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=A Comparison of Antidepressants, Treatment Methods, and the Mechanisms by Which They Work to Counteract Major Depression=

Gabrielle Arnold, Department of Chemistry, Drexel University
CHEM 367: Research Paper

Introduction: What is Depression?
Before considering different types of antidepressants and how they work to treat moderate to severe cases of depression, it is necessary to consider what exactly these drugs are being used to treat. Depression can affect the way an individual thinks, behaves, & feels. However depression is not always a psychiatric disorder, sometimes it can be a normal reaction to an intense situation. Symptoms of depression can include: changes of appetite, difficulty concentrating and remembering details, changes in sleeping patterns, decreased energy/fatigue, digestive problems, aches and pains [1]. Clinical depression is known by several other names, such as major depressive disorder (MDD), recurrent depression, and unipolar depression to name a few [2]. There is a differentiation between clinical/major depression and a temporary depressive mood brought on by life experiences. However, in order to diagnose a patient who is clinically depressed mental health professionals can only rely on a mental status examination, in addition to reported thoughts, experiences, and behaviors of the patient from the patient’s family and friends or the patient himself. The initial onset of major depression usually occurs in the young adult years, and is generally to be followed by a recurrence in the next decade of the individual’s life.

Many factors must be considered when discussing the causes of depression. The biopsychosocial model considers the presence of biological, psychological and even social triggers within an individual’s life. There is no generally accepted and supported theory describing the mechanism behind depression. However, there are many different hypotheses based on various observations and the effects that various medications have on individuals suffering from clinical depression, known neurological responses to various stimuli also play a role in these attempts to describe the mechanism. The main focus of theories regarding this mechanism usually involves monoamines (serotonin and norepinephrine) that are naturally present as neurotransmitters in the brain. Neurotransmitters such as serotonin and norepinephrine are often referred to as catecholamines. The term catecholamine describes the chemical structure of these compounds, which contain a catechol bonded to a side-chain amine. Some models seem to suggest that individuals can have a certain predisposition to clinical depression, as a result of learned behaviors or the transfer of certain sections of DNA genetic code. In a paper describing the effects that life stress can have on depression, the authors suggest that there is an increased likelihood of an individual developing depression if he has some alteration in the genetic coding for the 5-HTTP serotonin transporter [3]. In his paper, Caspi performs a multiple regression analysis to explore the depressive response of three groups of people: those containing just the alleles being examined (homozygous), those not containing these alleles (homozygous), and those containing one of each (heterozygous). A fairly clear trend can be seen between individuals with homozygous short alleles and an increased rate of depression [4]. This 5-HTTP gene is thought to have such a strong influence over depression, because it is responsible for coding a serotonin transporter protein and thus influences the serotonin pathways in the brain[5].

Figure 1: This is a depiction of allilic variation of the 5-HTTP gene. The short gene has an altered presence in the serotonin transporter proteins.

Nearly all of the theories regarding the mechanism behind major depression suggest the involvement of a class of monoamine neurotransmitters. These include serotonin, norepinephrine, and to a lesser extent dopamine which are present in the synaptic cleft between neurons. These neurotransmitters serve as “messengers” between the neurons, which “read” them with various receptors on the surface of the neuron. There have also been suggestions that low serotonin levels can adversely impact the levels of norepinephrine present in the synaptic cleft. The Monoamine Hypothesis postulates that the mechanism of depression is linked in some way to a deficiency in these monoamine neurotransmitters, and the common symptoms of depression do seem to suggest some abnormality in the presence of these monoamines. Energy, alertness, attention, anxiety, and interest in life are some of the effects that can be connected with norepinephrine; a deficiency in serotonin can be linked to anxiety, obsessions, and compulsions. One can clearly see some overlap between the effects related to these neurotransmitters and the previously described symptoms of depression. However, there are two common counter-points to this theory. The first suggests that this is an incredibly simplistic view of the human central nervous system, which is a complex and adaptable network of neurons and nerve cells through out the body. The central nervous system is responsible for sensory details and perception of one’s environment, in addition to playing a role in the biological response to various situations (including stress). The second counter-point points out that there are certain drugs available to counter the depressive effects caused by abnormal serotonin and/or norepinephrine levels, but weeks can pass by before any change in the patient’s mood occurs. This lag in the time that it takes for these types of medications to start working seemingly conflicts with the theory, because these types of drugs should be affecting the amount of monoamine present in the synaptic cleft within a couple of hours of being administered.

Figure 2: This shows serotonin transport between pre-synaptic and post-synaptic cells. Serotonin passes out of the pre-synaptic cell through transport proteins, and is present in the synaptic cleft where it is able to bind to receptors on the post-synaptic cell's surface.

