Personalised choice of antidepressants. The effects of sertraline, escitalopram, mirtazapine, venlafaxine and bupropion illustrated by clinical cases

Introduction

Certain assumptions, which differ from traditional approaches to thinking about psychopharmacotherapy, form the theoretical basis of this paper. These assumptions can be summarised as follows:
• Medications used to treat depression and anxiety have a substance-specific profile of effects on mental function (rather than on the symptoms of the disorder) [1-4]. These drugs have a specific effect that is manifested in most patients to whom they are administered. However, this action extends to specific mental functions related to emotion, cognition and, indirectly, interpersonal relationships, resulting in clinically observable effects (e.g. improved mood, reduced anxiety).
• This characteristic profile of effects on mental functions is reported indirectly by patients when they describe subjective treatment outcomes (experiences). Patients’ words are important because they describe what a particular medication changes in their experience. This is described indirectly at subsequent visits during the treatment process [4]. These subjective reports differ; patients describe their experiences differently during treatment with escitalopram, mirtazapine or bupropion. All these drugs belong to the antidepressant group (although they have different mechanisms of action), but their use is associated with different effects on subjective mental life. It is also possible to see more subtle differences, for example between groups of patients taking drugs with similar mechanisms of action, such as sertraline and escitalopram.
• A key factor in the success of pharmacotherapy is the right match between two elements: the drug’s profile of action and the patient’s profile of needs. On the one hand, this has the potential to lead to symptomatic improvement (reduction of anxiety and depression, as well as other symptoms such as sleep disturbance). On the other hand, it promotes good compliance with treatment (as the patient perceives benefits from taking the medication) [5]. Some directions of scientific research in psychiatry that support the above assumptions are briefly outlined below.

Drug-centered psychopharmacotherapy

Drug-centred psychopharmacotherapy was described by Yeomans, Moncrieff and Huws in the “British Journal of Psychiatry Advances” [1]. According to these authors, each drug has its own specific profile of action, which results from its biological action, but which can be assessed and defined in practice on the basis of reports from patients treated with the drug. Patients with a confirmed diagnosis who are taking a particular therapeutic agent report its effects subjectively to the psychiatrist. This is an invaluable source of information about the profile of action of this substance when used in a group of patients with a diagnosed condition. Listening carefully to these reports allows the psychiatrist to become sensitive to differences in patients’ experiences of specific substances used, for example, in the treatment of depression or anxiety disorders. This can be summarised as follows: “Patients with depression generally report this type of subjective experience after taking drug X, whereas they report the following subjective experience after taking drug Y”. This opens the way to the process of matching the drug profile to the patient’s needs. It is important to emphasise these two elements: listening carefully to the reports of patients taking a particular drug, and generalising the subjective experiences of patients reported during treatment with that particular drug.
According to this way of thinking, the effects of drugs are not considered within diagnostic categories (such as depression, anxiety disorders) but in the context of their effects on specific phenomena that transcend the boundaries of specific diagnoses. Yeomans et al. propose a change in approach to pharmacological treatment. These authors advocate a shift from thinking of the effects of drugs as specific to a particular disorder (associated with a particular diagnosis) to an approach based on drug-centred psychopharmacotherapy. The traditional approach focuses on psychiatric diagnoses and drugs are seen as related to the treatment of a specific disorder (e.g. ‘an antidepressant’ or ‘an anti-anxiety drug’). In the approach proposed by Yeomans et al, the focus is on the drug itself or, more specifically, its effect on mental processes (or, more broadly, psychophysiological processes). In this perspective, the action of a drug can be thought of in terms of how this action can be used to provide effective psychopharmacotherapy for patients who are experiencing disturbances in the very processes to which the drug’s action applies. According to these authors:
• The approach, in line with the concept of drug-centred psychopharmacotherapy, is to assess whether the effects of the drug on mental functions and behaviour can be beneficial for the patient (taking into account the patient’s specific life situation).
• According to the drug-centred psychopharmacotherapy, the desired effects of pharmacological treatment are one of the consequences of a general change in the clinical state induced by the drug. Therefore, they belong to the same conceptual category as adverse effects.
• Psychotropic drugs are psychoactive substances that influence the clinical characteristics of symptoms by exerting specific effects on physiological phenomena that control mental processes. They also determine the nature of emotional experience and affect behaviour (even in healthy people).
• Many psychiatrists are guided by drug-centred psychopharmacotherapy (although they may not explicitly state this), especially in the case of pharmacotherapy that is not in line with the registered indications or the summary of product characteristics. This is often the case when drugs are used for their effects on emotions or behaviour.

