we don't
know. It is interesting that when we were writing the first
edition of this book, published reports of antidepressant
efficacy estimated the drugs worked approximately 65%. This
figure came from analyzing published results; however, as
became known in the late 20th century, when pharmaceutical
companies started paying to have research done on their own
medications, they often retained the rights to all results and in
many cases chose to suppress unfavorable results and redesign
the study to increase the probability of favorable results
(Petersen, 2009). That was when the debate began about true
efficacy. Researchers began analyzing not just published studies
but all studies logged in the FDA database. Based on this initial
findings were that efficacy rates seemed closer to 50%
(Armstrong & Winstein, 2008). As noted, the debate on efficacy
is ongoing but there is a robust placebo response seen in
antidepressant studies that you do not see in studies treating
disorders like Schizophrenia. This may be because depression is
overdetermined, meaning there are many ways one could get
depressed (Ingersoll & Marquis, 2014) whereas Schizophrenia
(though we still don't know its etiology) seems more rooted in
the brain and nervous system.
Review Questions
• What are the point and lifetime prevalences for Major
Depressive Disorder?

6. • What conditions are most commonly comorbid with Major
Depressive Disorder?
• What are the sex differences in reported rates of depression?
• What do meta-analyses suggest the overall efficacy of
antidepressants to be?
Learning Objectives
• Be able to describe the amine, reuptake inhibition and
downregulation theories as they relate to antidepressant action.
• Understand how each of these theories built on its
predecessor.
• Understand the barriers and failed attempts at measuring
levels of neurotransmitters in the brain.
Researchers have sought to delineate profiles of clients with
depression, to gauge the degree to which a particular client's
depression is biological in nature. They have assumed that
clients with depression that was more biological in nature would
be better candidates for antidepressant medications, whereas
clients whose depression was more psychological in nature
would be better candidates for counseling or psychotherapy. As
Stahl (2000) concluded, however, “The search for any
biological markers of depression, let alone those that might be
predictive of antidepressant responsiveness, has been
disappointing” (p. 145). Today, the field of pharmacogenetics
aims to match antidepressant response to idiosyncrasies of
client's genomes but this research has just begun and it remains
to be seen if it will bear results that are applicable (Jones &
Perlis, 2006).
How do antidepressants work? Various theories from the
medical model perspective are proposed to explain
antidepressant action. Each tends to build on its predecessors.
In this sense, these theories actually demonstrate one of the
ideals of scientific method— new theories ideally are built on
older theories. However, although these theories do build on
one another, scientists still do not understand why
antidepressants alter mood. Perhaps Healy (2002) captured the

7. ultimate usefulness of theories when he stated, “[H]aving a
theory is scientifically useful primarily because having a theory
leads to action” (p. 118). In this case, the action depends on the
theory. From an integrative perspective, we will see that even
rigorous theories of how antidepressants work only correlate the
drug mechanisms of action with symptom relief. It must be
noted, however, that this correlation is not causation. In the
case of depression, many times the theories about
medications lead to diagnoses rather than the other way around.
This has been emphasized both by psychiatrists with knowledge
of pharmacology (such as Healy) and by laypeople such as
Elizabeth Wurtzel. In her memoir of suffering from depression,
Wurtzel (1994) commented that once she was prescribed Prozac,
she had a diagnosis. She wrote,
Rather than defining my disease as a way to lead us to
fluoxetine, the invention of this drug has brought us to my
disease. Which seems backward, but … this is a typical course
of events in psychiatry, that the discovery of a drug to treat,
say, schizophrenia, will tend to result in many more patients
being diagnosed as schizophrenics. This is strictly Marxian
psychopharmacology, where the material—or rather,
pharmaceutical—means determine the way an individual's case
history is interpreted. (p. 265)
The amine theory of depression began as the proposed by Ernst
Albert Zeller and his research team (Zeller, Barsky, Fouts,
Kirchheimer, Van Orden, 1952). Catecholamines are organic
compounds derived from the amino acid tyrosine and include
the neurotransmitters norepinephrine (NE), dopamine (DA), and
epinephrine (Epi). A broader chemical class is the amines that
are compounds derived from ammonia by replacing one or more
hydrogen atoms with organic groups. The neurotransmitters
serotonin (5-HT), DA, NE, Epi, and acetylcholine (Ach) are all
amines. Thus, as soon as researchers began to suspect serotonin
(5-HT) played a role in depression the catecholamine hypothesis
was made broader into the amine hypothesis.

