Open Access Library Journal
How to cite this paper: Fakhoury, M. (2014) Affective Disorders and Antidepressant Drugs. Open Access Library Journal, 1:
e597. http://dx.doi.org/10.4236/oalib.1100597
Affective Disorders and Antidepressant
Drugs
Marc Fakhoury
Department of Neuroscience, Faculty of Medicine, University of Montreal, Montreal, Canada
Received 4 June 2014; revised 10 July 2014; accepted 18 August 2014
Copyright © 2014 by author and OALib.
This work is licensed under the Creative Commons Attribution International License (CC BY).
http://creativecommons.org/licenses/by/4.0/
Abstract
Affective disorders are a group of psychiatric diseases that can affect an individual at any given
age. Also called mood disorders, they can be distinguished into two different types: major depres-
sive disorder, also called major depression, and bipolar disorder, which is known as manic de-
pression. People affected by major depression most often have a low mood, and are consistently in
a state of unhappiness. Although it was shown that genetics play a role in the predisposition of
depression, this disease most often occurs in response to a variety of external factors such as a
stressful life event, the loss of a loved one, and following drug or substance abuse. A variety of an-
tidepressant drugs, such as the monoamine oxidase inhibitors (MAOIs), the tricyclic antidepres-
sants (TCAs), and the second-generation antidepressants are able to provide significant relief for
people suffering from affective disorders like depression. However, several of these pharma-
ceutical agents can cause serious side effects to the patients. Therefore, there is a need to identify
novel antidepressant therapies that are more efficient and that present minimal side effects. A
better understanding of the neurobiology of depression will definitively help scientists develop
new therapeutic ideas. This paper will first discuss the clinical profile of depression and explain
the physiological mechanisms and the neurochemistry involved in this disease. It will then give
you an overview of the effectiveness of the most common antidepressants used, with a description
of their mode of action and most notable side effects.
Keywords
Antidepressant Drugs, Bipolar Depression, Depression, Neurobiology
Subject Areas: Drugs & Devices, Neurology, Psychiatry & Psychology
1. Introduction
Antidepressants are medications that are very useful in treating affective disorders such as depression, which is
characterized by extreme and inappropriate exaggerations in mood, and an affective state of sadness. Antide-

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pressants are primarily prescribed because they have the ability to significantly enhance the mood of depressed
patients relatively quickly. Typical signs and symptoms of depression include feeling of sadness, sleep distur-
bances (insomnia or hypersomnia), reduced appetite, and increased suicidality. Physical symptoms include loca-
lized pain, difficult breathing and severe digesting disturbances. Clinical depression can be found worldwide,
and affects individuals of all ages and cultural origins. However, women tend to be more affected than men in
general, which is often the result of experiencing a stressful event such as parental death, loss of a loved one,
miscarriage or a divor ce [1]. There are several factors that predispose someone getting affected by a mood dis-
order, and they are mainly genetic, psychosocial, and biological. Depression can also be the result of a stressful
event, and can be precipitated by pharmacological agents or drug abuse [2]. Treatment of depressive disorders
includes psychotherapy as well as the use of antidepressant drugs. Most of these drugs act by increasing the
availability of specific brain chemicals called neurotransmitters, including dopamine and serotonin. It is believed
that these brain chemicals can help improve emotions in depressed patients. The antidepressants commonly used
to treat major depressive disorder are the monoamine oxidase inhibitors, the tricyclic antidepressants and the
second-generation antidepressants. Most of these antidepressants work equally well to relieve depression and
results can be seen after just couple of weeks of treatment. Although these pharmaceutical agents are useful in
enhancing the symptoms of depressed patients, not every individual responds in the same manner to pharmaco-
therapy and some o f these antidepressant drugs may present few or many side effects. This paper will give you
an overview of the biological mechanisms implicated in affective disorders, and will discuss the effectiveness of
antidepressant drugs and other pharmaceutical compounds in treating this disease.
