Introduction
The possibility to include pharmacogenetic data in the case management of patients with major depressive disorder (MDD) paves the way toward a personalized approach, which has the potential benefits of a lower rate of adverse events and a higher rate of therapeutic response and remission. This is not just a theoretical perspective, because evidence to support this approach is gathering. In a prospective, randomized clinical trial, 685 patients diagnosed with depression and/or anxiety were enrolled in a pharmacogenetic-guided therapeutic program, after the application of a 10-gene test(1). Recommendations for gene-drug and drug-drug interactions for more than 40 pharmacological agents could be formulated based on the respective test(1). Patients were randomized on genetic-guided treatments or the usual standard of care (USC) and monitored using the Hamilton Depression Rating Scale (HAMD-17) and the Hamilton Anxiety Rating Scale (HAMA) for 12 weeks(1). In patients diagnosed with depressive disorders, significantly higher response and remission rates were reported in the case of pharmacogenetics-guided approach versus controls at the endpoint (according to the HAND scores)(1). Also, when pharmacogenetics was used, anxiety significantly improved (as assessed by the HAMA scores) compared to the USC, at week 12(1). Individuals diagnosed with anxiety or depressive disorders who received genetic testing for pharmacokinetic or pharmacodynamic variables (N=817) experienced a 40% lower rate of all-cause emergency room visits and almost 60% fewer inpatient all-cause hospitalizations (both differences were significant) than individuals in the control group (N=2745)(2). The pharmacoeconomic analysis supported a lower cost over six months in the tested group(2).
These considerations are not limited to MDD/anxiety disorders or antidepressants, but extend to other psychiatric pathologies and pharmacological agents as well. Several antipsychotic drugs also have specific dosing recommendations depending on various pharmacogenetic variations – for example, CYP2D6 metabolizer status has a significant impact on the aripiprazole plasma half-time, and the dose of brexpiprazole should be decreased by half in CYP2D6 poor metabolizers(3). A retrospective, naturalistic, multicenter study that included adult patients with various psychiatric disorders (N=182), who were assessed using a pharmacogenetic test, showed that guided treatment had four-times greater odds of success than USC (OR=3.86)(4). When the distribution of patients on nosological categories was included as a variable in evaluating clinical improvement, it was observed that psychiatric diagnosis did not significantly impact the OR(4). In a subgroup analysis, a higher Clinical Global Impressions-Severity (CGI-S) score correlated significantly with higher stabilization rates at follow-up in patients who received pharmacogenetic-guided treatment(4).
A prospective project compared two cohorts of patients with psychiatric disorders who had switched or added a new psychotropic agent after failed monotherapy (N=2168), the first cohort receiving a pharmacogenetic-guided treatment, while the second cohort receiving non-guided treatment, based on USC principles(5). All patients had recorded data on their clinical evolution for one year(5). The pharmacoeconomic evaluation showed that the pharmacogenetic-oriented approach led to a significant saving in the total medication costs, and the same type of guidance was associated with improved adherence treatment(5). Therefore, it was considered that pharmacogenetic testing may offer “real world” cost savings in the short and medium term(5).
Different risk factors for the evolution of neuropsychiatric disorders in vulnerable populations – e.g., elderly patients – were explored(6-8). Combinatorial pharmacogenomic testing was investigated for potential economic impact in treating old patients(7). In a one-year prospective assessment of medication cost, congruent prescribing (pharmacogenetic-based recommendations) was associated with higher savings in patients older than 65 versus those below 65 years old diagnosed with neuropsychiatric disorders(7). Congruent prescribing was also correlated with fewer psychotropic medications for patients older than 65(7). These results confirmed another analysis which supported that antidepressant and antipsychotic prescribing congruent with combinatorial pharmacogenomic test guidance led to significant cost savings on Canadian prescription medications, especially in patients above 65 years old(9).
Taking into account the high rate of therapeutic nonresponse and the lower tolerability in MDD, pharmacologically-guided decision-making could be of significant help to clinicians(10,11). Omic, personal and environmental factors should all be included in the decision algorithm(10), although the economic costs of determining the first category of variables are still quite high. However, psychiatrists’ attitudes towards pharmacogenetic testing are changing worldwide(11), and it is not a utopia to consider that, in the near future, such tests will be applied on a larger scale than they are now.