Other observations and hypotheses regarding the mechanism of depression tend to suggest other biological factors that can contribute to the onset of a major depressive episode. In some cases a drastic drop in estrogen levels can be associated with an increased risk of depression, which can generally occur in women following childbirth. Certain comparative studies have used MRI scans to examine the brain structure of depressed and non-depressed individuals [6]. These scans have revealed that depressed patients tend to have enlarged adrenal glands and lateral ventricles, in addition to decreases in the size of their basal ganglia, thalamus, hippocampus, & frontal lobe. Another theory considers the relation between depression and the body’s ability to generate nerve cells in the hippocampus [7], which is based on the observations of antidepressants that increase the levels of serotonin present. The increase of serotonin would promote neurogenesis in the hippocampus and help restore mood and memory, usually affected by depressive episodes [8] [9]. Another biological explanation for depression considers abnormal activity of the Hypothalamic-Pituitary-Adrenal (HPA) axis, which is responsible for the body’s response to stress [10]. If the hypothalamus secretes too much of a certain hormone, then a prolonged neuroendocrine response to stress could take place. This would involve increased levels of cortisol, and account for the enlarged pituitary and adrenal glands.

Depression: Management and Treatment Options
Depression is commonly treated in three different ways, which vary in intensity and effectiveness. These three methods are psychotherapy, medication, and electroconvulsive therapy. These treatments can be combined to create a specially tailored the treatment plan for each patient, depending on what will be most helpful. Treating depression is tricky for any mental health practitioner because they must make an informed decision based solely on what they are being told. In addition to being presented with potentially incomplete information, in many cases the treatment for a more severe case of depression can make a mild or moderate depressive episode worse. Psychotherapy is used in nearly every case of depression, because it poses the least amount of risk to the patient. In cases of mild or moderate depression especially, it is usually most productive for a professional psychologist to meet regularly with the patient to discuss what the patient is thinking and feeling and how that affects their life and behaviors.

Some cases of moderate depression and most cases of severe depression, it can be necessary to pair psychotherapy with medication of some kind. If medication is necessary, the dosages may be adjusted or different medications may be taken simultaneously to create the exactly right mixture for an individual and their specific cause for depression. However, in many cases of mild and less moderate depression antidepressants can increase the severity of the depressive episode [11]. Monoamine Oxidase Inhibitors (MAOIs) are among some of the first antidepressants to be developed, but they are rarely used today because they can have fatal results if strict dietary/medical restrictions are not followed. Today the primarily prescribed antidepressants are Selective Serotonin Reuptake Inhibitors (SSRIs), because they are less toxic and are accompanied by relatively mild side effects. These and other medications will be discussed in the next section.

Electroconvulsive Therapy (ECT) is reserved for only the most severe cases of depression, for which other treatment options have already been exhausted. ECT induces a seizure in the patient by sending pulses of electricity through a persons brain, using electrodes placed on either side of the patient’s head (at the temples). The mechanism behind this procedure is not well understood, but it is believed to act in a similar way to defibrillation. The theory behind ECT suggests that interrupting the central nervous system’s electrical current serves to restart or “jumpstart” the brain [12]. As would be expected, there are some adverse effects involved with ECT including headache, disorientation, and memory loss [13]. In many cases ECT is an extreme action to provide a temporary reprieve from depressive symptoms, because patients who receive ECT can still relapse [14] [15]. This method can be moderated in three different ways to produce the most effective treatment. The placement of the electrodes may be altered, he frequency of ECT treatments may be increased or decreased, or the stimulating current can be changed. The effects of ECT on patients, seems to suggest that this procedure acts primarily on the hippocampus, which is known to affect mood and memory in individuals.

Antidepressants
As the name suggests, antidepressants are used to treat individuals suffering from severe depressive disorders. Antidepressants are also commonly used during the treatment of anxiety disorders, Obsessive-Compulsive Disorder, certain eating disorders, snoring, migraines, ADHD, & sleeping disorders. Two of the first used medications for the treatment of depression were opioids and amphetamines; once awareness of their specific side effects and addictiveness increased, their use became restricted. There are several classes of antidepressants available for the treatment of depression, the most common of which are: monoamine oxidase inhibitors (MAOIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), and tricyclic antidepressants (TCAs).

