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Zdravniški vestnik, priloga | Recommendations for treatment of unipolar depressive disorder
Copyright (c) 2023 Slovenian Medical Journal. This work is licensed under a
Creative Commons Attribution-NonCommercial 4.0 International License.
Recommendations for treatment of unipolar depressive 
disorder
Priporočila za zdravljenje unipolarne depresivne motnje
Anja Plemenitaš Ilješ,1 Maja Drobnič Radobuljac,2,3 Blanka Kores Plesničar,2,3 Peter Pregelj,2,3 Borut Škodlar,2,3  
Tea Terzić,2 Jurij Bon2,3
Abstract
Depression is a common mental disorder with a high burden of disease worldwide and requires effective treatment. On 
behalf of the General Advisory Council for Psychiatry, clinical recommendations were formed to help clinicians make de-
cisions to improve the treatment of patients with unipolar depressive disorder; several international guidelines served 
as the basis for developing these recommendations. In terms of therapeutic approaches, pharmacological treatment is 
discussed with additional recommendations on the management of a partial response to treatment and treatment resis-
tance. Psychotherapy, psychoeducation, and other psychosocial approaches represent non-pharmacological interven-
tions for the treatment of depressive disorder. Biological methods for treating depression include non-invasive brain stim-
ulation methods. The second part of the recommendations addresses special populations: children and adolescents, the 
elderly, and the treatment of depression in the perinatal period.
Izvleček
Depresija je pogosta duševna motnja z velikim bremenom bolezni po vsem svetu in zahteva učinkovito zdravljenje. Pod 
okriljem Razširjenega strokovnega kolegija za psihiatrijo so bila oblikovana klinična priporočila kot vodilo zdravnikom za 
izboljšanje zdravljenja bolnikov z unipolarno depresivno motnjo. Za pripravo teh priporočil je služilo več mednarodnih 
smernic. V smislu terapevtskih pristopov je obravnavano farmakološko zdravljenje z dodatnimi priporočili pri zdravljenju 
delnega odziva in pri terapevtsko odporni depresiji. Nefarmakološki pristopi za zdravljenje depresivne motnje so: psihote-
rapija, psihoedukacija in drugi psihosocialni pristopi. Biološke metode zdravljenja depresije vključujejo neinvazivne me-
tode stimulacije možganov. Drugi del priporočil je namenjen posebnim populacijam: otrokom in mladostnikom, starejšim 
ter zdravljenju depresije v obporodnem obdobju.
1 Department of Psychiatry, University Clinical Centre Maribor, Maribor, Slovenia
2 University Psychiatric Clinic Ljubljana, Ljubljana, Slovenia
3 Department of Psychiatry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Correspondence / Korespondenca: Anja Plemenitaš Ilješ, e: anja.plemenitas@ukc-mb.si
Key words: major depressive disorder; clinical practice guidelines; pharmacotherapy; psychotherapy; biological methods
Ključne besede: velika depresivna motnja; klinične smernice; farmakoterapija; psihoterapija; biološke metode
Received / Prispelo: 7. 3. 2023 | Accepted / Sprejeto: 19. 4. 2023
Cite as / Citirajte kot: Plemenitaš Ilješ A, Drobnič Radobuljac M, Kores Plesničar B, Pregelj P, Škodlar B, Terzić T, et al. Recommendations 
for treatment of unipolar depressive disorder. Zdrav Vestn. 2023;92(7–8):D9–D24. DOI: https://doi.org/10.6016/ZdravVestn.3431
eng slo element
en article-lang
10.6016/ZdravVestn.3431 doi
7.3.2023 date-received
19.4.2023 date-accepted
Psychiatry, clinical psychology, psychosomat-
ics Psihiatrija, klinična psihologija, psihosomatika discipline
Professional article Strokovni članek article-type
Recommendations for treatment of unipolar 
depressive disorder
Priporočila za zdravljenje unipolarne depresivne 
motnje article-title
Recommendations for treatment of unipolar 
depressive disorder
Priporočila za zdravljenje unipolarne depresivne 
motnje alt-title
major depressive disorder, clinical practice 
guidelines, pharmacotherapy, psychotherapy, 
biological methods
velika depresivna motnja, klinične smernice, far-
makoterapija, psihoterapija, biološke metode kwd-group
The authors declare that there are no conflicts 
of interest present.
