I’m warning you, this is going to be a long one! But it’s interesting, I promise.
There is a lot of confusion and mixed opinions when it comes to depression. Some people use the term inappropriately, to describe what is in fact grief (the feeling of sadness that humans, and presumably other animals, experience after a loved one has died, for instance), others tend to label depressed individuals as “weak”, “selfish”, “useless”, “cowards” etc.
At the same time, for the past 30 years, there have been extremely important discoveries in the field of affective disorders, which have helped eliminate many misconceptions and laid the foundation for a better understanding of what this set of disorders (affective disorders) are and what is actually happening in the brain of the ones “affected”. Moreover, according to some new theories, depression is in fact an evolutionary advantage in situations such as physical illness and dominance. When the body is sick it needs time and energy in order to recover, so the organism experiences depression in order to avoid activity and focus on recovery; in nature, many animals with a dominant status are forced (by a variety of factors) to occupy a lower hierarchical level, in which case “depressive” behaviours such as avoiding eye contact or sexual contact helps reduce the risk of attack by other dominant, more powerful individuals. There are many theories, as you can see, and this article is meant to present and analyse some of them.
We should start by clarifying a very important aspect: depression is different from grief. While the latter is a normal reaction to some external factor(s) with a negative emotional impact on our day-to-day lives, and dissipates by itself after a certain period of time, depression is a pathological, abnormal condition (either in its own right or as a symptom of other metabolic or neurodegenerative diseases). However, it should be noted, and this is one of the key concepts in understanding depression, that the way individuals interpret and react to various external events, which affect their mood, differs, which means that some individuals have a stringer predisposition to depression than others. Now, why is that? A variety of factors, both genetic and epigenetic (developmental, such as child abuse, neglect) play a role and often act synergistically, but we will deal with them (especially, the genetic factors) a bit later in the article.
Different types of depression
Major depressive disorder, also known as “the classical depression”, which is characterised by insomnia, anorexia and lack of joy and interest in things. At the opposite side of the spectrum, there is atypical depression, which manifests itself through increased sleepiness, weight gain and anxiety. Dysthimia is another form of depression, more difficult to diagnose, due to the fact that it presents itself with mild depressive symptoms. All these types discussed so far have been categorized as monopolar.
Bipolar depression refers to a kind of depression accompanied by periods of mania – manic episodes are characterised by elevated, euphoric mood, impulsiveness, hyperactivity and even psychotic symptoms (hallucinations, delusions). A case described by Dick Swaab in his book “We are our brains – from the womb to Alzheimer’s” portrays a woman, who developed mania following the death of her husband. She would talk and laugh hysterically, call the police in the middle of the night for no reason and eventually began to make up stories about people whom she had never met before, but who she believed were longtime friends of hers. After her manic episodes disappeared as a result of treatment, she developed severe depression. Luckily, her story has a happy ending, as she made a full recovery.
Bipolar depression is also associated with Seasonal Affective Disorder (SAD), characterised by extreme mood seasonal swings. In this article, I have dedicated an entire section to SAD, so I am not going to delve into it for now. Given all these particularities of BD, it is often regarded as a separate disorder (bipolar disorder or manic disorder), rather than another type of depression. As there are so many things to mention about depression, I will leave BD for future article.
In order to be diagnosed with depression, one must have at least one of the two main symptoms: persistent sadness and marked loss of interest, as well as at least five secondary symptoms: disturbed sleep (either increased or decreased), disturbed appetite (increased or decreased), fatigue, poor concentration, feeling of worthlessness and excessive guilt, suicidal thoughts.
Depending on the number of these symptoms, as well as the degree to which they manifest, monopolar depression can be sub-divided into: sub-threshold depression (fewer than five secondary symptoms; no treatment needed), mild depression (fewer than five, but in excess secondary symptoms), moderate depression (more than five, plus functional impairment between mild and severe depression) and severe depression (most of the secondary symptoms and also true psychotic symptoms – yes! they can occur in severe monopolar depression as well, not just BD).
