Depressing Anti-Depressants

by Rina Therese R. Madelar 062147

Mrs. W, an eighty year old lady comes into a clinic with complaints of frequent tiredness and weakness. She has been living alone for eight years, from the time her husband died. She is fully capable of managing her home and stocking up on groceries until recently when she started feeling too weak to perform the chore. According to this lady, she feels unsteady when walking and she has not been out that much recently because she “just doesn’t feel like it.” In an incident during the winter, she fell on the ice and broke her arm but this has now completely healed (Depression Case Study #2).

The woman denied feeling sad but admitted that she is scared of falling again because she might injure her hip. This fear appears to have emerged from family members who broke their hip and lost the ability to fend for themselves (Depression Case Study #2). Ultimately, after further examination, Mrs. W has been diagnosed to have depression, rooted from her constant fear of falling which has led her to change her pattern of living and hindered her to perform activities that she is fully capable of doing until recently. Here it can be seen that the simplest factors such as weakness and imbalance may seem perfectly normal and naturally part of the human life cycle (old age) can already be a symptom of depression.

Symptoms and Treatment

Melancholia, commonly known as depression, is the most familiar psychiatric disorder to the population. Because of this, it has been called the “common cold of psychopathology” by clinicians specializing in this field. According to a study by Dunn, Sham and Hand in 1993, most people may think that frequent and episodic complaints of individuals who claim to be depressed signify that what they are experiencing is not serious and thus can be shrugged off. The fact that the causes of these complaints are confounded after a while seems to send a message that the condition can easily be resolved. In reality however, depression, which takes on many forms, is a very serious condition which can ultimately lead to suicide deaths (G. Dunn, 1993). In fact, in a year, 19 million Americans or almost 10% of the whole population are affected by this condition (What is Depression?).

Depression is characterized by continual sadness and inability to “enjoy normally pleasurable experiences” due to “reduced sensitivity to pleasurable stimuli”. Characteristics of depression are listed below (Strickland, 2001).

1. Unique quality of sadness, different from what a normal person would feel even during intense grief and pain such as the death of a loved one
2. Depression is worse in the morning
3. Waking up early in the morning, at least two hours before regular waking time
4. Change in physical movement
5. Extreme weight loss
6. Inappropriate guilt

A person is said to be suffering from depression if sadness is coupled with at least three of the symptoms above (Strickland, 2001). As treatment for melancholia, patients are subjected to electroconvulsive therapy where seizures are induced to create a calming effect. Despite the benefits it brought to depressed individuals, this showed to cause memory problems (Electroconvulsive therapy, 2010). Today, patients are encouraged undergo psychotherapy and take antidepressants to manage their condition (Donald J. Franklin, 2003).

Antidepressants Behind the Scenes

Figure 1: Brain Structure - Depressed vs. Not Depressed  (What is Depression? (Depression #1), 2007)

An individual experiencing depression not only shows changes in physical behaviour, there are physical changes in brain structure as well (What is Depression? (Depression #1), 2007). The image on the right side shows significantly greater activity in the brain compared to that on the left of a person who is experiencing depression (Nazario, 2009).

Figure 2: Brain Synapse (Nazario, 2009)

Neurotransmitters are chemical messengers that pass information about behaviour, emotions and the like from neurons to target neurons in different locations in the body. Serotonin and norepinephrine are directly attributed to depression and low levels of such are known to cause this condition. When neurotransmitters exit the pre-synaptic cleft and enter the synapse, receptors bind to these chemical messengers and delivered to the post-synaptic cleft of the receiving neuron. Reuptake can happen after this wherein the released neurotransmitters go back to the sending neuron and the signals can be reused a number of times (Hasselbring).

Figure 2: Fluoxetine (Fluoxetine)

Antidepressants such as Prozac (common name fluoxetine) ensure the constant supply of serotonin by serving as reuptake inhibitors. As a result, released serotonin from the sending neuron which are already attached to the receptors can undergo semi-reuptake wherein the messenger dissociates from the receptors, pass through the synapse in a retrograde manner, bounce from the blocked ports and bind again to receptors (Mason, 2009).

Because of the bouncing back mechanism, antidepressants supposedly take immediate effect but it has been observed through clinical studies that Prozac and other selective serotonin reuptake inhibitors (SSRIs) are not exactly efficient in taking action to fight depression—a depressing fact for an antidepressant (Hasselbring). These drugs seem to have a delayed effect, functioning only after several weeks of drug intake (Hamilton, 2006).