Avtorji so izjavili, da ne obstajajo nobeni 
konkurenčni interesi. conflict
year volume first month last month first page last page
2023 92 7 8 D9 D24
name surname aff email
Anja Plemenitaš Ilješ 1 anja.plemenitas@ukc-mb.si
name surname aff
Maja Drobnič Radobuljac 2,3
Blanka Kores Plesničar 2,3
Peter Pregelj 2,3
Borut Škodlar 3
Tea Terzić 2
Jurij Bon 3
eng slo aff-id
Department of Psychiatry, 
University Clinical Centre 
Maribor, Maribor, Slovenia
Oddelek za psihiatrijo, 
Univerzitetni klinični center 
Maribor, Maribor, Slovenija
1
University Psychiatric Clinic 
Ljubljana, Ljubljana, Slovenia
Univerzitetna psihiatrična klinika 
Ljubljana, Ljubljana, Slovenija 2
Department of Psychiatry, 
Faculty of Medicine, University 
of Ljubljana, Ljubljana, Slovenia
Katedra za psihiatrijo, Medicinska 
fakulteta, Univerza v Ljubljani, 
Ljubljana, Slovenija
3
Slovenian Medical Journallovenian Medical Journal
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1 Introduction
Depression is a common, recurrent mental disorder 
associated with decreased functioning, poorer quality 
of life, medical comorbidity, and increased mortality 
(1). Regarding the global burden of disease, depression 
ranks highly, even when compared to somatic disorders 
(2). Effective treatment of depressive disorders is a pub-
lic health priority and is associated with a significantly 
reduced disease burden (3).
The purpose of these recommendations is to assist cli-
nician decision-making and thereby improve the treat-
ment of patients with unipolar depressive disorder. The 
13th edition of Maudsley Prescribing Guidelines in Psy-
chiatry (4), the British Association for Psychopharma-
cology Guidelines (BAP) (5), the American Psychiatric 
Association Practice Guidelines (APA) (6), World Fed-
eration of Societies of Biological Psychiatry Guidelines 
(WFSBP) (7), Canadian Network for Mood and Anxiety 
Treatments Clinical Guidelines (CANMAT) (8), Nation-
al Institute for Health and Care Excellence Guidelines 
(NICE) for the treatment of depressive disorders in chil-
dren and adolescents (9) and adults (10) served as the 
basis for the development of these recommendations.
The Expert Council for Psychiatry at the Slovenian 
Medical Association approved these recommendations 
on 18 January 2023, and the Main Expert Council of the 
Slovenian Medical Association approved these recom-
mendations on 27 March 2023.
Unipolar depressive disorder may consist of one or 
more depressive episodes. European International Clas-
sification of Diseases, 10th Revision - ICD-10 (11) states 
that a depressive episode is characterized by decreased 
mood, energy, and activity. Symptoms of a depressive 
episode include persistent low mood, sleep, and appetite 
disturbances, anhedonia, decreased interest and poor 
concentration, marked fatigue, decreased self-esteem, 
feelings of guilt or worthlessness, psychomotor retarda-
tion or agitation, and suicidal behaviour.
Various questionnaires or rating scales can serve as 
basic tools for monitoring the course of the illness and 
response to treatments. A partial response to treatment 
is defined as at least a 50% improvement in clinical 
symptoms. In Slovenia, the Zung Self-Rating Depression 
Scale (13), the Hamilton Rating Scale for Depression 
(HAM -D) (14), the Montgomery-Åsberg Depression 
Rating Scale (MADRS) (15), and the Hospital Anxiety 
and Depression Scale (HADS) (16) are commonly used 
when screening for a depressive episode. The Patient 
Health Questionnaire - 9 (PHQ-9) can be similarly used 
for screening in primary care (17). The Geriatric Depres-
sion Scale is suitable for use in the geriatric population 
with depressive disorder (18). Currently, the Slovenian 
validation of clinical questionnaires and scales is on the 
way that will serve as formal tools for objective assess-
ment of clinical pictures of patients.
Based on the principle included foreign guidelines, 
we defined Criteria for the level of evidence in line of 
treatment and Strength of recommendation listed in Ta-
ble 1 and Table 2. Table 3 contains a list of Slovenian rec-
ommendations for the treatment of unipolar depressive 
episode.
Level Criteria
I Meta-analysis with narrow confidence 
intervals and/or 2 or more RCTs with an 
adequate sample size, preferably placebo 
controlled
II Meta-analysis with wide confidence intervals 
and/or 1 or more RCTs with an adequate 
sample size
III Small-sample RCTs or nonrandomized, 
controlled prospective studies or case series 
or high-quality retrospective studies
IV Expert opinion/consensus
Table 1: Criteria for the level of evidence in line of treatment.