The cognitive neuropsychological theory of antidepressant action

In a paper published in 2020 [6], Godlewska and Harmer summarise the current state of the cognitive neuropsychological theory of antidepressant action, which has been developed over more than a decade. According to this theory, the biological action of antidepressants changes over time in response to clinical treatment by correcting the negative bias (dysfunction) in the processing of emotional information that occurs in depression. Correcting this cognitive bias is crucial to the effects of treatment. However, for mood improvement to occur, this restored state of emotional processing must be experienced in interactions with other people and the patient’s social environment. One of the key assumptions of the cognitive neuropsychological theory of antidepressant action is that:
• change in automatic processing of emotional information is critically important for clinical improvement;
• however, this change is not a sufficient condition for improvement;
• the second key element is engagement in social interactions (contact with other people), which allows the acquisition of positive experiences. Contact in a more positive context, which is achieved by removing the negative bias of the way of experiencing during drug action, can lead to gradual mood improvement.
The authors of this paper cite a number of studies that highlight the latter condition as crucial to the effect of medication. For example, studies have shown that a change in information processing as a result of treatment in elderly people with depression led to clinical improvement only when the patients perceived that they had emotional support from those around them.
Young et al. [7] outline a similar perspective on the effect of medication on anger, aggression and irritability. They suggest that antidepressants act in part by effects on social behaviour, which leads to a gradual improvement in mood. They argue that in depression irritability and the resulting behaviour are the common symptom. Decrease of antagonistic and increase of affiliative social behaviours by medication leads to a gradual improvement in relationships with the social environment and, consequently, to positive reinforcement in interactions with others and an improvement in mood. The administration of antidepressants can thus alter the reactivity of brain centres to positive and negative stimuli.
In a meta-analysis published in “Molecular Psychiatry” [8], the neuropsychological mechanisms underlying the effects of antidepressants were described in detail. A meta-analysis of the effects of antidepressants on brain activity was carried out on the basis of 60 studies involving 1,569 patients and healthy volunteers who received antidepressants and underwent fMRI scans. The results showed that several brain regions and neural circuits were involved in the effects of antidepressants. In both patients with depression and healthy volunteers, the medial prefrontal cortex and centres of emotional response in the limbic system (the anterior cingulate cortex, amygdala and thalamus) showed an increased response to positive stimuli and a decreased response to negative stimuli under the influence of antidepressants. Antidepressants increased activity in the dorsolateral prefrontal cortex, a key region involved in emotional regulation, for both positive and negative stimuli. The results of this meta-analysis suggest that antidepressants work by normalising the abnormal neural response in patients with depression – by increasing brain activity in response to positive stimuli and decreasing brain activity in response to incoming negative stimuli. This action involves a wide range of brain regions, including both the emotional response network and cortical emotion regulation mechanisms.

Clinical cases

The following are clinical cases of the use of antidepressants (escitalopram, sertraline, venlafaxine and mirtazapine). The case descriptions include two points in time: the patient’s complaints at the first visit to the psychiatrist before treatment began, and statements about changes in well-being after treatment, when the patient perceived a subjective improvement. Attention was paid to both traditionally considered psychopathological dimensions of depressive syndrome (depressed mood, reduced drive, anxiety, sleep disorders) and the direction of the drugs’ effects on the mental functions of the patients presented here. Contextual factors in which depressive and anxiety symptoms may occur in those patients were also outlined.

Case 1

First visit
Patient report: “What bothers me is my nerves. I’m nervous, everything irritates me. Everything affects my family, I shout at my children, everything becomes a big problem. Whatever happens, I get really upset and I’m so afraid of it. I wake up at 4 in the morning and start worrying. Everything irritates me and I explode over everything. I’m always sad, in a deep low state. I’ve never been too cheerful, but sometimes I felt a bit calm and relaxed. But now I’m like a volcano of anger. My mind is always racing”.
A 36-year-old woman describes a conflict with her manager at work. She thinks her family situation is generally good. She likes it when everything is organised, enjoys the daily routine and feels calm when she knows what is going to happen. Then she feels at peace. Pleasure and joy are rare for her and she can’t remember the last time she felt them. She usually remembers states of relaxation when everything in her life was stable.

