DANIEL MALONE: In this section, you’ll be guided through the causes of depressive disorders, followed by a discussion about how depressive disorders can be treated either with or without medicines. In particular, you’ll see how the antidepressant fluoxetine affects neurons in the brain.
So what is the cause of depressive disorders? No single factor has been identified as the cause of depressive disorders. Changes in a number of brain regions are thought to be important in depression, in particular in the frontal cortex, which is the planning and reasoning centre of the brain. I mentioned in the introductory week that neurons are nerve cells that are capable of generating electrical signals, and neurotransmitters are chemicals that are released from neurons. Many factors have been associated with depressive disorders, including the way in which neurons are connected to each other.
It is known that brain neurotransmitters such as serotonin and noradrenaline are important in depressive disorders, and most drugs on the market to treat depressive disorders act to increase levels of these neurotransmitters. The alterations that occur in the brain are probably as a result of genetic predisposition coupled with personal experience. In the case of Maria, perinatal depression is associated with environmental factors, such as the many changes and challenges that occur following the birth of a baby. It is well known that depression has a genetic basis. Evidence of this is that people with a family history of depressive disorders are more likely to have a depressive disorder. And some drugs can cause a person to become depressed.
For example, some medicines used for high blood pressure. Let’s now look at how to treat depressive disorders. Psychotherapy is the process of treating a condition by psychological means. In the case of depressive disorders, psychotherapy aims to change a person’s negative thoughts, maximise their potential, and offer strategies to deal with bouts of depression. Most often, psychotherapy is conducted by a psychologists or a psychotherapist. But now, a number of online mental health tools are available that can help or aid people who cannot seek face to face help. An example is called MoodGYM, which is a free self-help programme designed at the Australian National University that helps people learn cognitive behavioural therapy skills for preventing and coping with depression.
Psychotherapy is often used in conjunction with antidepressant medication, or in milder depressive cases, instead of the antidepressant medication. Studies using PET scans have compared brain regions following antidepressant use or psychotherapy. Whilst the changes are not identical, certainly similar changes are produced, and similar brain regions are involved. And this reflects the brain’s dynamical or plastic nature and reinforces the value of psychotherapy in depressive disorders. A second way to treat depressive disorders is through the use of antidepressants. As mentioned earlier, by increasing brain neurotransmitters, such as serotonin, some depressive symptoms can be reduced. Selective Serotonin Reuptake Inhibitors, or SSRIs, are the most common drug class used for depressive disorders.
Fluoxetine was the first SSRI released onto the market, and David will discuss its important place in antidepressant drug discovery in the next section. SSRIs are often the first drugs recommended to treat depressive disorders and can also be used for other mental conditions such as anxiety and obsessive compulsive disorder. So before looking at how fluoxetine works, let’s recap how neurotransmitters such as serotonin are released from neurons. When an electrical signal travels along a serotonin neuron, this triggers serotonin filled sacs or vesicles in the neuron to move towards the surface of the neuron to release their contents. Once neurons release serotonin, serotonin receptors on other neurons are activated.
An efficient recycling occurs constantly to transport serotonin back into the neuron using a serotonin transporter. In the neuron, serotonin is either repackaged back into vesicles ready for release again, or is broken down by enzymes. Thus, serotonin neurons are good global citizens, as they practise sustainable living.
Fluoxetine binds to serotonin transporters, which decreases serotonin going back into the neuron, leaving more serotonin free to bind to serotonin receptors on other neurons. Although fluoxetine starts to work at the neuron level fairly soon after a person takes it, improvement of depressive symptoms isn’t seen for at least a week and more likely three to four weeks. This is because the inhibition of reuptake of serotonin probably triggers other events in the brain that are required to relieve depressive symptoms. What these active events are is the subject of ongoing investigation.
While SSRIs have fewer side effects than most other antidepressants, they still have a range of side effects. When serotonin is released from nerves, it activates serotonin, or 5-HT receptors. But there are many different types of 5-HT receptors, 5-HT 1, 2, 3, et cetera. And their various activation is probably responsible for the range of side effects produced by the increases in serotonin outside neurons that are produced by SSRIs. For example, nausea is probably caused by increased activation of 5-HT3 receptors in the gut while insomnia is probably caused by activation of many different types of 5-HT receptors in brain regions. This range of responses highlights serotonin’s important role in many bodily processes.
So in summary, you’ve seen some changes in the brain that occurs in depressive disorders and how psychotherapy and antidepressants can be used to treat depressive disorders. You also saw how fluoxetine works to treat depression. In the next section, David will guide you through an historical medicinal chemistry journey of antidepressant discovery.