Strength of 
recommendation Criteria
A directly based on category I evidence
B directly based on category II evidence 
or extrapolated# recommendation from 
category I evidence
C directly based on category III evidence 
or extrapolated# recommendation from 
category I or II evidence
D directly based on category IV evidence 
or extrapolated# recommendation from 
category I, II or III evidence
S standard of good practice
Table 2: Criteria for the strength of recommendation in line 
of treatment.
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Zdravniški vestnik, priloga | Recommendations for treatment of unipolar depressive disorder
Description of the recommendation Level of evidence
Strength of 
recommendation
In a mild depressive episode, use pharmacotherapy. B
In a mild depressive episode, use psychological therapies. S
In moderate or severe depressive episode, use pharmacotherapy as the initial treatment. I A
In a depressive episode that lasts more than two years, regardless of the severity of symptoms, 
use pharmacotherapy. A
Selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine 
inhibitors (SNRIs) and mirtazapine represent the first-line therapy in depression treatment. A
Bupropion, trazodone and vortioxetine represent the first-line therapy in depression 
treatment. B
Agomelatine, tianeptine, tricyclic antidepressants (TCAs) represent the second-line therapy in 
depression treatment. A
Reboxetine and moclobemide represent the second-line therapy in depression treatment. B
In a severe depressive episode, TCAs may be used as the first choice of treatment. A
In a depressive episode with psychotic symptoms, an atypical antipsychotic can be added to 
the antidepressant. I A
In the initial phase of depression treatment, it is useful to add benzodiazepines or a hypnotic. A
For the first depressive episode, it is reasonable to continue medication at an effective dose for 
at least 6 to 9 months after remission has been achieved. A
In recurrent depressive episodes, chronic depressive episodes with residual symptomatology, 
and in the presence of family stress, persistent psychosocial stressors, suicidality, or associated 
psychosis, it is reasonable to continue maintenance therapy for at least 2 years.
A
If lowering or discontinuing the antidepressant leads to a relapse, it is reasonable to 
reintroduce the antidepressant at the original dose and continue treatment for another 6 
months.
B
In the second phase of treatment, switching to another antidepressant from the first or second 
group of choice, augmenting the response (using other types of medication in combination 
with an antidepressant), and combination therapy (a combination of two antidepressants from 
different therapeutic groups) can be used.
III A
In the second phase of depression treatment, an antidepressant with psychotherapy can be 
used. B
In the second phase of depression treatment, an antidepressant with non-invasive brain 
stimulation electroconvulsive therapy – ECT can be used. B
In the second phase of treatment, transcranial magnetic stimulation – TMS can be used. D
In the third phase of depression treatment, all strategies mentioned for treating treatment-
resistant depression – TRD are used, as well as other methods, such as third-line 
antidepressants.
S
For severe major depression, psychological or behavioural treatment is not recommended as 
sole therapy. B
Cognitive behavioural therapy (CBT) is a useful method in the treatment of depressive 
episodes. I A
Interpersonal psychotherapy is a useful method in the treatment of depressive episodes. I A
Psychodynamic psychotherapy is a useful method in the treatment of depressive episodes. II B
Table 3: List of Slovenian recommendations for treatment of unipolar depressive episode.
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Description of the recommendation Level of evidence
Strength of 
recommendation
Problem-oriented psychotherapy is a useful method in depression treatment. S
If partner or family conflict is present, partner or family psychotherapy in depression treatment 
is recommended. II S
The addition of intense physical exercise to antidepressant therapy may help patients with a 
mild or moderate depressive episode. B
Dietary supplements - omega-3 fatty acids can be used as potentially effective additions to the 
treatment of depression. II B
St. John's Worth can also be used as a dietary supplement in depression treatment, but 
patients should be advised of interactions with SSRIs. D
High-frequency (10 Hz or more) repetitive transcranial magnetic stimulation – rTMS of the left 
dorsolateral prefrontal cortex (DLPFC) is the most commonly used biological method in the 
treatment of depressive episodes.
A
Low-frequency (1 Hz) rTMS of the right DLPFC can be used in the treatment of depressive 
episodes. B
Intermittent TBS of left DLPFC is also possible in the treatment of depressive episodes. S
rTMS is recommended as a possible first-line treatment for patients who cannot take 
antidepressant medication. C
Transcranial direct current electrical stimulation (tDCS) techniques are also possible in the 
treatment of depressive episodes. B
ECT is used to treat severe depressive episodes, especially when psychotic features are present 
and in life-threatening conditions such as agitation, stupor, severe physical exhaustion due to 
refusal to eat, and high risk of suicide.