Monoamine Oxidase Inhibitors (MAOIs) act as an inhibitor on the enzyme monoamine oxidase, which is used in the body to break down the neurotransmitters: dopamine, norepinephrine, and serotonin. MAOIs have a tendency to interact with other medications, which makes them an unlikely first choice to treat most patients. The two types of Monoamine Oxidase Inhibitors are reversible MAOIs and irreversible MAOIs. Reversible MAOI’s usually do not require dietary restriction, or if they do they are less strict. Irreversible MAOIs on the other hand are notorious for interacting with certain drugs and foods; any deviation from the very strict dietary and medicinal restrictions is met with potentially fatal results.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) work by inhibiting the reuptake of both serotonin and norepinephrine. Selective Serotonin Reuptake inhibitors (SSRIs) only inhibit the presynaptic neuron to prevent the reuptake of serotonin, which creates a higher concentration of serotonin in the synapse. There are several classes of antidepressants that act in a similar way to “inhibit” the reuptake of neurotransmitters like serotonin, norepinephrine, and dopamine (or some combination). These are all named in a pretty self-explanatory manner; norepinephrine reuptake inhibitors (NRIs) are commonly used for ADD/ADHD because they inhibit the reuptake of norepinephrine. Additionally, the reuptake of norepinephrine and dopamine would be inhibited by NDRIs.

Several antidepressants antagonize certain receptors in order to counter the effects of depression. These “antagonistic” antidepressants include: Noradrenergic & Specific Serotonergic Antidepressants (NaSSAs), Serotonin Antagonist and Reuptake Inhibitors (SARIs), Norepinephrine-Dopamine Reuptake Disinhibitors (NDDIs), and Serotonin Modulators & Stimulators (SMSs). These names describe the presence of which neurotransmitter the drugs in these classes will promote. By antagonizing specific receptors, these antidepressants promote the outflow of neurotransmitters into the synapse instead of preventing their reuptake.

Tricyclic Antidepressants (TCAs) and Tetracyclic Antidepressants (TeCAs) block the reuptake of both norepinephrine and serotonin. Their mechanism is similar to that of the SSRIs. TCAs are structurally different from the previously mentioned inhibitors, including SSRIs and SNRIs and dopamine reuptake inhibitors, which do not contain three rings of atoms.

In certain cases adjuncts can be used in conjunction with antidepressants to increase the effectiveness or decrease the severity of the side effects. In some cases the adjunct may be another antidepressant. This can help with the treatment of depression by affecting a specific part of the brain more strongly with two antidepressants of the same class, or multiple parts of the brain can be affected by using two antidepressants of different classes. Other common adjuncts include antipsychotics, nicotine, and lithium (in cases of bipolar disorder). Antipsychotic medications block dopamine receptor to effectively treat “hallucinations, delusions, disorganized thinking, & aggression” (Merk).

Other substances that are thought to have some positive effect against depression include caffeine, ketamine, and omega-3 fatty acids. While both caffeine and nicotine are stimulants; within the body caffeine increases the number of adenosine receptors, while nicotine stimulates the release of endorphins as a result of promoting the release of dopamine and norepinephrine. Excessive consumption of caffeine can result in increased anxiety in an individual (regardless of their mental state). Ketamine is an anesthetic typically used in veterinary practices, which seems to affect depressive disorder in humans by one of two mechanisms. Ketamine is theorized to work by either antagonizing the NMDA receptor, or by blocking the NMDA receptor with then forces the AMPA receptor to increase it activity. Research into the effects of omega-3 fatty acids has been met with inconsistent results. There is very little hard evidence to suggest that these omega-3 fatty acids have any beneficial effect with regards to depression or developmental disorders (such as autism and ADD).

Selected Antidepressants: Mechanisms
As mentioned previously monoamine oxidase inhibitors work by inhibiting the monoamine oxidase activity. However there are two isoforms of these inhibitors: MAO-A and MAO-B. MAO-A works to treat depression by removing an amine group from serotonin, melatonin, dopamine, epinephrine, and norepinephrine. The removed amine group is converted to ammonia within the body. In the human body, ammonia is toxic but can be converted to urea or uric acid through the addition of carbon dioxide. Once transformed, urea or uric acid can be excreted through urine. MAO-B also works by removing amine groups, but it tends to target phenylethylamine, other trace amines, in addition to dopamine. With regards to the reversibility of MAOIs, the irreversible MAOIs permanently deactivate the monoamine oxidase enzyme. The body naturally generates replacement enzymes, but a cessation in the administration of MAOIs will not immediately return the functionality of the monoamine oxidase enzyme. Contrastingly, reversible MAOIs can detach from the enzyme based on the concentration of the substrate and MAOI in the “environment” of the enzyme. Once the MAOI has detached from the enzyme the enzyme is able to function properly again. In low doses drugs that target the MAO-B receptors do not require dietary restrictions, because amines introduced into the body through food (such as tryptophan and tyramine) can still be broken-down. Higher concentrations of MAO-B or inclusion of MAO-A will require dietary restrictions, because the catabolism of tryptophan and tyramine will also be inhibited. Consumption of foods containing tyramine will tend to cause a hypertensive reaction in patients being treated with MAOIs, while consumption of tryptophan will result in serotonergic syndrome. Lethal reactions can also occur in patients taking MAOIs in addition to painkillers, stimulants, and other antidepressants (including tricyclics & SSRIs). Additionally, increased levels of dopamine in conjunction with the use of MAOIs can result in psychosis, which is accompanied with impaired thoughts/emotions and potentially could involve a “break” from reality.