Biochemical pathways and brain systems involved in depression
In Ancient Greece, there was a biochemical theory of depression. It was believed that depression was caused by the failure of liver to eliminate toxic substances from the digested food, resulting in the accumulation of “black bile” (melan means “black” and chole means “bile”, which give the words melancholy). Biochemical theories nowadays have at their core three monoamines, which I am sure you are all familiar with: noradrenaline (a neuromodulator very similar to adrenaline) and serotonin and dopamine.
These two substances have long and diffuse projections throughout the nervous system and in levels lower than otherwise normal, they are said to be involved in affective disorders. For example, drugs such as Reserpine, used to treat the positive symptoms of schizophrenia by depleting dopamine (and also serotonin and noradrenaline) elicited depressive symptoms in schizophrenic patients.
Therapies involving monoamines
The idea is, you want to higher levels of monoamines in order to treat depression. Enzymes involved in the monoamine re-uptake mechanism from the synaptic cleft back into the presynaptic level and enzymes involved in the monoamine metabolism, such as monoamine oxidases (MAO) are the most common targets for the majority of anti-depressants.
- Selective serotonin re-uptake inhibitors (SSRI) and selective noradrenaline re-uptake inhibitors (SNRI) – Prozac (Fluoxetine), Zoloft (Sertraline), Celexa (Citalopram), Paxil (Paroxetine) block serotonin reuptake and Effexor/Viepax/Trevilor/Lanvexin (Venlafaxine), Cymbalta (Duloxetine) inhibit the noradrenaline reuptake enzymes. For those of you who are currently under this treatment, be careful! Side-effects such as sexual dysfunction, insomnia, increased aggression and self-harm/suicide can occur. Moreover, SSRI are not so effective. They have a very long induction, which means that it takes a long time (2-3 weeks) for the therapeutic effects to start working, during which time there is a high risk of suicide (due to depression). They also have a placebo effect of 50%, which is not necessarily a bad thing as long as it works, but raises the question whether the monoamine hypotheses is really that valid in the case of depression.
- Tricyclic antidepressants – also block the reuptake mechanism, resulting in more monoamines in the synaptic cleft. Amitril (Amitriptyline), Aventyl/Norpress/Noritren (Nortriptyline) and Tofranil (Imipramine) are a few examples. They are derived from Phenothiazines (such as Chlorpromazine), which are antipsychotic drugs (used to treat schizophrenia). Some of the side-effects are: chronic pain and suicide overdose.
- MAO inhibitors – Nardil/Nardelzin (Phenelzine), USAN (Thanylcypromine), Marplan/Enerzer (Izocarboxazid) and Amira/Aurorix/Clobemix (Moclobemide) are very effective and widely prescribed for in major depressive disorder, bipolar disorder and anxiety disorder, although the first three pose the high risk of hypertensive crisis and death if the patient is consuming cheese or wine.
The big problem with these drug therapies is dependence – if antidepressants, esoecially Paroxetine and Venlafaxine are administered for a long period of time and then stopped, the patient is likely to experience Antidepressant discontinuation syndrome, characterised by flu-like symptoms, motor and cognitive disturbances.
An alternative to pharmaceutical treatments is represented by transcranial magnetic stimulation of the cortex, electroshock therapy – this is, apparently, very effective, BUT might result in impaired memory – and gene therapies. The latter refers to the insertion, via a vector or a plasmid, of genes that encode neurotransmitter molecules, receptor proteins or neurotrophic and neuroprotective substances. Given that many variations in genes for chemical messengers in the brain are responsible for the predisposition of certain individuals to depression, gene therapies, although still at a developing stage, provide powerful approaches to the treatment of affective disorders.
Over-activation of the stress axis
Another theory for the development of depression, which goes hand-in-hand with the “monoamine hypothesis” is that in depressed individuals there is an exaggerate amount of cortisol (a steroid) in the blood, which can affect the brain. Basically, our brains react to stressful situations by producing some hormones in the hypothalamus and pituitary gland (hypophysis), which eventually result in the production of cortisol. In turn, cortisol acts on these structures to inhibits their activity and, thus, preventing further increases in its level – this is an example of a negative feedback mechanism.