2. Clinical Profile of Depression: Demography, Signs and Subtypes
Mood disorders are very common among individuals. For instance, the prevalence of depression in the United
States can g o up to 25% in women, and 12% in men [3]. Although this disease cou ld occur at any age, the me-
dian age is about 40 years old. In contrast to depression, bipolar disorder is characterized by episodes of elevated
mood known as mania, usually alternating with episodes of depression. This disorder affects men and women
equally, the average age of onset being between 27 and 33 years old. Patients affected by depression often report
signs such as loss of appetite, insomnia, loss of motivation and general fatigue. Low self-esteem and thoughts of
suicide are also very common among depressed people. According to the Diagnostic and Statistical Manual of
Mental Disorders [4], at least 5 of these symptoms must be present in order to diagnose someone from major
depression: depressed mood most of the day, decreased interest or pleasure, change in weight and appetite,
change in sleep, change in activity, loss of energy, feeling of worthlessness, diminished ability to concentrate
and thoug hts of deat h or suicide .
Recent research have tried to identify the subtypes of depression in order to better predict the effectiveness of
a given antidepressant drug [5]. There exist six different types of depression: major depression with melancholia
or endogenous features, major depression with melancholia (most common), major depression with psychotic
features, bipolar depression, dysthymic disorder, and treatment-resistant depression. The most common form of
depression is when it’s experienced in conjunction with melancholia. Patients in this group of disease often ex-
hibit signs such as anhedonia, emotional withdrawal and insomnia, but can be easily treated with tricyclic anti-
depressants. In contrast, antidepressant drugs are less effective with patients affected by major depression with
psychotic features, unless they are administered concomitantly with an antipsychotic drug. People with bipolar
disorder often need antidepressant drugs to alleviate the symptoms of depression, as well as a mood stabilizer
such as lithium carbonate to control the mania. Dysthymic disorder, also referred to as premorbid neurotic de-
pressive disorder, is a mood disorder consisting of the same cognitive and physical problems as seen in depres-
sion, with less severe but longer-lasting sympto ms [6]. It is most effectively treated with tricyclic antidepres-
sants after the patients have recovered from episodes of major depression [7]. Treatment-resistant depression is a
term used in clinical psychiatry to describe cases of major depressive disorder that do not respond adequately
appropriately to at least two antid epressants [8]. People in this category are often treated with a combination of
two different types of antidepressants, or with th e addition of a non-antidepressan t medication that has the abili-
ty to enhance the effectiveness of the antidepressant.
3. Physiological Mechanism of Depression
1) Abnormal cortisol secretion in depressed patients.

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Cortisol is a steroid hormon e produced by the zona fasciculata of the adrenal cortex. It is released in response
to stress and a low level of blood glucocorticoid [9]. Altered patterns of serum cortisol levels have been ob-
served in connection with abnormal adrenocorticotropic hormone (ACTH) levels, clinical depression and psy-
chological stress. Approximately 50% of the patients show an elevation of adrenal cortisol in response to a
higher release of ACTH from the pituitary [10]. ACTH is an important component of the hypothalamic-pitui-
tary-adrenal axis and is often produced in response to biological stress, and is regulated by the secretion of its
precursor corticotropin-releasing hormone from the hypothalamus. It’s also well believed that the abnormal cor-
tisol levels found in depressed individuals are the result of a defect in the brain at or above the level of the hy-
pothalamus [11]. In order to evaluate the function of the hypothalamic-pituitary-adrenal, scien tists are using the
dexamethasone suppression test, which assesses adrenal gland function by measuring how cortisol levels change
in response to an injection of dexamethasone [12] [13]. In the depressed patients who were treated with dex-
amethasone, the plasma level of cor tisol and beta-endorphin was found to be significantly reduced.
2) Biogenic amine hypothesis.
In the early 1950s, scientists tested several drugs that altered mood and behavior in order to evaluate their
pharmacological mechanism of action. Reserpine, which reduces sympathetic constriction of blood vessels, was
found to induce symptoms that are very similar to those found in depressed individuals. Because the reserpine-
induced model of depression depletes stores of several monoamines such as dopamine, norepinephrine and se-
rotonin [14] [15], the development of drugs that restore the normal level of these neurotransmitters was the main
focus of clinical research. The biogenic amine hypothesis states that depression is caused by a deficiency of
monoamines, particularly norepinephrine, dopamine and serotonin, and that it can be alleviated by the adminis-
tration of antidepressan t drugs that increase the availability of these neurotran smitters. As illustrated in Table 1,
serotonin plays an important role in sleep, memory and anxiety. Norepinephrine, which is mainly related to at-
tention and alertness, also continues to be a major focus in research. Another neurotransmitter of interest in de-
pression is dopamine. It is well documented that this hormone is related to alertness, motivation, pleasure, and
memory, as well as interest in life [16].
