Depression and why some of us are SAD

I am 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. Dysthymia 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 categorised 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.

Diagnosing depression

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, especially 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.

Non-drug therapies

An alternative to pharmaceutical treatments is represented by transcranial magnetic stimulation (TSM) 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 light-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 melatonine 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!

References
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

Narcolepsy

Can you think of any situation when, let’s say, you were talking to someone and suddenly that person would glance at you with boredom and their eyes seemed to slowly close as if they were on the verge of nodding off? This sort of situations can be very annoying and it would be a lie to say that you didn’t feel mad or at least slightly pissed off when they happened. You probably either ignored them or chose a more aggressive approach, in order to ‘wake’ them up.

But what if instead of just a very rude or uneducated person you would have to deal with someone who suffers from narcolepsy? Not only the person you would supposedly talk to is actually asleep, but waking them up is very likely to trigger unwanted behaviours.

As odd as it sounds, there are people in this world who can fall asleep instantaneously, without any previous warning, in the middle of doing anything ranging from reading and talking to cooking and driving. These people are called ‘narcoleptics’.

So what is narcolepsy?

Narcolepsy or the so-called syndrome of excessive sleepiness is a chronic neurological disorder that affects less than one percent of the population, therefore it is considered a relatively rare disease. Due to the multiple causes that lead to this disorder, narcolepsy has been considered either an autoimmune or a neurodegenerative disease. Often it is hard to be identified and wrong diagnosis is given, such as epilepsy (because cataplexy could resemble epileptic seizures) or schizophrenia (due to visual and sometimes auditory hallucinations).

Symptoms

The most common symptoms of narcolepsy are: sleep disturbance, cataplexy (muscle weakness), excessive daytime sleepiness, sleep paralysis, hypnagogic hallucinations and abnormal rapid eye movement (REM) – in narcoleptics REM occurs extremely fast (within a few minutes), whereas normally it should manifest after one hour and a half. Nevertheless, patients who suffer from narcolepsy have also experienced increased appetite, automatic behaviour, sleep apnoea and memory problems (this is not due to cortical dysfunction, but to impaired attention).

Except for cataplexy, sleep paralysis and hypnogogic hallucinations, reduced attention and disorientation after waking from daytime naps are also common. Moreover, patients could suffer from aggressive behaviour, with temper outburst and irritability especially if woken up and they might also deny their condition.

Interestingly enough, despite the fact that narcoleptics have trouble with being awake during the day, they would often experience insomnia during the night. Their sleep deficiency can be accentuated by some forms of medical treatment.

Causes

It has been demonstrated that many factors are involved in the initiation and development of narcolepsy; these range from genetic factors, including the human leukocyte antigen DQ and DR (HLA-DQ and -DR) genes and polymorphism of certain type of genes (for instance tumour necrosis factor alpha or monoamine oxidase genes, both located on chromosome 6) to environmental factors (head trauma and various infections, such as the infection with Streptococcus pyogenes). HLA genes code for the HLA complex called antigens, proteins with an essential role in the immune functions and usually associated with autoimmune diseases.

In addition, latest discoveries have shown a decrease in levels of hypocretin-1 and -2 (also known as orexin-A and-B) in the cerebrospinal fluid and hypothalamus could account for the trigger of narcolepsy. Deficiencies of this neuropeptide might produce changes in monoamine oxidases, enzymes with an important role in the degradation of amine neurotransmitters, such as serotonin and dopamine. Low levels of dopamine dramatically influence the development of some psychiatric and neurodegenerative disorders (ADHD and Parkinson’s disease, respectively) including narcolepsy.

Treatment

Given the fact that the decrease of hypocretin tone plays an important role in the production of narcolepsy, an efficient solution would involve the increase in the concentration of these peptides. One way of achieving this is by intracerebroventricular administration of hypocretin-1 peptide, which appears to reduce the frequency of cataplexy and stimulate arousal in mice. Another even more efficient and less invasive method is represented by the intranasal administration, hence the neuropeptides being directly delivered to the central nervous system.