A
In the treatment of depression in children and adolescents, cognitive-behavioral 
psychotherapy and interpersonal psychotherapy are recommended. II D
In the treatment of depression in children and adolescents, psychodynamic psychotherapy 
and brief psychosocial interventions are recommended. I D
Family-oriented therapies are more effective than individual therapies in treating depression in 
children, and group therapies are effective in adolescents in addition to individual therapies. II D
Combining psychotherapy and treatment with antidepressants in treating depression in 
children and adolescents is more effective than either treatment alone. D
For moderate to severe depressive episode in children and adolescents, psychotherapy is 
recommended first, to which fluoxetine may be added. D
In children older than 12 years, fluoxetine may be added immediately; in younger children, 
it may be added after at least four psychotherapy sessions have failed to produce adequate 
effects. 
D
In the case of ineffective initial treatment, TRD, psychotic or recurrent depressive disorder in 
children and adolescents, fluoxetine, sertraline, citalopram or antipsychotic augmentation 
during intensive psychotherapy are recommended.
D
Sertraline or citalopram are recommended as second-line antidepressants; venlafaxine, 
paroxetine, or tricyclic antidepressants should not be prescribed because of significant side 
effects in the treatment of depression in children and adolescents.
D
In the treatment of depressive disorders in the elderly, the first choice pharmacotherapy is 
duloxetine, mirtazapine, nortriptyline. I
In the treatment of depressive disorders in the elderly, the first choice of pharmacotherapy 
is also bupropion, citalopram/escitalopram, desvenlafaxine, sertraline, venlafaxine, and 
vortioxetine.
II
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Zdravniški vestnik, priloga | Recommendations for treatment of unipolar depressive disorder
2 Therapeutic approaches in the treatment 
of depression
2.1 Pharmacological treament
Treatment of depressive disorder is divided into treat-
ment of an acute depressive episode and maintenance 
treatment. In the acute phase, the goal is to achieve re-
mission and restore functionality. Further on, treatment 
is needed to prevent relapse or recurrence of the disorder 
(5-8). In a mild depressive episode, therapeutic effects 
can be achieved using pharmacotherapy (Strength of 
recommendation B) or psychological therapies (Strength 
of recommendation S). In moderate or severe depressive 
episodes, pharmacotherapy is recommended as the initial 
treatment (Strength of recommendation A) (4-8,10). An 
antidepressant is also recommended as first-line therapy 
for a depressive episode that lasts more than two years, 
regardless of the severity of symptoms, as in dysthymia 
(Strength of recommendation A) (5).
Considering different clinical guidelines (6,8), se-
quential steps are recommended in the treatment of a 
patient with a depressive episode:
1. A structured approach to the diagnosis of a depressive 
episode using objective clinical scales and identifica-
tion of dimensions that may affect treatment resistance.
Description of the recommendation Level of evidence
Strength of 
recommendation
In the treatment of depressive disorders in the elderly, the second choice of pharmacotherapy 
is replacement with nortriptyline and combination with aripiprazole, and lithium. I
In the treatment of depressive disorders in the elderly, the second choice pharmacotherapy is 
also moclobemide, phenelzine, quetiapine, trazodone, and methylphenidate. II
In the treatment of depressive disorders in the elderly, the third choice of pharmacotherapy is 
replacement with amitriptyline or imipramine. II
In the treatment of depressive disorders in the elderly, the third choice pharmacotherapy is 
also a combination of SSRI or SNRI with bupropion, SSRI. III
The prescription of psychotropic drugs to women of childbearing age should be guided by the 
latest evidence on the risks to pregnancy and the fetus. Treatment decisions should include 
the use of non-pharmacological methods such as psychoeducation, psychotherapy, and other 
modalities (meditation, relaxation techniques, mindfulness, hypnosis, and occupational 
therapy).
S
In mild to moderate perinatal depressive episodes, psychoeducation, psychotherapy, and 
sometimes medication is required. S
In moderate to severe depressive perinatal episodes, medication is usually required in addition 
to psychoeducation, and psychotherapy. S
Benzodiazepines and hypnotics are avoided in the postpartum period, with the exception of 
short-term treatment of severe anxiety and agitation. S
Long-acting benzodiazepines should not be prescribed before delivery. S
Atypical antipsychotics may be prescribed in low doses to enhance antidepressant effects. S
If pharmacological treatment before and during pregnancy is required, continue with 
an effective current antidepressant if its benefits outweigh the risk and if the drug is not 
contraindicated during pregnancy.