Tricyclic antidepressants are a general term to describe antidepressants whose chemical structure contains three rings of atoms. TCAs were used for decades as the primary drug of choice for treating depression. They are now reserved mainly for treatment of depression that has proved resistant to other medications. Since there are a greater variety of antidepressants to choose from generally drugs with less severe side effects will be prescribed preferentially. When using TCAs to treat depression, oftentimes the side effects will take effect before the antidepressant effects. The main side effect of TCAs is increased volition, which empowers individuals to take action on their thoughts or wills. This can be especially problematic in suicidal patients; this increased volition will significantly increase the probability will attempt suicide before the alleviation of their depression[16]. Some of the other side effects of concern associated with TCAs include: dizziness, fatigue, apathy, sexual dysfunction, nausea, and ventricular dysrhythmia. Commonly TCAs will block the serotonin transporter and the norepinephrine transporter, which results in increases of serotonin and norepinephrine concentrations; this mechanism is similar to that of SNRIs. Additionally tricyclic antidepressants have a tendency to act as antagonists on many different receptors. These antagonistic reactions in addition to the range of receptors is responsible in part for their efficiency in treating depression in addition to the range of side effects. TCAs also tend to block sodium channels and calcium channels, though inhibition. This is relevant to the cardiovascular effects of TCAs and explains the fatality behind overdosing on TCAs.

Figure 3: This is the chemical structure of Fluoxetine (Prozac), which is one of the rare antidepressants deemed "safe" for use in treating Clinical Depression in youth.

Selective serotonin reuptake inhibitors are the most commonly prescribed medication in the treatment of depression. The mechanism of SSRIs is largely the same as TCAs. However, SSRIs specifically target serotonin receptors, and as a result they have less of an effect on norepinephrine or dopamine. In high doses, SSRIs can still influence the levels of these other monoamines though. These are preferable to TCAs or MAOIs because the have fewer side effects. Additionally the side effects are less severe and better tolerated [17], and mostly do not affect the cardiovascular system (like certain side effects of TCAs)[18]. Another benefit of SSRIs is that the toxic dose in humans is high enough to make overdose improbable. In fact the side effects are adequately mild such as to make this one of the few medications for depression and anxiety that is considered for pediatric use. Many SSRIs are substrates of Pgp, which means that Pgp transporter proteins can remove them from the brain. In cases where this diminishes the effectiveness of the treatment, a different SSRI can be prescribed instead. Fluoxetine, better known as Prozac [19], is not a Pgp substrate and as a result it will not be removed from the brain as readily by the Pgp transporter proteins. This allows the fluoxetine to more effectively inhibit the serotonin receptors in the brain, when a patient doesn’t respond to other SSRIs[20]. In addition to acting as an SSRI, it also antagonizes the HT2C receptor to inhibit the release of norepinephrine and dopamine [21]. Use of fluoxetine in treating depression has also been shown to reduce stress and improve sleep in some cases. The stress alleviating effects of fluoxetine make it adept at treating other stress disorders, such as obsessive-compulsive disorder, trichotillomania, etc.

Conclusion
Psychiatric disorders are tricky to diagnose and treat, because they are fairly ambiguous. While the symptoms for something like depression are defined, these symptoms can be caused by a number of things. Thus a person exhibiting these symptoms isn’t necessarily clinically depressed. This is part of the reason that there are so many hypotheses regarding depression and antidepressants instead of solid, well-known mechanisms. This being said, it is difficult not to see a bit of a dilemma in the treatment of depression. Is it ethical to administer to patients chemical substances with suggested effects to treat a disorder that nobody knows very much about for certain? Yes, in many cases antidepressants do seem to help people get through major depressive episodes but the determination of which drug to use seems like it is primarily “guess work”, albeit educated guess work. In some cases, like electroconvulsive therapy, it has even been suggested that doctors are trying to cure depressive symptoms by causing brain damage in their patients. However, even if you agree that the many of these treatments involve risk and potentially physical damage to the body, it seems that the worst possible option would still be to leave a patient without any kind of treatment. By having various treatment methods, a patient can still hope that things will get better. If doctors stopped treating these patients because they lack a firm understanding of the mechanisms behind these drugs, many patients will lose this last speck of hope that there is some treatment and will allow them to feel some positive emotion again.