In normal people, a stressful situation will result in increased levels of cortisol, but this steroid will then revert to its normal levels. In depressed individuals, the stress axis (hypothalamus-pituitary-adrenal axis) becomes hyperactive and, as a result, a stressful event will result in the overproduction of cortisol.
In excess, cortisol affects brain structures involved in the control of emotions and fear, such as the cingulate cortex and amygdala (which explains the anxiety symptoms experienced by people suffering from atypical depression) and memory, such as the hippocampus, which explains the cognitive dysfunctions. Moreover, the activity in the prefrontal cortex, which normally inhibits the hypothalamus (overactive in depression) is decreased by cortisol. So, really, it is like a vicious circle.
Why is the stress axis hyperactive in the first place? Possibly due to decreased sensitivity of the cortisol receptors to cortisol, which might be the result of genetic as well as developmental factors (previously mentioned).
Monoamines play a role here, as increased levels of monoamines (by the administration of antidepressants) can determine neurogenesis in the prefrontal cortex and hippocampus, so these areas can function properly again and can, thus, inhibit the hypothalamus, so no longer hyperactivity of the stress axis!
Seasonal affective disorder (SAD)
Although I am planning to write about bipolar disorders in another article, I thought it is worth discussing SAD in this article as well, given that so many people, especially those living in the Northern hemisphere, suffer from it.
In the References section there is a document called “The recent history of seasonal affective disorder (SAD)”, which is a transcript of the 2013 Witness Seminar in London. I highly recommend this reading for two reasons: it is full of remarkable, extremely important information regarding SAD and the participants at this seminar included personalities such as Prof. Josephine Arendt, Prof, Norman Rosenthal, Prof. Alfred Lewy, Prof. Rob Lucas, who are pioneers of the SAD diagnostic criteria and underlying causes (for instance, Rosenthal is the first psychiatrist who diagnosed SAD).
As many of you probably know, and sadly from personal experience, SAD is a seasonal mood change disorder, a type of bipolar disorder, which determines depression during the autumn/winter seasons and hypomania during summer. In order to understand SAD, we must remember a few things about the circadian rhythm, which I have previously discussed in two articles: Why “sleep” and Even flies sleep and learn. In short, we have an internal, genetic “clock” inside our brains (in the Suprachiasmatic nucleus – SCN), which determines the body to function in an approximately 24-hour cycle and which is also entrained by the ligh-dark cycle. This is not only a circadian (day-night) clock, but also a seasonal clock, which means that changes in the environment (especially light and temperature) across the year entrain this clock and determine physiological and psychological changes in our bodies.
In SAD, there is an abnormal secretion of melatonin (the hormone that triggers sleep, when it is dark outside). Light inhibits this hormone: cells in our retina, which are not coding for visual information, send projections via a distinct pathway than the rods and cones. These cells, containing the peptide melanOPSIN, project via the retinohypothalamic tract to the SCN, “telling” the brain that it is dark outside, so the brain (SCN) determines the synthesis and release of melatonin from the pineal gland. When there is light outside, the production of melatonin is inhibited. The duration of melatonin secretion is also affected by the circannual changes – long secretion in short days and short in long days. The scientists who took part in the Witness Seminar discovered that malatonin production was increased during the depressive/winter phase and that sunlight decreased its production, thus, alleviating the symptoms of depression in SAD. A note here, sunlight is an effective treatment for SAD, not ordinary room light. This explains why, during winter, when people tend to spend more time indoors, their levels of melatonin increase. The reasons why room light does not inhibit melatonin production are the intensity of light (sunlight is five times more intense than room light) and spectral differences. More about SAD and bipolar disorder in a future article!
I hope this article made sense and that you enjoyed reading it!
SAD – Pdf of The Witness Seminar transcript
Beatty, 2000. The Human Brain – Essentials of Behavioural Neuroscience. Sage Publications. Inc., pg.464-471
Dick Swaab, 2014. We are our brains – From the womb to Alzheimer’s. Penguin Books, pp. 112-122
Image by Damaris Pop