S
If pharmacological treatment before and during pregnancy is required, SSRI is prescribed as 
the first choice (not paroxetine or fluoxetine in the first trimester) and an SNRI as the second 
choice.
S
If pharmacological treatment is required during birth, a therapeutic dose of the same 
antidepressant is maintained. S
If pharmacological treatment is required after birth, the currently effective antidepressant is 
continued, and the dose may need to be adjusted. If an antidepressant is needed, an SSRI that 
allows breastfeeding is prescribed.
S
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2. Selection and initiation of first-line antidepressant 
treatment.
3. Objective determination of the response rate after the 
appropriate duration of treatment.
4. In partial response to treatment, the dose of antide-
pressant is optimized to the maximum tolerated dose.
5. In the absence of response to first-line treatment, 
treatment methods for treatment-resistant depres-
sion (TRD) are used, including switching the antide-
pressant, combination therapy (two antidepressants, 
an antidepressant and psychotherapy, or non-inva-
sive brain stimulation), or augmentation (antidepres-
sant and a drug from another therapeutic class).
6. Once the response has improved or remission has 
been achieved, consideration should be given to the 
length of maintenance treatment.
According to a report by the National Institute of Pub-
lic Health, 7.3% of the Slovenian population received anti-
depressants in 2020. They report that the most commonly 
prescribed antidepressants have been selective serotonin 
reuptake inhibitors for many years. In line with prescrib-
ing recommendations, there has been a steady increase in 
the prescription of antidepressants and a decrease in the 
prescription of anxiolytics (20).
Antidepressants do not differ significantly in terms 
of efficacy (Level of evidence I) (21,22). Significant dif-
ferences exist in side effects, tolerability, and other char-
acteristics, necessitating flexibility in choosing the right 
antidepressant for the individual patient (4). Which an-
tidepressant is appropriate is decided based on its po-
tential therapeutic effects, taking into account potential 
side effects, the likelihood of withdrawal symptoms, and 
the estimated time to respond (4). Previous responses to 
drugs and the patient’s wishes (5-8) are also important, as 
well as the level of risk in the event of an overdose (5,7) 
(Strength of recommendation S).
Table 4 shows the recommended distribution of anti-
depressants by groups of choice, which takes into account 
the latest guidelines, established clinical practice and for-
mal prescribing rules, and the availability of individual 
medications in Slovenia. Selective serotonin reuptake in-
hibitors (SSRIs) represent the first-line therapy (4,5,10), 
together with selective serotonin and norepinephrine 
inhibitors (SNRIs) (Strength of recommendation A) and 
some other antidepressants such as mirtazapine (Strength 
of recommendation A) bupropion, trazodone, and vor-
tioxetine (Strength of recommendation B) (7,8). Sec-
ond-line antidepressants include agomelatine, tianeptine, 
tricyclic antidepressants (TCAs) (Strength of recommen-
dation A), reboxetine, and moclobemide (Strength of rec-
ommendation B). In a severe depressive episode, TCAs 
may also be used as the first choice of treatment (Strength 
of recommendation A) (7). In a depressive episode with 
psychotic symptoms, an atypical antipsychotic can be 
added to the antidepressant at the beginning of treatment 
(5,7,8), which is more effective than monotherapy with 
an antidepressant (Strength of recommendation A, Lev-
el of evidence I) (23). Quetiapine and olanzapine are the 
most recommended because of their partial antidepres-
sant effects (Level of evidence I) (4). In the initial phase 
of treatment, it is useful to add benzodiazepines or a hyp-
notic (e.g., zolpidem) (6) to relieve symptoms of anxiety 
(Strength of recommendation A) (6,7).
MEDICATION THERAPEUTIC 
DOSE
MECHANISM OF ACTION SPECIAL FEATURES
FIRST CHOICE
SSRI Inhibition of serotonin reuptake
fluoxetine 20–60 mg registered for treatment in children over 12 years of age
paroxetine 20–50 mg not recommended for children
sertraline 50–200 mg in children and adolescents as second-line therapy
citalopram 20–40 mg in children and adolescents as second-line therapy
escitalopram 10–20 mg
fluvoxamine 100–300 mg
Table 4: Antidepressants by groups of choice.