One way of increasing monoamines lies around the use of monoamine oxidase inhibitors (MAOIs) [17].
MAOIs are chemicals that inhibit the activity of the monoamine oxidase enzyme family. They are particularly
effective in treating atypical depres sion [18]. Because of their ability to block the action of monoamine oxidase,
which catalyzes the oxidative deamination of monoamines, they are able to significan tly increase the availability
of neurotransmitters in the brain. Other drugs, called tricyclic antidepressants (TCA), were developed in the
1950s in order to increase the level of neurotransmitters [19]. These endogenous chemicals transmit signals
across a synapse from one neuron to another one. In the presynaptic neuron cell, there are several synaptic ve-
sicles that contain neurotransmitters. They get released in the synaptic cleft and then get taken up by the postsy-
naptic cell of another neuron. TCA’s mode of action involves blocking the process of reuptake by the postsy-
naptic cell, which increas es the amoun t of neuro transmitter in the synaptic cleft.
There are several other molecules that play a role in depression, such as acetylcholine, histamine, and both
opioid and non-opioid peptides. Understanding their anatomical and neurochemical interaction is crucial for the
development of effective treatment of depression. The remaining of this article will discuss the effe ctiveness of
antidepressants drugs and other molecules used to treat affective disorders, by illustrating their mode of action
and their side effects.
4. Monoamine Oxidase Inhibitors
Monoamine oxidase inhibitors were the first type of antidepressant developed. They are a class of enzyme that
selectively inhibits the activity of the monoamine oxidase enzyme family. Used in the early 1950s to treat tu-
berculosis, it was found that iproniazid had a significant mood-elevating effect, which encouraged scientists to
Table 1. Main neurotransmitters involved in depression and their physiological effects.
Neurotransmitter Physiological Effects
Dopamine Alertness, Attention, Clarity, Motivation, Wor king Memory
Norepinephrine Attention, Concentration, Determination, Endurance
Serotonin Satisfaction, Relaxation, Insomnia, Pleasure, Anxiety, Learning Memory

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conduct clinical trials [20]. This enabled clinicians to discover its ability to inhibit monoamine oxidase, which
led to the development of drugs having the same mode of action. MAOIs are currently used to treat the most
challenging affective disorders, including those with atypical depression, bipolar depression and treatment-re-
sistant depression [21], but are also useful for the treatment of panic attacks, posttraumatic stress and obses-
sive-compulsive disorder.
One example of a MOA is tranylcypromine (Parnate), which is very commonly prescribed in North America.
Other MAOIs such as isocarboxazid (Marplan), phenelzine (Nardil) and Selegiline (Emsam) can also provide a
safe treatment for depressed individuals [21]. The chemical classification of these drugs comprises the hydra-
zines and the non-hydrazine. Table 2 provides a list of the most commonly used MOAIs with their chemical
classifications and most notable side effects.
These drugs are also divided into two groups, MAO-A inhibitors and MAO-B inhibitors, depending on their
ability to inhibit the A or B form of the MAO en zyme. Both MAOs are crucial to the inactivation of monoami-
nergic neurotransmitters, and they both break down dopamine, tyramine, and tryptamine equally. However,
these two isoenzymes display different specificities. While MAO-B breaks down phenethylamine and benzyla-
mine, MAO-A is important for the catabolism of serotonin, melatonin, noradrenaline, adrenaline, and monoa-
mines ingested in food. Like most antidepressants, MAOIs work by modifying the levels of one or more of the
neurotransmitters naturally found in the brain. The MAOIs act on the monoamine oxidase enzyme in an irre-
versible manner, preventing their enzymatic deamination. Despite their relatively short plasma half-life, these
drugs have a relatively long duration of action. Studies have shown that treatment with an MAOI increases the
level of norepinephrine, serotonin and dopamine in rat brain for several weeks, which helps boost mood by im-
proving brain cell communications.
A disadvantage of using MAOIs is that the patient needs to adhere to a strict diet since their use can cause a
significant increase in b lood pressure when taken w ith certain foods or other pre scriptions. Patien ts treated with
MOAIs also commonly report adverse signs such as hypertension, insomnia, frequent awakenings, reduced
sleep time, weight gain and impaired sexual responses. Moreover, MAOIs can target non-specific enzymes, such
as the cytochrome P450, which degrades a variety of drugs as well as biogenic amines. Significant drug interac-
tion can also occur upon using their administr ation. Because of this, monoamine oxidase inh ibitors are being r e-
placed by other antidepressants, such as the tricyclic antidepressants, which are gene ra l ly safer to use.