8. The began with researchers observing the effects of
antidepressants on norepinephrine. Simply put, the amine
hypothesis proposed that people who suffered from depression
did not have enough amines, particularly NE, in their synapses,
and if you could increase the NE then they would not be
depressed. It was a parsimonious theory and, as with most
parsimonious theories, it did not address the complexity of the
situation. It is important to note though that researchers in the
mid-20th century can be forgiven for adhering to the overly
simple amine hypothesis because at that point all they knew
about the drugs was that they somehow increased amines.
The first step in the amine hypothesis is credited to Ernst Albert
Zeller (mentioned above) who was working as a biochemist at
Northwestern University in the 1950s. Zeller and his research
team had discovered that one function of the
enzyme monoamine oxidase (MAO) was to disable
neurotransmitters after they had been fired from the terminal
button (Zeller et al., 1952). This made sense because scientists
knew neurotransmitters did not just float in the synapse forever
and that the body must have a way to disable them. While
screening chemicals for this disabling ability, Zeller found that
iproniazid/Marsilid (the antitubercular drug Nathan Klein used
as an antidepressant) was a powerful inhibitor of MAO (thus the
name MAO inhibitor) (Snyder, 1996). Further research
confirmed that iproniazid/Marsilid, by disabling MAO, did
indeed raise NE levels in the synapse. In 1957, Udenfriend,
Weissback, and Bogdanski (1957) observed that
iproniazid/Marsilid also increased the release of serotonin (5-
HT) in the brain.
It is widely believed that scientists at the time used a drug
called reserpine/Serpalan to deplete the brain of amines and
cause an animal model of depression. The story is that
researchers gave both reserpine/Serpalan and
iproniazid/Marsilid to monkeys. First the reserpine/Serpalan
made them appear lethargic and fatigued (the animal model of
depression) and then the iproniazid/Marsilid led the monkeys to

9. become highly animated. This then led to the notion that
perhaps iproniazid/Marsilid was a (Snyder, 1996) or what the
reserpine research team called a “marsilizer” referring to the
trade name of the compound (Lopez-Munoz & Alamo, 2009).
This was found to be more speculation than fact on the part of
Nathan Klein (1970) who popularized the MAO Inhibitors for
their antidepressant properties (Baumeister, Hawkins, & Uzelac,
2003).
Researchers later discovered that reserpine/Serpalan did cause
both norepinephrine and serotonin to leak out of the synaptic
vesicles into the synaptic cleft, where MAO disables it. Thus,
disabling MAO greatly increases the newly leaked
norepinephrine and serotonin in the synaptic cleft, allowing
more binding to area receptors than does an undrugged state.
These discoveries (exaggerated though they seem to have been)
were the primary support for the amine theory. Historical
review of the reserpine/Serpalan studies revealed that in
actuality only a subset of patients developed depressive
symptoms while on reserpine/Serpalan (Akiskal & McKinney,
1973). Again, to clarify, the amine theory of depression was
that people who are depressed do not have enough amines (such
as norepinephrine) in the synapses between important neurons.
Drugs that increased the amines thus alleviated depression.
To this point, this first MAO inhibitor (iproniazid/Marsilid) had
only been used to treat tuberculosis. It was noticed that the drug
also had power to stimulate the CNS in patients being treated.
This was initially thought to be a side effect (Selikoff,
Robitzek, & Ornstein, 1952). This then led Jackson Smith
(1953) to try the drug on depressed patients. They noted
improvement in 2 of the 11 in the group and other studies
followed [it is thought that one of the later researchers, Max
Lurie, coined the term antidepressant (Lopez-Munoz & Alamo,
2009)]. Nathan Klein carried out the same procedures on
subjects and reported that 70% showed substantial improvement
(Loomer, Saudners, & Kline, 1958). Given that the response
rate in Smith's study was only 18%, it is curious that response