Serotonin was also discovered to have significant role in wakefulness and REM regulation, hence decrease levels of serotonin (5-HT) might induce narcolepsy. Therefore, medicines that could increase the levels of serotonin in narcoleptic humans might be a solution for this disease.

Most of the patients diagnosed with narcolepsy are recommended pharmaceutical treatments, which usually consist of the intake of certain doses of stimulants. Nevertheless, taking into consideration the side effects of these drugs and the limited adherence of the patients to the medications, alternative methods have been discovered. One of them is represented by behavioural and psychological approaches, for instance regularly scheduled naps during the day and daily exercises (but avoidance of activities that increase body temperature).

Since treatment involving cognitive stimulants is the most wide-spread, a lot of drugs are used in order to cure narcolepsy. A very common example is represented by amphetamines (such as Ritalin), which are known to increase levels of dopamine in the brain, reduce daytime sleepiness and inhibit the monoamine oxidases. Also Mazindol, Modafil and Selegiline are used as treatment for narcolepsy, as they reduce cataplexy and inhibit the monoamine oxidases. The amino acid L-tyrosine stimulates the production of noradrenaline and dopamine, therefore it also represents a solution (although more tests of its effects are required).

Some very important drawbacks that should be considered when using pharmaceutical stimulants in treating narcolepsy, and any disorder that affects the nervous system in general, are the possible adverse effects and the chances of dependence, abuse and tolerance. Although serious addiction problems haven’t been registered, high dosages increase the risk. According to some studies, 30-40% of narcoleptic patients using medicines have developed tolerance, therefore 1-2 days per week of no medication is recommended.

The most common adverse effects of the psychostimulants are headaches, insomnia, anorexia, irritability, heart palpitation. Patients must acknowledge that these drugs cannot be taken as brain enhancers and they must also be aware of the side effects and possible risk of addiction before deciding to undergo a medicine-based treatment.

I hope you enjoyed reading this article 🙂 It is actually highly based on an essay I had to write in my first year of university and therefore I am going to add the literature I used at the time in order to gather information.

Further reading:

Aldrich, M. S. (1990). Narcolepsy. The New England Journal of Medicine, Vol.323(6), pp.389-394 ].

Allsopp, M., & Zaiwalla, Z. (2001). Narcolepsy. Archives of Disease in Childhood, Vol.67, pp.302-306.

Bassetti, C. R., & Scammell, T. E. (2011). Narcolepsy. Dodrecht: Springer.
Conroy, D., Novick, D., & Swanton, L. (2012). Behavioral Management of

Hypersomnia. Sleep Medicine Clinics, Vol.7, Issue 2.

Danis, P. (1939). Narcolepsy. The Journal of Pediatrics, Vol.15(1), pp.103-106.

De La HerrĂĄn-Arita, A., & GarcĂ­a-GarcĂ­a, F. (2013). Current and emerging options for the drug treatment of narcolepsy. Drugs, Vol.73(16), 1771-1781.

M.M Mitler, M.S Aldrich, G.F Koob, et al. (1994). Neuroscience and its treatment with stimulants. Sleep, Vol. 17 (4), pp. 352–371.

Thorpy, M. (2001). Current concepts in the etiology, diagnosis and treatment of narcolepsy. Sleep Medicine, Vol.2(1), 5-17.

Image edited by Isuru Priyaranga

Mechanisms of schizophrenia

It took me a while to figure out whether to divide this article into two parts or to sum up everything in one long, possibly tedious reading. Honestly, I still don’t know, so I’ll just start writing and we shall see what it turns out to be.

I’m sure you’ve all heard of schizophrenia – the disease of thought disorder, or know people who suffer from it. But only a few actually understand what it is about.

No wonder scientists have been struggling to develop efficient treatments for schizophrenia; not only is it largely uncommon (1% of the world’s population is affected), but also its causes are usually unknown. Scientists generally refer to schizophrenia as a psychiatric disease involving a progressive decline in functioning, which begins in early adolescence and persist throughout the patient’s life. Due to its heterogenous symptoms and multiple possible causes, there are many hypotheses that intend to explain what triggers schizophrenia and how it develops.