5. Tricyclic and Second-Generation Antidepressants
The tricyclic antidepressants (TCAs) were first discovered in the early 1950s and were subsequently introduced
as antidepressant drugs [22]. Their name is derived from their chemical stru cture, which contains three rings of
atoms. Although T CAs are chemical compounds that are mainly used as antidepressants, they are also effective
in treating other medical disorders such as generalized anxiety and social phobia. Common tricyclic an tidepres-
sants include imipramine (Tofranil), amitriptyline (Elavil), amoxapine (Asendin) and protriptyline (Vivactyl).
Several other newer antidepressants drugs (second-generation) have been developed in order to reduce the side
effects and improve the efficacy. TCAs antidepressant effect is attributed to inhibition of the neuronal uptake
mechanism that normally stops the action of neurotransmitters. The majority of the TCAs are serotonin-norepi-
nephrine reuptake inhibitors. By inhibiting reuptake of neurotransmitters, TCAs help improve the communica-
tion between neuronal cells since the duration of neurotransmitter action at the synapse is prolonged [23]. Al-
though being effective in treating depression, the use of TCA can cause several side effects. Some of the most
frequent side effects experienced by patients are constipation, dry mouth, fatigue, tachycardia, weakness and
urinary retention. For this reason, they have been increasingly replaced by newer antidepressants, which present
few er side e ffects. These new drugs are the second-generation antidepressants, which include the selective sero-
tonin reuptake inhibitors, the serotonin-norepinephrine reuptake inhibitors, and the norepinephrine reuptake in-
hibitors. The term “Third generation antidepressant” is sometimes employed to refer to even newer antidepres-
sants, which often include selective serotonin reuptake inhibitors such as fluoxetine (Prozac), paroxetine (Paxil)
and sertraline (Zoloft) [24]. The second-generation drugs wer e introduced in the 1970s and they differ from the
TCAs in their tricyclic nucleus that is largely modified. The earliest drugs in the market were iprindole (Pron-
dol), doxepine (Sinequan) and amoxapine (Asendin). Moreover, two bicyclic compounds were developed in the
mid-1970s with the ability to prevent the reuptake of serotonin without affecting other neurotransmitters. Exam-
ples include fluoxetine and citalopram. Table 3 provides a list of the most common tricyclic and second-gener-
ation antidepressants including their class and trade name [25].

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Table 2. Most commonly prescribed monoamine oxidase inhibitors.
Chemical classifications Drugs Side Effects
Hydrazine
Isocarboxazid, Phenelzine, Selegiline
Headache, Vomiting, Nausea
Non-Hydrazines
Pargyline, Tranylcypromine
Blurred Vision, Dizziness, Vomiting
MAO-A Inhibitors
Clorgyline, Cimoxatone, Amiflamine
High Blood Pressure, Drug Interaction
MAO-B Inhibitors
Deprenyl, Caroxazone
Insomnia, Altered Heart Rythm
Table 3. Most common tricyclic and second-generation antidepressants.
Class Antidepressant Drugs
Classic Tricyclics Amitriptyline (Elavil), Desipramine (Norpramine), Imipramine (Tofran il )
Modified Tricyclics Amoxapine (Asendin), Doxepine (Sinequan), Iprindole (Tertran), Trimipramine
(Surmontil), Protriptyline (Vivactyl)
Serotonin Reuptake Inhibitors Clomipramine (Anafranil), Citalopram (Cipramil), Fluoxetine (Prozac), Fluvoxamine
(Luvox), Sertraline (Zoloft), Venlafaxine (Eff ex o r)
Atypical Antidepressants Trazodone (Serzone) Bupropion (Wellbutrin), Maprotiline (Ludiomil), Mianserin (Tolvon),
Studies have shown that depressed patients treated with selective serotonin reuptake inhibitors, such as cita-
lopram and clomipramine can anticipate a high probability of symptom improvement within few days [26]. Al-
though the second-generation drugs can cause some side effects, they are more effective and safer that the TCAs
and the MAOIs, especially when tak en in larg e quantities.