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Zdravniški vestnik, priloga | Recommendations for treatment of unipolar depressive disorder
MEDICATION THERAPEUTIC 
DOSE
MECHANISM OF ACTION SPECIAL FEATURES
SNRI Inhibition of serotonin and norepinephrine reuptake
venlafaxine 75–375 mg not recommended for children and adolescents
duloxetine 60–120 mg
NaSSA Alpha2 adrenergic receptor antagonism
mirtazapine 30–45 mg
SARI Inhibition of serotonin reuptake and 5-HT2A receptor 
antagonism
trazodone 75–600 mg
NDRI Inhibition of norepinephrine and dopamine reuptake
bupropion 150–300 mg
Others
vortioxetine 10–20 mg Inhibition of serotonin reuptake and modulation of serotonin receptors
SECOND CHOICE
NRI Inhibition of norepinephrine reuptake
reboxetine 8–12 mg
TCA Inhibition of serotonin and norepinephrine reuptake; 
interactions at other receptors
amitriptyline 50–150 (300)* mg
maprotiline 75–150 mg
clomipramine 50-150 (250) mg
imipramine 50-200 (300) mg
MAO-I
moclobemide 300–600 mg Reversible monoamine oxidase inhibition
Other
tianeptine 37.5–75 mg Serotonin uptake enhancement and glutamate transfer modulation
agomelatine 25–50 mg MT1 & MT2 receptor agonism, 5-HT2C receptor antagonism
THIRD CHOICE
esketamine 56–84 mg NMDA glutamate receptor antagonism indication for resistant depression, special rules for prescribing and use
Legend: * Values in parentheses denote maximum permitted in-hospital doses; MAO -I – monoamine oxidase inhibitors; 
NaSSA – noradrenergic and specific serotonergic antidepressants; NDRI – norepinephrine and dopamine reuptake inhibitors; 
NMDA – N-methyl-N-aspartate; NRI – norepinephrine and dopamine reuptake inhibitors; MT – melatoninergic receptors, 
5HT2A  ;  2C – serotonergic receptors; SARI – serotonergic receptor antagonists and various monoamine reuptake inhibitors; 
SSRIs – serotonin reuptake inhibitors; SNRI – serotonin and norepinephrine reuptake inhibitors; TCA – tricyclic antidepressants.
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For the first depressive episode, it is reasonable to con-
tinue medication at an effective dose for at least 6 to 9 
months after remission has been achieved (Strength of 
recommendation A) (4,5,7,8). In recurrent depressive ep-
isodes, chronic depressive episodes with residual symp-
tomatology, and in the presence of family stress, persistent 
psychosocial stressors, suicidality, or associated psycho-
sis, it is reasonable to continue maintenance therapy for 
at least two years (Strength of recommendation A) (6,8).
If no relapse occurs during maintenance therapy, the 
antidepressant is gradually discontinued. During this 
process, the patient is constantly monitored for the sta-
bility of remission. The antidepressant is discontinued 
gradually over several weeks to avoid withdrawal symp-
toms unless other clinical reasons are present (4-6,8). If 
lowering or discontinuing the antidepressant leads to a 
relapse, it is reasonable to reintroduce the antidepressant 
at the initial dose and continue treatment for another 6 
months (Strength of recommendation B) (5).
2.2 Dealing with partial response to treatment 
and treatment resistance
In 15% to 33% of patients, repeated attempts to 
modify treatment are ineffective despite intensive drug 
therapy and other therapeutic approaches (24,25). For 
Figure 1: Clinical pathway for treatment of depression. Adapted from Kasper S, et al., 2020 (28).
Image shows generally recommended course of treatment. Inadequate response is defined as less than 50% reduction in 
symptoms on a clinical rating scale (e.g., MADRS) after 4 to 8 weeks of treatment.
Legend: AD – antidepressant; SSRI – serotonin reuptake inhibitor; SNRI – serotonin and norepinephrine reuptake inhibitor. 
Non-pharmacological treatments, such as psychotherapy and non-invasive brain stimulation, are considered combination 
therapies at each stage of treatment.
Second treatment phase
(4 – 8 weeks)
First treatment phase
(4 – 8 weeks)
Adequate
response to first-
line treatment
Inadequate 
response to first-
line treatment
Maintenance
treatment
Partial response to 
first-choice AD
Increase of medication
dose
Non-pharmacological treatment options can be considered as combination therapies at any point in treatment pathway
Third treatment phase 
and beyond
Switch to first- or second-
choice AD
Augmentation
Adequate response
to second-line
treatment
Inadequate
response to second-
line treatment
Maintenance
treatment
Increase of
medication dose
Adequate 
response
Inadequate
response
Switch to first- or second-
choice AD
Combination antidepressant
therapy
Augmentation
SSRI/SNRI + esketamine
Experimental treatments
Combination antidepressant
therapy
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Zdravniški vestnik, priloga | Recommendations for treatment of unipolar depressive disorder
Legend: * – Strength of recommendation; # – Level of evidence.