In spite of the fact that is it a genetic disorder, the environment and external factors (such as viral infections during the intrauterine and infant period) may be crucial to the development of schizophrenia. The symptoms have been divided into two categories. The positive symptoms include thought disorder, hallucinations, delusions, disorganised speech etc., whereas the negative symptoms are characterised by poverty of speech, reduced expression or emotion, memory impairment, anergia, abulia etc. In addition, the brains of schizophrenics show structural macroscopic abnormalities (for instance, the enlarged ventricles and the shrinkage of the surrounding brain tissue), as well as microscopic changes, such as the dysregulation of dysbindin gene in the formation of abnormal dendritic filopodia. There are three types of schizophrenia, according to its symptoms: paranoid schizophrenia – auditory hallucinations, delusions, strong belief of being chased by powerful people; disorganized schizophrenia – reduced emotions and lack of emotional expressions, incoherent speech (mostly negative symptoms); catatonic schizophrenia – impairment of movement, usually immobility and catatonia, bizarre grimacing (this is similar some of the symptoms of hysteria, which has been described as a sexually related and later on, as a psychiatric disorder up until the beginning of the 20th century).

But enough with the boring general details! Let’s get to the fun part: The monoamine hypothesis of schizophrenia! Here we are going to talk about two very important neurotransmitters in the central nervous system: dopamine and glutamate. The second one is the main excitatory neurotransmitter in the brain. There are four main types of glutamate receptors: AMPA, NMDA, kainate and mGluRs. It has been demonstrated that reduced activity of the NMDA receptors can result in some of the negative symptoms of schizophrenia (lack of social behaviour, catatonia).

Dopamine is the metabolic precursor of another neurotransmitter, noradrenaline (norepinephrine). But there is a lot more to dopamine and its roles in the brain than this. There are four main dopaminergic pathways: the mesolimbic pathway – related to the “reward” system and significance; it has its roots in the ventral tegmental area and projects to the nucleus accumbens (in the ventral striatum) and the limbic system; the mesocortical pathway – involved in cognition and motivation; the tuberoinfundibular pathway – roles in lactation; these dopamine neurones originate in the hypothalamus; the nigrostrial pathway – involved in movement planning and connects the substantia nigra (midbrain) to the striatum.

Schizophrenia and another mental illness, a neurodegenerative one, Parkinson’s disease, are also linked to dopamine. When it comes to schizophrenia, it seems that the mesocorticolimbic pathways have more influence on its onset: the ‘positive’ symptoms appear to be triggered by dopaminergic hyperactivity in the mesocorticolimbic system. At the same time, hypoactivity of dopamine is this region is the cause of ‘negative’ symptoms. Nevertheless, it has been discovered that overexpression of the dopamine receptor D2 (DRD2) gene in the striatum also reduces motivational behaviour in mice, therefore mimicking psychotic ‘negative’ symptoms. Similar findings show that increased density of dopamine D2 receptor in the striatum, along with lower thalamic density of this receptor appear to induce divergent thinking, which is associated with schizophrenia.  

All these changes may account for the abnormalities that we see in “mad” people. It seems that we are so fragile, given that often small chemical and physical disruptions can trigger something as big and terrifying as schizophrenia. Imagine hearing, seeing, feeling, smelling things everyone says are not real (schizophrenics often have multiple hallucinations: auditory, visual, gustatory, tactile, olfactory). But to you they are so real and disturbing! Many schizophrenics even hear their own thoughts as if they are coming from the outside and therefore believe that everyone knows what’s in their heads. Imagine having the constant feeling that someone is after you (paranoia) or being certain that you are dead (the Cotard’s Syndrome) or that your husband has an affair (the Othello Syndrome).

I think this topic can never be fully covered and we would spend days talking about schizophrenia, so this article should better come to an end. As I am sure you have lots of questions and comments, don’t be shy and post anything you think it’s relevant to what has been discussed above. Hope you enjoyed this reading.