This case report explores the utility of pharmacogenetic testing in clinical practice, starting with the pragmatic reasons to recommend such an investigation and ending with the implications on the efficacy and tolerability of guided therapeutic recommendations.
Case report
A 46-year-old Caucasian male, married, working as an engineer, was transferred to the Psychiatry Department after discharge from the ICU Toxicology Department because of a voluntary drug ingestion with suicidal intent. He ingested all the medicines he had at hand, but when first evaluated, he could not specify the doses/type. Later, after 60 minutes, he announced the event to his wife by phone, losing consciousness during the call. He was transported to the emergency room two hours after ingestion, and gastric lavage was performed. The patient was admitted to the ICU Department of Toxicology, receiving ventilation support and cardiovascular plus respiratory supportive treatment; he was in a coma for the first three days of hospitalization. Toxicology reports detected benzodiazepines, barbiturates and alcohol; also, valproate capsules were found by his wife near his bed when the ambulance arrived (still, the exact quantity of the ingested pills could not be assessed).
The onset of depressive symptoms occurred three months before the current hospitalization, with the patient presenting to the psychiatrist, where he received treatment with escitalopram 20 mg/day and sodium valproate/valproic acid 600 mg/day. According to the patient’s statement, this therapeutic association led to a partial remission of the core depressive symptoms, and the treatment was interrupted by the patient, without the knowledge of his family, 30 days before the suicide attempt.
According to the statement of the patient’s wife, two weeks before the suicidal behavior, the patient requested a leave of absence from work, he began to isolate himself constantly, had a blank stare, did not communicate with others, and presented days when he did not get out of the bed. From the heteroanamnesis, it is also important to note the existence of a psychologically stressful context in his family – i.e., multiple episodes of conflict with the son’s partner’s family, episodes that apparently were not triggered by the patient.
The symptoms detected at the hospital admission were markedly depressed mood, a decrease of interest and pleasure in daily activities, insomnia consisting of early awakenings (with less than 5 hours of sleep per night), much-reduced appetite for food (but without weight loss, the patient claiming he had no interest for meals and constantly refusing them), psychomotor retardation, poor self-care (the patient stays in bed all day long), delusional ideas of guilt (the patient accuses himself of destroying his son’s relationships and health, and states that “I am an extremely bad person because of what I have done”), and current suicidal ideation (the patient considers that in the days before the suicide attempt he fought many times with the temptation of killing himself; in the morning of the day he was admitted to the ICU Toxicology Department, he said “I couldn’t bear these thoughts anymore”; present transient suicidal ideation, but without any specific plan).
From the personal psychiatric history, it should be mentioned that the onset of the disease was ten years ago, when the first depressive episode of moderate intensity did not require hospitalization. He was treated on an outpatient basis with fluoxetine 20 mg plus psychological counseling, and he achieved complete remission of depressive symptoms after six months. No particular medical or surgical antecedents were retrieved in this patient. He also denied psychiatric antecedents for any of his known relatives. He was born in a rural community (both parents were farmers), and he described his family as harmoniously organized. He had a stable professional history (two jobs in 21 years).
The current mental state examination shows a patient in hospital clothes, relatively well-groomed, partially maintained hygiene – with the exception of the unshaven, unkempt appearance, fully oriented in time, place, self and others, with a cooperative attitude, but he does not initiate the conversation, he responds adequately to questions, the visual contact is possible, hypomobile mimicry and gestures, in accordance with his speech; he denies qualitative disorders of perception; decreased voluntary attention, storage and reproductive hypomnesia, lacunar amnesia of the interval in which he was in a coma; slow ideational rhythm and flow, he speaks slowly, monotonously, but logical associations are possible; he is able to perform simple arithmetic calculations, he has the ability to generalize and make abstract tasks; delusional ideas of guilt, frequent depressive-type ruminations, he admits transient autolytic ideation at the time of examination: “I don’t know how I was able to do such a think…, but maybe they would be better without me”; decreased appetite with significant weight loss of 12 kg in the last three months; decreased daily functionality, fatigue, apathy, hypobulia; he has good insight and admits the need for psychotropic treatment.