Medication Therapeutic dose Special features
MOOD STABILIZERS
lithium *(A) #(I) target plasma level 0.4 - 0.8 mmol/l, possibility of dose escalation up to 1.0 mmol/l with partial response
lamotrigine *(C) 100–400 mg
ATYPICAL ANTIPSYCHOTICS
olanzapine + fluoxetine 5–15 mg + 20–60 mg most data for this combination is available for bipolar depression
olanzapine *(B) #(I) 5–15 mg
quetiapine *(A) #(I) 150–300 mg
risperidone *(B) #(I) 0.5–3 mg
aripiprazole *(A) #(I) 2–20 mg
OTHER
thyroid hormones *(B) #(I) 20–50 μg
Table 5: Augmenting the response using other types of medication. Adapted from Taylor DM, et al., 2018 and Cleare A, et 
al., 2015 (4,5).
patients who do not respond to therapy, the term treat-
ment-resistant depression (TRD) is used (26). A simpler 
definition of TRD, also used by the European Medicines 
Agency (EMA), states that resistance occurs when with 
the use of at least two antidepressants (from the same or 
different groups and at the appropriate dose and dura-
tion) fails to achieve an adequate response (27). Some-
times the term “refractory depression” is used, which 
denotes an inadequate response to three treatment at-
tempts, one of which is electroconvulsive therapy. Be-
cause the duration of an inadequately treated depressive 
episode is increasingly recognized as relevant for devel-
oping resistance, recent guidelines recommend shorter 
periods of individual antidepressant treatment trials. 
The use of additional treatments (psychotherapy, new-
er groups of antidepressants, non-invasive brain stimu-
lation) is recommended at an earlier stage of treatment 
when the development of treatment resistance is less 
likely (28).
When treating TRD, it is always important to recog-
nize the possibility of pseudoresistance, which can be 
present in up to 60% of all patients with an initial di-
agnosis of TRD (29,30). Pseudoresistance may include 
inappropriate diagnosis, a wrong type of treatment, in-
appropriate dose or duration of treatment, poor treat-
ment adherence, or significant psychiatric and/or phys-
ical comorbidities (31). The clinical pathway used in 
treatment-resistant depression is shown in Figure 1. In 
the event of a partial therapeutic response in the initial 
treatment phase, the antidepressant should be continued 
and the dose adjusted within the recommended range. 
When an antidepressant is introduced, it is reasonable to 
continue treatment for 4 to 8 weeks (with a minimum of 
2-3 weeks at higher doses) before it can be judged inef-
fective (4,5,26,32).
In the second phase of treatment, which should also 
last at least 4 to 8 weeks (Strength of recommendation 
B), different strategies can be used, such as switching to 
another antidepressant from the first or second group of 
choice (Table 4), augmenting the response (using other 
types of medication in combination with an antidepres-
sant, Table 5), and combination therapy (a combination 
of two antidepressants from different therapeutic groups 
(Strength of recommendation A), an antidepressant with 
psychotherapy (Strength of recommendation B) for CBT 
specifically (Strength of recommendation A), or an an-
tidepressant with non-invasive brain stimulation – ECT 
(Strength of recommendation B) and TMS (Strength of 
recommendation D) (5-8,28).
In the third phase of treatment, all of the strategies 
already mentioned for TRD treatment are used, as along 
with other methods, such as third-line antidepressants 
(Table 4). Esketamine is approved for clinical use in 
moderately and severely resistant depressive disorder 
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(EMA and US Food and Drug Administration - FDA, 
since 2019). In Europe, esketamine is used in combina-
tion with an SSRI or SNRI. Due to the complexity of 
its use and the possibility of complications, treatment 
is performed in a supervised, preferably inpatient, set-
ting. The introduction of esketamine is possible after 
two failed treatment attempts with first- or second-line 
antidepressants (28).
Electroconvulsive therapy (ECT) is also effective for 
treatment-resistant perinatal depression. There is no 
evidence of harm to the mother or fetus with ECT, al-
though general anesthesia during pregnancy may have 
side effects (33).
2.3 Psychotherapy, psychoeducation and 
other psychosocial approaches
There are no significant differences between the effi-
cacy of psychological and pharmacological approaches 
in the initial treatment of depression in adult patients. 
Treatment outcome is better when both approaches 
are combined (Level of evidence III) (34). Psychother-
apeutic/psychological therapies are uniformly recom-
mended as the treatment of choice for a mild depressive 
episode or in combination with pharmacotherapy for 
patients with a moderate to severe depressive episode. 