SSRIs being the most common antidepressants used at present not only function specifically for depression. They are also used in other psychiatric conditions and target several parts of the brain to stimulate activity in a number of pathways (Pridmore, 2010).

Figure 4: SSRI Pathways (Pridmore, 2010)

1. Pre-frontal cortex – low mood
2. Basal ganglia – Obsessive Compulsive Disorder (OCD)
3. Limbic system – panic and anxiety
4. Hypothalamus – eating disorders

However, SSRIs are not advisable for use in conditions involving mid-brain structures and the spinal cord such as insomnia and sexual dysfunction respectively (Pridmore, 2010).

Mood Protein

This inefficiency prodded Pers Svenningsson of the Karolinska Institute in Stockholm and a group of US scientists to explore the serotonin mechanism in the brain. The researchers used helpless H/Rouen mice to serve as the model of depression while nonhelpless NH/Rouen mice are those at relaxed states. In helpless mice, there was observable low levels of p11 (alternative names: S100A10, calpactin I light chain or annexin II light chain) mRNA and protein. Upon further analysis, they found out that among the fourteen receptors of serotonin, p11 only interacted with one serotonin receptor which is 1B (5-hydroxytryptamine (5-HT_1B) receptor). Seen through immunofluorescence, its interaction with the protein appears to cause dispersion of the receptor at the surface of cells, resulting to greater availability of binding to serotonin and causing relaxed states (Svenningsson, 2006).

Figure 5: p11 Protein Tetramer (Boghog2, 2009)

Svenningsson and his team explored the effects of the link between 5-HT1B and p11 on the efficacy of anti-depressant action. Genetically modified mice with “doxycycline and overexpression of p11 under calcium/calmodulin-dependent protein kinase II (CamKII)” were used. Different controls were set up and their comparison showed that without doxycycline, there were increased amounts of functioning 5-HT_1B, a lower anxiety level and decreased depression-like states noticed in the group of mice. However, a group which had normal p11 level showed no such change. The increased level of p11 in mice seemed to have calming effects similar to how antidepressant drugs would normally work (Svenningsson, 2006). p11 and 5-HT_1B teaming up would produce better serotonin communication due to the directly proportional relationship between these two. As p11 levels increase, 5-HT_1B on the surface of the cell also follows suit (S100A10, 2010). This finding provides possible remedy for formulating better and more efficient antidepressant drugs.

Tandem Proteins

Figure 6: Annexin II (Emw, 2009)

Another calcium-binding protein, p36 or annexin II is known for its function in signal transduction, relaying extracellular messages to the internal networks of the cell. Other than that, it was found out to influence the action of DNA polymerase by reinforcing replication in the lagging strand. These are just a few of p36’s functions but its importance in the action of antidepressants is manifested in the way it works with p11 (Puisieux, 1996).

Annexin II and p11 is collectively called calpactin I, forming a heterotetrameric protein derived from two different monomers (Heterotetramer, 2007). Both constituents were detectable during the study only in the presence of the other. Researchers found out that p11 protein in the cell is affected by the level of annexin II available. Through a post-translational mechanism, annexin II boosts the volume of p11 by increasing its half-life six times (Puisieux, 1996). As a result, more p11 protein in the cell can work as relaxants in depressed states and consequently increase the volume of available 5-HT_1B serotonin receptors.

The Future of Antidepressants

Figure 7: Good things come to those who wait... forever? (Bell, 2008)

With the findings above, the formulation of a drug stimulating not only the regulation of p11 but p36 as well seems promising in providing antidepressants that work more efficiently than those currently available in the market. Soon enough, gone will be the days when patients experiencing depression will have to wait several weeks to feel the calming effects of improved serotonin uptake. Antidepressants are envisioned to work like pain killers, targeting the problem area within a few minutes of ingestion.

The World Health Organization (WHO) has reported in 2007 that depression is slowly becoming a global health problem due to the burden it brings to patients as well as the immediate support system of the affected individuals (Ten Statistical Highlights in Global Public Health, 2007). A drug that would function like a switch, turning on the mechanism for the efficient binding of serotonin to its receptor would greatly benefit the individuals affected as this could also make living day by day more bearable for patients and at the same time, reinforce and boost the efficiency of other depression treatments such as psychiatric therapy.

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