The somatic examination did not find abnormal values, his blood pressure was 130/80 mmHg, and his pulse was 80 beats/min, regular. The paraclinical examinations were also performed, with heart-lung radiography and abdominal pelvic ultrasound having results within normal limits. The laboratory analyses were also normal, except for a significant hepatocytolitic syndrome (AST and ALT were 3.5 times the normal values). The psychological examination at admission showed a Hamilton Depression Rating Scale (HAM-D-21) score of 29, a Positive and Negative Syndrome Scale (PANSS) of 84, and a Global Assessment of Functionality Scale (GAFS) of 9, due to the recent severe suicidal act with the desire to die. Also, the initial Columbia-Suicide Severity Rating Scale (C-SSRS) that incorporated data from the previous week and current status (highest scores are mentioned) showed active suicide ideation, intensity of ideation 4/5, frequency of ideation 4/4, and suicidal behavior – actual lethality 4/5.
The positive diagnosis of recurrent MDD, currently a severe major depressive episode, is supported by the DSM-5 TR criteria(12). Also, the specifier “with psychotic elements congruent with the mood” can be added, because the patient presents delusions of guilt. According to the ICD-11 system, the diagnosis is „recurrent depressive disorder, current episode severe, with psychotic symptoms”(13).
The differential diagnosis includes types I and II bipolar disorder (but there are no data in the history/anamnesis to suggest the existence of a hypomanic, manic, or mixed episode), dysthymia/cyclothymia (he does not have a two-year history of depressive symptoms that do not meet the criteria of a major depressive episode), adjustment disorder with depressed mood (but the patient meets the criteria for a major depressive episode), posttraumatic stress disorder (although the heteroanamnesis identified interpersonal conflicts between the patient and the family of the son’s partner, these did not endanger the life or bodily integrity of the patient or those close to him), schizoaffective disorder/schizophrenia (criterion A for schizophrenia, according to the DSM-5 TR(12), requires the existence of at least two of the following symptoms: delusional ideas, hallucinations, disorganized language, catatonic or flagrantly disorganized behavior and negative symptoms; delusional ideas are present, but they are not bizarre enough to fulfill criterion A; hallucinations, disorganized language and catatonic behavior are not evident in this patient), delusional disorder (which is excluded because criteria D and E are not met(12) – namely, if the mood episodes occurred concomitantly with the delusional ideas, their duration should be short in relation to the duration of the delusional periods and also the daily functioning is not significantly damaged; also, the mood is the core symptom in our case), mood disorder due to a general medical condition (the influence of a somatic pathology could not be detected from the medical history or paraclinical explorations), and mood disorder induced by a substance (from the clinical and paraclinical data obtained, the patient does not have a general medical condition and does not consume substances that could cause depressive symptoms; the patient admitted he consumed alcohol only in the day he attempted suicide, and benzodiazepines/barbiturates were not used on daily basis).
The prognosis of this patient should be estimated by including (a) negative factors, like male sex (increased risk of recurrence), the existence of psychotic elements, and a suicidal attempt, and (b) positive factors, such as stable family environment, socio-professional functioning five years before the episode, absence of psychiatric comorbidities, absence of another comorbid psychiatric disorder, and a single psychiatric admission.
The case management involved general measures, choosing an antidepressant and associated pharmacological agents, but also selecting the appropriate psychosocial/auxiliary intervention(s).
The treatment of the acute episode required medical supervision, due to the recent suicidal attempt, which was accomplished by the patient’s hospitalization. Factors to consider when selecting an antidepressant are: (1) patient-related clinical features and core symptoms, comorbid diseases, response and adverse events during previous trials, and patient preference, and (2) medication-dependent comparative efficacy and tolerability, potential pharmacologic interactions, simplicity of use, cost and availability(14,15).
Because of the prior partial response to escitalopram and the favorable response to fluoxetine in this patient, the last antidepressant was chosen as the first-line treatment. Fluoxetine was initiated at 20 mg/day, and the dose was raised to 40 mg/day, because of a lack of response after two weeks; however, when raised to 40 mg, there was still no significant improvement after another two weeks, and a set of gastrointestinal adverse events (nausea, vomiting and diarrhea) also appeared. Cinolazepam 40 mg QD at bedtime was added for insomnia. Mood stabilizers, usually recommended when suicidal ideation, impulses or behaviors exist, were not recommended in this case due to their hepatotoxicity.