10. rates in Klein's studies rocketed to 70%. To date we are not
aware of any re-analysis of this early work. Be that as it may,
iproniazid/Marsilid, was on the map as an antidepressant.
Tricyclic antidepressants evolved in Europe through the work of
Roland Kuhn (1958) about the same time MAO inhibitors were
developing in the United States. Given the MAO research, Kuhn
and his colleagues thought tricyclics worked in the same way,
by disabling MAO or some related enzyme and increasing NE in
the synaptic cleft. The clinical actions of both drugs, after all,
were quite similar. This assumption soon ran into problems,
however, when researchers discovered that much of the MAO in
the nervous system exists inside the cells rather than in the
synaptic cleft. Also, all antidepressants seemed to have a time
lag of at least two weeks before they took effect. This didn't
make sense, because MAO began to inhibit iproniazid within
hours after the patient took the first dose.
As noted, the amine theory proved too parsimonious. For one
thing, the idea of depressed clients being deficient in a
neurotransmitter should correlate with lower levels of the
metabolite for the neurotransmitter they are supposed to be
lacking. Although some subjects in studies show this
correlation, others do not. Stahl (2000) noted that when the
metabolite for serotonin (5-HT) is low, it is more likely
correlated with impulsive behavior than with depression proper.
Plus, the amine theory did not explain why it took the
antidepressants four to six weeks to work.
The next researcher to make important discoveries in this area
was Arvid Carlsson who discovered how tricyclics blocked
reuptake of serotonin at the brain level (Carlsson, Fuxe, &
Ungerstedt, 1968). After this discovery, Izyaslav Lapin and
Gregory Oxenkrug (1969) postulated the serotonergic theory of
depression, similar to the amine theory only focusing on
serotonin rather than norepinephrine. In the 1950s, working at
the National Institutes of Health in Bethesda, Maryland, Julius
Axelrod discovered that with tricyclic antidepressants,

11. norepinephrine was increased in the synaptic cleft when the
drug inhibited the reuptake mechanism discovered by Carlsson.
The mechanism works like this: When norepinephrine is
released into the synaptic cleft, it has a period of time to bind to
receptors. After this period, it is either broken down by MAO or
a transporter molecule attaches to the NE neurotransmitter and
takes it back inside the cell that released it in the first place,
where enzymes store it in synaptic vesicles so it can be released
again. In this way, the transporter molecule provides something
like a recycling service.
Other researchers have identified a similar mechanism for most
other neurotransmitters, with the exception of acetylcholine,
which is deactivated by the enzyme acetylcholinesterase (just as
norepinephrine can be deactivated by monoamine oxidase). This
discovery only served to reinforce the amine theory of
depression, because researchers eventually discovered that
drugs such as tricyclic antidepressants work by inhibiting this
reuptake mechanism and thus allowing released
neurotransmitters to stay longer in the synaptic cleft. For his
work in this area, Axelrod shared the 1970 Nobel Prize in
Medicine with Ulf von Euler and Sir Bernard Katz. (It is one of
the few Nobel prizes awarded for work related to psychotropic
medications because most discoveries in the area of
psychotropic medications are more luck and serendipity than the
result of carefully crafted hypotheses).
Nevertheless, the same time lag noted for MAO inhibitors
existed with tricyclic antidepressant drugs that inhibited
reuptake. For example, about an hour after the person takes a
tricyclic antidepressant the reuptake inhibition begins and the
amount of neurotransmitter in the synaptic cleft increases, but
symptoms do not abate for between two and four weeks (maybe
even as long as six weeks). So, despite making important
contributions to the understanding of reuptake inhibition,
Axelrod had not solved the riddle of how tricyclic
antidepressants actually work to change mood.

12. Although enzyme deactivation and reuptake inhibition are
important elements in most antidepressants' mechanism of
action, they still don't account for the two- to six-week lag of
the antidepressant effect. The reuptake properties of tricyclic
antidepressants and selective serotonin reuptake inhibitors
begin increasing levels of neurotransmitters within an hour of
someone's taking the medicine. Another problem is that other
drugs that dramatically boost the levels of similar
neurotransmitters (cocaine) do not act as antidepressants.
Although they may induce euphoria, they also cause an
emotional “crash” when the drug wears off. This knowledge
contributed to the development of postsynaptic receptor
desensitization (downregulation) theory as a complement to the
amine theory. This theory proposes that initially the receptors in
the depressed person are hypersensitive to neurotransmitter
because depressed people have less of that neurotransmitter
(remember these are just theories that were partially but not
totally accurate). Because there was supposedly less
neurotransmitter, the researchers hypothesized that receptors act
as if they are “starved” for it, so they upregulate (increase in
number). (Remember, this is a theory using metaphors—not
concrete truths. In the metaphor used to explain this theory,
receptors are not really “starved” for a neurotransmitter but if
they had human qualities one might say they would act as if
they were. Such of things like neurons is replete with ways it
can be misunderstood). With antidepressant treatment, as more
neurotransmitter becomes available, the receptors get more
neurotransmitter than is needed because they previously
increased in number (upregulated) to make use of the available
neurotransmitter in the synaptic cleft. At this point, the cell gets
bombarded with neurotransmitter, because the increased levels
of neurotransmitter are now binding with the increased numbers
of receptors. The theory suggested that the cells then adjust by
decreasing the number and sensitivity of receptors, because
more neurotransmitter is available. Theoretically, this
normalizes transmission or provides the “balance” that is