For further information: 

Bear et al., 2006. Neuroscience – Exploring the Brain. s.l.:Lippincott Williams & Wilknins, pp. 679-684

de Manzano et al., 2010. Thinking Outside a Less Intact Box; Thalamic Dopamine D2 Receptor Densities Are Negatively Related to Psychometric Creativity in Healthy Insividuals. Public Library of Science

Jia et al.,  2014. The Schizophrenia Susceptibility Gene Dysbindin Regulates Dendritic Spine Dynamics. The Journal of Neuroscience, Oct.pp. 34-41

Kandel et al., 2011. Modeling Motivational Deficits in Mouse Models of Schizophrenia: Behavior Analysis as a Guide for Neuroscience. Behavior Processes, pp. 149-156

Kolb et al., 1996. Fundamentals of Human Neuropsychology. 4th Edition ed. s.l.:W.H. Freeman and Company

Image by Damaris Pop

Why drugs are actually bad!

We are all well aware of how serious and, unfortunately, wide-spread drug addiction is, yet we don’t actually know what makes people so dependent of a drug after they have started using it. Even more intriguing is why former addicts, who have stopped using drugs for weeks or months, revert back to drug use, knowing full well that the substance they were addicted to in the past pretty much ruined their lives.

As I am sure you expect this article to shed light on the problem, I’m not going to keep you guessing. Two weeks ago, a team of researchers at the Icahn School of Medicine in US published a greatly revealing study in The Journal of Neuroscience. They appear to have found the answer to how cocaine affects decision-making in addicts as well as why abstinent users often choose to start taking cocaine again.

Dopamine is one of the commonest neurotransmitter in our brains. It is involved in many cognitive processes, including prediction and recognition of loss. Therefore, dopamine plays a very important role is some mental and also neurodegenerative diseases, such as schizophrenia (where dopamine levels are overly increased) and Parkinson’s disease (caused by decrease in dopamine secretion in the midbrain and degradation of dopamine receptors).

This recent study shows that cocaine acts on dopamine signalling, influencing the so-called Reward prediction error (RPE). It has been recorded, fallowing neuroimaging and pre-clinical studies, that dopamine signalling is increased in response to an unpredicted reward (which is scientifically referred to as positive RPE) and decreased as a result to a negative outcome or the omission of a predicted reward (negative RPE). The team of researchers demonstrated, therefore, that cocaine reduces the response to unpredicted loss (impaired negative RPE), while leaving the positive RPE almost intact.

In order to obtain these results, the team used 75 subjects, who were divided into two groups: 25 non-cocaine users and 50 cocaine addicts. Moreover, the second group was also divided as fallows: 25 cocaine users who had taken cocaine within 72 hours of the study and 25 cocaine users who had abstained from taking cocaine within 72 hours of the study. All subjects had to play a computer game that involved prediction and guessing.

As you may expect, the non-users responded normally to both unexpected  loss and predicted reward, as well as to predicted loss and unpredicted positive outcome. On the contrary, the cocaine users responded far less to unexpected negative outcome. This means that their brains were reacting less strongly to the negative result of a prediction than the normal subjects’ brains.

Moreover, and this is the most fascinating part, the users who hadn’t taken cocaine within 72 hours, showed deficit in positive RPE, whereas the other addict group (who had consumed cocaine in the previous 72 hours), had unaffected positive RPE, but impaired negative RPE. Also dysregulation in serotonin system in drug addicts might lead to this kind of results (serotonin signalling has been registered in response to negative prediction, in normal brains).

So, to cut the story short and in a more simplified version, if you use cocaine, you are more likely to omit the bad things in your life. But if you take cocaine and then you give up, you get the opposite result: you become less able to enjoy positive aspects. This might account for the fact that people who stopped taking drugs tend to start using them again after rehab. Does this mean we have to become drug addicts? It seems like this is the solution. Well…NO! Definitely not! And I’m not saying this because I might get into trouble for promoting drug use, but there is a very important reason for that. We DO need to anticipate and recognize negative outcomes. This is how all creatures in this world survive. This is how more advances creatures (like humans) are capable of making good decisions and learn from mistakes.

Some might argue, though, that it is preferable to be happy all the time, despite how much you fail and that there is no such thing as actual failure, as it’s all about how our own brains perceive the environment. What do you think? Is this true or not? Either way, I strongly suggest you don’t start using drugs!

The study

Image modified by Isuru Priyaranga