After four weeks since the initial visit, it was considered opportune to recommend a pharmacogenetic test, in order to guide the following therapeutic steps, due to the absence of significant therapeutic response. The results showed the presence of: (1) SLC6A4 (serotonin transporter) S/S genotype – associated with a lower likelihood of MDD remission and increased side effects risk with serotonin selective reuptake inhibitors (SSRIs) in Caucasians; (2) Met/Met variant of the brain-derived neurotrophic factor (BDNF) – associated with altered BDNF secretion and lower response to SSRIs in Caucasians, but improved response to serotonin and norepinephrine reuptake inhibitors (SNRIs); physical exercise was linked to improvements in cognition and stress response in Met carriers; (3) Met/Met genotype of catechol-O-methyl-transferase (COMT) – associated with reduced enzyme activity and increased dopamine transmission in prefrontal cortex(16-19). Based on this report, an SNRI agent was chosen – more specifically, venlafaxine. The initial dose was 75 mg QD, titrated up to 225 mg/day, and a partial improvement was observed – i.e., the HAMD score decreased to 20 after two weeks. However, because insomnia, anhedonia and hypobulia were still present, an augmenting strategy was initiated, also based on the pharmacogenetic profile: aripiprazole, olanzapine and risperidone were avoided because they were associated with higher drug exposure and side effects risk, but quetiapine did benefit from the support of the testing, and its pharmacodynamic profile corresponded well to the current symptoms of the patient. Also, exercise therapy was supported as add-on therapy, based on the previously mentioned Met/Met COMT genotype.
Quetiapine 150 mg QD was initiated and titrated up to 300 mg/day, while venlafaxine was titrated to 300 mg/day. The depressive symptoms responded well, with a more than 50% decrease on the HAMD score, and the GAF score increased to 70 after another two weeks. The C-SSRS administration indicated the absence of current suicidal ideas/behaviors, and the need for benzodiazepines was virtually absent after initiating quetiapine.
The treatment led to the remission of depressive and associated psychotic symptoms (HAMD score <7, PANSS=42) at week 10, and the patient returned to work.
The patient refused to participate in the physical exercise program recommended by his treating psychiatrist. Psychoeducation of the patient and his family about the need to continue the treatment for depression as long as the psychiatrist recommends and about the risk of suicide was initiated during hospitalization and continued after discharge from the hospital. Also, the patient was informed about the signs and symptoms of MDD relapse. Establishing an emergency plan in case the patient starts having suicidal thoughts again was included in the case management. The patient was encouraged to attend support groups and was informed about other community resources (such as the hotline for suicide attempters). Cognitive behavioral therapy (CBT), which focuses on identifying and changing negative thought patterns, was recommended for the patient, but he refused it.
Regarding the duration of the maintenance treatment, the following factors should be considered: frequency of the depressive episodes, the severity of these episodes, chronicity, psychiatric or other comorbidities, residual symptoms, and difficulty in attaining a response/remission(14). Based on these aspects, the recommended maintenance treatment duration in this case was two years, with the continuation of the antidepressant plus a gradual reduction of the atypical antipsychotic.
The particularities of the case consist in the recurrence of depression in a psycho-stressful context in a patient with a moderate depressive episode 10 years ago, and in the fact that the current psychopathological picture wears the aspect of depression with psychotic elements with suicide attempt. The pharmacogenetic testing helped the case manager to decide on the second-line treatment and augmentation strategies. Validated instruments for monitoring the patient’s clinical status were used regularly, in order to allow for the quantification of the treatment response.
Conclusions
Integrating psychiatric, psychological and pharmacological data in the case management of psychiatric disorders is important for extracting the maximum chances of reaching therapeutic remission. The quality of life and functional recovery in patients with MDD depend on the tolerability and efficacy of the antidepressants recommended(20,21). Therefore, incorporating data from all the possible sources in situations where the tolerability is low, the responsiveness to the recommended drugs is insufficient, or when a personal history of treatment resistance exists, is crucial for therapeutic success. Also, maintaining the treatment for a sufficient duration is another important aspect for ensuring the durability of remission in major depressive disorders.
Institutional Board Review Statement: The Local Ethical Committee of “Dr. Carol Davila” University Emergency Central Military Hospital approved this study – decision no. 632/14.09.2023.
Funding: No funding was received for this research. The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.
Authors’ contribution: All authors equally contributed to the case conceptualization, data analysis, and final revision of the manuscript.
Informed consent: All patients signed an informed consent that included permission to use relevant medical data for educational purposes.