Second visit
The patient was started on escitalopram at a dose of 10 mg. The drug was chosen for its ability to reduce anger, improve stress tolerance, change the way stimuli from the environment are interpreted into more positive ones, and reduce attachment to irrelevant stimuli (Table 1).
Patient report: “I see an improvement. I haven’t noticed any euphoria during this time, but I am very calm. I no longer get upset about trivial things. I’m beginning to feel like myself again. Before I came here, the smallest problem would become a huge problem. Now I approach it differently, very calmly. What was a problem three weeks ago is normal now. I used to be very emotional about everything and now I’m not. It’s immediately better at home. And there are no more problems with my boss. He used to start talking and I’d cry, but now I don’t. I can even calmly tell him what I think, just express my opinion”.

Case 2

First visit
Patient report: “I am completely different from two months ago. I used to get by for so long. Now I’m always sad, I could cry at any moment. Sometimes I cry, I don’t even know why, I just can’t show it to my child. I have no strength for anything, no energy at all, as if someone had taken it away from me. I used to be able to do so much in a day. My own child annoys me, I shout at him for no reason, especially in the morning when we’re getting ready for school. Breakfast and getting dressed for school takes three times as long as it used to. I sleep very badly, I wake up all the time, several times a night. I’m always afraid of something, but now I don’t know what it is. I wasn’t like this before. There was never a time when I was always worried and stressed about things. And these palpitations. I went to see a cardiologist; he said I need to get checked out”.
The woman had experienced a series of unfortunate life events in the past year. First, her father fell ill and was hospitalised (with a suspected serious, life-threatening heart condition), and she became partly responsible for his care. Then financial problems arose and she began to worry about the family’s economic stability, loan repayments and her child’s future. These worries turned out to be disproportionate to reality. She was also worried about her siblings, who were experiencing difficulties in their relationships. At first she bought over-the-counter sleeping pills, but they did not help.

Second visit
The patient was started on sertraline at a dose of 100 mg. The medication was chosen for its balanced effects on mood, drive, levels of irritability and anger, and anxiety symptoms. It was taken into account that the patient reported many current difficulties in relationships with those close to her (correcting the perception of the importance of these relationships may be helpful) (Table 2).
Patient’s report: “I’m in a much better mood now and I want to do things again. And it even gives me pleasure, just like before. I’m much calmer; I don’t worry about these problems and worries anymore. I sleep better. I can concentrate at work, think more logically. I don’t shout at my child anymore, I have more patience and it’s harder to get upset. This medication has calmed me down very quickly; overall things are better. I find satisfaction in everything I do”.

Case 3

First visit
Patient report: “I can’t do anything. The simplest task takes my whole day. It takes me several days to make a single phone call. I only get dressed in the afternoon. I don’t even have the strength to look after myself. Each moment feels like an eternity. I feel nothing but pain and despair. Every day is an endless agony. Before dawn, when I wake up, I wish it would all end once and for all. I’ve been treated before, and maybe it got better for a while, but nothing really changed. I’ve given up everything I used to do, everything I cared about. I don’t care about anything, I don’t react to what’s going on around me. I wake up at night and then several hours earlier than before, even before dawn (?). In the morning I feel terrible, I feel an overwhelming sadness. I can’t do anything all day. It’s only in the evening that I can do something. I’ve stopped eating, I’ve lost weight, I don’t know how much. My whole body hurts. I feel pain, despair, I think about loss. I’m preoccupied with it, nothing else matters. Time doesn’t flow. But it doesn’t stand still either. I feel suffering that never ends. Waiting and suffering. I don’t remember anything. When a person isn’t here and in the present, it’s hard to remember anything. It’s all indefinite, somewhat uniform, filled with pain and suffering. It takes my life away. I exist but I’m absent. Then it turns out that I wasn’t there because the day has passed but I didn’t remember it”.
The patient was brought to the appointment by his wife. Over the course of several months, he experienced significant losses in various aspects of his life. He was unable to work, socialise with others or pursue his interests. About 2-3 months ago, he almost stopped getting out of bed and taking care of himself. Two previous attempts at pharmacotherapy with SSRI-type drugs had failed to improve his condition. He tolerated the medication well, but it did not improve his mood or activity.

Second visit
The patient was started on venlafaxine at a dose of 225 mg. The choice of medication was based on the severity of the depressive episode, the severe inhibition of activity, the presence of pain and the data on the efficacy of venlafaxine after unsuccessful treatment with SSRI-type drugs. It was taken into account that the losses experienced by patients are permanent. The meta-analysis mentioned above [8] suggests a potentially different pattern of neuronal response with venlafaxine compared with SSRI therapy (Table 3).
Patient report: “It’s better. There’s improvement and I even find myself smiling sometimes. I feel better; almost everything that was bothering me has gone. I certainly sleep longer in the morning. I feel that my body is less tense and the pain is less. My muscles used to be tense, my hands, my thighs – everything, but not anymore, just my calves. I started to eat more. Most importantly, I can do things now. I’m able to get on with things and when I do, it feels good. I’ve fixed a few things around the house. I’m planning to go back to work.