6. Mood Stabilizer: Clinical Action and Use in Bipolar Disorder
Mood stabilizers are a group of medication used to treat mood disorders characterized by intense and sustained
mood shifts. This class of medication is primarily used for treating patients who suffer from bipolar disorder,
which is characterized by episode of mania or hypomania alternating with depression. During mania an individ-
ual feels abnormally happy, energetic, but most often have unrealistic ideas and makes poor decisions. Other
symptoms include irritable mood, pressured speech, and decreased need for sleep [27]. Moreover, the suicide
rate is higher than in patients affected with depression, and is estimated to be between 10% and 25 %. Th ere ar e
two main types of bipolar disorder: type I and type II. Type I is characterized by at least one manic episode,
which can alternate with depression [28] [29]. In type II bipolar disorder, there are no manic episodes, but one or
more hypomanic and major depressive episodes [28]. There are a number of pharmacological medications used
to treat bipolar disorder [30], with Lithium being the most commonly. Not only does it treat acute manic epi-
sodes and prevent relapses, but is also effective in trea ting depression [31]. When it’s administered to the patient,
lithium becomes distributed in the central nervous system and interacts with several neurotransmitters such as
serotonin. Animal studies have shown that when the serotonergic neurons from rat are treated with lithium, se-
rotonin release is enhanced compared to no lithium treatment [32]. One of the disadvantage of using lithium is
that is causes a variety of side effects. Because of its narrow therapeutic range (range between the therapeutical-
ly effective and toxic dose), drug monitoring is required to avoid toxicity. Signs and symptoms of toxicity in-
clude nausea, vomiting, diarrhea, and ataxia [33]. However, these symptoms can often be improved by lowering
the dose of lithium [34].
A number of other pharmaceutical agents can also be used for treating bipolar disorders, which are useful es-
pecially for patients who do not respond well to lithium therapy or who cannot tolerate its side effects. Such
drugs include the anticonvulsants, also known as antiepileptic drugs. Carbamazepine, which is typically used
treating seizure disorders and neuropathic pain, can also be used as a second line treatment for bipolar disorder.
However, it’s a poor antidepressant that is less effective then lithium, and that often requires the simultaneous
use of other antidepressants [35]. Carbamazepine was displaced by valproic acid (Depakote) in the 1990s. Since
then, Depakote has become a commonly prescribed treatment, which is more suitable for treating patients with
manic episodes [36]. Lamotrigine, another anticonvulsant, is also a good mood stabilizer that has been shown to
effectively treat bipolar depression [37]. Other agents, such as the antipsychotic medications, may be effective
for short-term treatment of bipolar manic episodes and appear to have a better efficacy than lithium and anti-

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convulsants [30]. Olanzapine and clozapine are both effective in treating bipolar disorder and preventing re-
lapses. However, medications such as lithium are preferred whe n us ed for a lon g pe riod of time [30].
7. Conclusion
Affective disorders are a group of disease with significant neurobiolog ical consequences that involve functional
and neuronal alterations in several regions of the brain. The biogenic amine hypothesis of depression has helped
us understand the biological mechanisms and brain circuits involved in this disease, and have led to the devel-
opment of several generations of antidepressants that include the monoamine oxidase inhibitors, the tricyclic and
second-generation antidepressants, as well as other mood stabilizers like lithium and the anticonvulsants. Anti-
depressant drugs clearly have an effect not only on serotonin, dopamine and noradrenaline, but also on other
molecules not discussed in this paper, such as histamine and acetylcholine. Such interactions are crucial in the
understanding of the theory of depression and the effectiveness of antidepressants. Although antidepressant
pharmacotherapy have shown to be very effective in the treatment of affective disorders, more work need to be
done to optimize the therapeutic effects and reduce the side effects. Scientists need to emphasize on neuropha r-
macology research and on the development of novel treatments. Other potential treatments for depression are the
use of electroconvulsive therapy, in which seizures are electrically induced, and deep brain stimulation, which
sends electrical impulses to spec ific parts of the brain to provide relief from psychiatr ic illnesses. Fin ally, future
research needs to focus on the identification of brain structures involved in mood disorders, and on the devel-
opment of animal models, which will help identify the subtype of depression and optimize the effectiveness of
pharmacological treatments.
Financial Disclosure
The author declares that they have no financial or other conflicts of interest to disclose.
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