13. correlated with decrease of symptoms. So according to
downregulation theory, the antidepressant effect is the result of
two mechanisms. The first is the increase of neurotransmitter
released into the synapse (accomplished through reuptake
inhibition or enzymatic inhibition), and the second is the
downregulation of receptors to a “normal” level of
responsiveness (to adapt to the increased levels of
neurotransmitter). The time frame required for neurons to
decrease the number of receptors correlates closely with the lag
time between taking a drug and experiencing the antidepressant
effect (two to six weeks depending on the client and dosage of
medication) (Stahl, Hauger, Rausch, Flieshaker, & Hubbell-
Alberts, 1993).
The downregulation theory led researchers to consider the role
of receptor sensitivity in mental/emotional disorders. This
combination of the amine theory and downregulation theory was
used to account for the action of antidepressants until very
recently. Remember, these were and still are just theories.
Researchers never had conclusive evidence that the theories
fully explained the function of antidepressants nor that there
was any “chemical imbalance” that caused depression. To be
clear, there is no direct way to measure an extracellular level of
any neurotransmitter in the human brain. Some postmortem
studies on the brains of people who committed suicide
suggested there were low levels of 5-HT in the brain stem tissue
but without a baseline it is not possible to say what is “low.”
Also the amount of 5-HT in tissue is not necessarily reflective
of extracellular amounts (amounts in the synapse) (Jacobson,
Medvedev, & Caron, 2012). For decades, researchers have
probed the brain with indirect measures looking for biomarkers
of 5-HT. Cerebrospinal fluid (CSF) levels of the 5-HT
metabolite 5 hydroxyindoleacetic acid (5-HIAA) have been
thought to reflect brain levels of 5-HT but the correlations
between lower levels of this metabolite are more consistent with
things like aggression, suicidality and impulsivity than
depression (Placidi et al., 2001).

14. There have been so-called challenge methods where 5-HT in the
central nervous system is challenged with another agent and the
resulting changes in things linked to 5-HT have been observed.
For example, fenfluramine/Pondimin has been used in depressed
subjects in this manner. Fenfluramine/Pondimin stimulates 5-
HT to trigger secretion of prolactin. The prolactin is measured
and a blunted response was thought to reflect low 5-HT level
and a robust prolactin response to reflect a high 5-HT level
(Mann, McBride, Malone, DeMeo, & Keilp, 1995). The problem
with this is that the triggering of prolactin secretion is a
complex process involving not just 5-HT but gamma-amino-
butyric acid (GABA), peptides, and oxytocin (Emiliano &
Fudge, 2004). As these examples illustrate, “… the association
of 5-HT deficiency, or any other singular biochemical anomaly,
with major depression as the all-encompassing syndrome is
inconclusive” (Jacobson et al., 2012).
Variations on these theories were proposed, such as the
permissive theory, which restated the amine hypothesis but
included serotonin rather than exclusively focusing on
norepinephrine. The permissive theory also tried to explain the
role of serotonin in regulating levels of norepinephrine
and dopamine. Although all these theories expanded available
data on antidepressant action, none fully accounted for
antidepressant effects or the strong placebo responses in many
studies of antidepressants (we return to these later). The latest
hypothesis to explain antidepressant effects takes the discussion
deeper into the mysteries of the cells called neurons, as we
describe next.
The neurotransmitter receptor hypothesis asserts that in
depression, something is wrong with particular receptors for
monoamine neurotransmitters. Researchers think this
“something wrong” leads to depression. It is also related to the
upregulation of receptors discussed earlier. Because this
hypothesis focuses on the receptors and because receptors are a
function of gene expression, this hypothesis also considers that

15. depression may relate to some function (or malfunction) of gene
expression. Certainly this is a possibility; however, where
genetics is concerned it is important to state hypotheses
tentatively and concisely to avoid lapsing into word magic.
Although admitting that direct evidence to support the genetic
hypothesis is lacking, Stahl (2000) discusses the previously
outlined postmortem studies of the brains of suicide victims
where test results show that the tissue in parts of these brains
have increased numbers of 5-HT2 receptors. He concludes that
further …
Week 2
Respond to the following in a minimum of 175 words minimum
of one scholarly citation with reference in all 3 responses:
Depression is a widespread disorder. The National Institute of
Mental Health (NIMH) estimates that about ten percent of
American adults face some form of depression.
What Is Depression?
What causes Depression? Please utilize the theories outlined in
the text within your response.
What Are the symptoms of depression?
Currently which class of antidepressants are approved to
treat Major Depressive Disorder? How do the class of
medications differ from one another?