Case 4

First visit
Patient’s report: “I feel very sad, I can’t sleep through the night. I can’t do anything, not even talk. I don’t do many things that I should do. I have no energy. I can lie in bed all day. If I have a job to do, I can’t do it. I do a lot of things in my head at the same time. I have so many thoughts in my mind. I wake up at night either with anxiety or with nothing, no thoughts. Anxiety is another problem. I used to have what seemed like panic attacks, with my heart pounding, or fear that my maze would stop working. Dizziness. The thoughts start with trivial things and lead to death or disability. When I have to leave the house, I think that once I’m out, I won’t come back. I don’t go to the shop, to the market or to visit my neighbour. I go to work, but I just sit there and can’t do anything. My friends told me to come here. What depresses me most is that I can’t go out and do anything, I have no joy in life. I don’t eat, I’ve lost a lot of weight, but I haven’t weighed myself. I can tell by the clothes”.
According to the anamnesis the patient is single, lives alone and has managed well to take care of her own needs. She works in the office of the cooperative, a job that does not involve a high mental workload. She enjoys her job very much, especially the opportunity to interact with other people, especially her colleagues. She has also worked irregularly as a nanny to earn extra income.

Second visit
The patient was started on mirtazapine at a dose of 45 mg. The co-occurrence of reduced mood, low energy and anxiety symptoms (different from those described in the previous cases) was taken into account. Because of the patient’s lifestyle, she may tolerate mild sedation well and find it beneficial. She will also accept some weight gain (Table 4). Patient’s report: “I don’t know when it happened, but it’s better now. I feel completely different. I sleep very well; I don’t have that anxiety anymore. I can go back to work and talk to people. I go to the bazaar, I go to the shop. I’m not afraid, I don’t have these thoughts that it’s all over, that I’m not coming back home. Where did I get these thoughts from? Now I don’t have those thoughts at all. And I’m going to buy some good food and eat it. And my mood is better and I eat more. But the most important thing is that I don’t think like that at night, I don’t wake up scared. So during the day I’m not nervous, I’m calm”.

Bupropion

This information on the effects of drugs whose mechanisms mainly involve the serotonin system can be contrasted with the effects of a drug with a different mechanism of action. The mechanism of action of bupropion involving inhibition of dopamine and norepinephrine reuptake [9, 10] corresponds with clinical observations that this drug is particularly beneficial in those patients whose depression is dominated by reduction in the extend of the so-called ‘positive affect’: diminished feelings of joy, pleasure, loss of interest, reduced energy levels and desire to act, reduced alertness and self-confidence. Increased noradrenaline function improves energy levels, has a beneficial effect on cognitive functions, and alters the processing of emotionally meaningful information - from a tendency to focus on negative aspects to perceiving and incorporating positive ones into the experience. An increase in dopamine, on the other hand enhances motivation to engage in various life activities and therefore also increases the opportunity for social interaction, which is an essential factor in changing negative cognitive distortions. It increases feelings of satisfaction or pleasure in the activities undertaken, and thus encourages repetition.
An important aspect of bupropion’s effect is that it does not induce emotional blunting, which is quite common in patients treated with SSRIs and sometimes SNRIs. Some of these people experience lack of emotions or a feeling of indifference to both negative and positive stimuli. This state, sometimes very distressing for patients, can be a residual symptom of depression, and for some it is a side-effect of medication from the above-mentioned groups. In such cases, it may be a good idea to change to bupropion or, less commonly, to add bupropion to the existing medication.
Bupropion is a good choice for patients complaining of a lack of energy and reduced feelings of pleasure and, as a consequence of both conditions, difficulty in engaging in work, social contacts or hobbies. In those depressed patients with predominantly ‘positive affect’ impairment: withdrawal, anhedonia, slowing down, loss of interest. Those experiencing cognitive decline, not accepting serotonergic side effects such as emotional shallowness or sexual dysfunction. For those who are overweight or obese, and who are concerned about weight gain or drowsiness as a result of treatment.

Conclusions

The case reports presented in this paper confirm that the use of a personalised choice of antidepressants with specific profiles of action is beneficial in patients’ subjective perception of therapy and leads to objective improvement in depressive symptoms.

References