Psychotherapy is also helpful in patients with partial 
response or poor adherence to pharmacotherapy. Psy-
chological and behavioural treatments should be ad-
ministered by appropriately trained practitioners with 
fidelity to techniques showing evidence-based efficacy 
(Strength of recommendation S). For severe major de-
pression, psychological or behavioural treatment is not 
recommended as sole therapy (Strength of recommen-
dation B) (4-8). Available evidence supports the effica-
cy of cognitive behavioural therapy (CBT) (Strength of 
recommendation A, Level of evidence I), interpersonal 
(Strength of recommendation A, Level of evidence I), 
psychodynamic (Strength of recommendation B, Level 
of evidence II), and problem-oriented psychotherapy 
(Strength of recommendation S), which can be delivered 
individually or in a group setting. CBT is recommended 
if psychological treatment is used as monotherapy for 
recurrent depression (Strength of recommendation B) 
(5,6,10,35). If partner or family conflict is present, part-
ner or family psychotherapy is recommended (Strength 
of recommendation S, Level of evidence II) (6,10). The 
NICE guidelines also recommend using specific psy-
chotherapeutic methods in the treatment of depression, 
such as CBT-based self-help techniques and structured 
group exercises (10). Behavioural activation is a similar 
and comparably effective brief psychotherapeutic ap-
proach (Level of evidence II) (36).
In Slovenia, mindfulness is positioned as a modern, 
scientifically and anthropologically based psychother-
apy for treating depressive disorders (37). According 
to our experience in Slovenia, the combination of sys-
temic family therapy and pharmacotherapy is a useful 
and effective method for treating depressive disorders 
when unfavourable life circumstances and problems in 
interpersonal relationships coincide (38). Group psy-
chotherapy for the geriatric population with depressive 
symptoms offers partial compensation for losses, the 
possibility to recognise and strengthen preserved as-
pects of the personality, and a place for processing inev-
itable losses in old age (39).
During treatment, it is important to maintain the 
therapeutic relationship and monitor the risk of suicidal 
behaviour, response to therapy, the occurrence of side 
effects and changes in physical well-being (7,10). Psy-
choeducation and psychotherapeutic/psychosocial ap-
proaches can significantly improve patient participation 
in the treatment, decrease suicide rates, improve treat-
ment efficacy, help patients and their families recognize 
signs of relapse, and understand the purpose and bene-
fits of various forms of treatment (40).
Adding intense physical exercise to antidepressant 
therapy may help patients with mild or moderate de-
pressive episodes (Strength of recommendation B) (5,7). 
Studies have shown an association between healthy eat-
ing and a lower risk of depression (41) or suicide (42). 
Dietary supplements such as omega-3 fatty acids (Lev-
el of evidence II), S-adenosylmethionine (SAM), and 
folates can be used as potentially effective additions to 
therapy (Strength of recommendation B). St. John’s wort 
can also be used as a dietary supplement, but patients 
should be advised of interactions with SSRIs (Strength 
of recommendation D) (5,6).
Nutritional counselling services in Slovenia can con-
tribute to the holistic treatment of our patients. A com-
bination of nutrients that meet the body’s natural phys-
iological needs can be much more effective than taking 
isolated supplements (43).
2.4 Brain stimulation methods in the 
treatment of depression
Biological methods for the treatment of depression 
include non-invasive methods in which the brain is 
stimulated with electric current (transcranial electri-
cal stimulation - tES, ECT) or electromagnetic pulses 
(transcranial magnetic stimulation - TMS) (44). The use 
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Zdravniški vestnik, priloga | Recommendations for treatment of unipolar depressive disorder
of invasive methods in treatment-resistant depression 
(TRD) is currently not justified because the exact ana-
tomical targets in the brain have not yet been identified 
(45). In Slovenia, the Mental Health Act (ZDZdr) (46) 
explicitly prohibits the use of invasive methods for men-
tal disorders treatment in general.
Among non-invasive brain stimulation methods, re-
petitive transcranial magnetic stimulation (rTMS) has 
recently gained popularity in TRD treatment due to its 
combination of practicality, safety, and efficacy (6-8,10). 
rTMS is a safe method without significant side effects 
and with high short-term efficacy, although the indi-
vidual patient response is variable (47). Various treat-
ment protocols can be used. High-frequency (10 Hz or 
more) rTMS of the left dorsolateral prefrontal cortex 
(DLPFC) is the most commonly used method (Strength 
of recommendation A), whereas low-frequency (1 Hz) 
rTMS of the right DLPFC is also possible (Strength 
of recommendation B). Newer versions of treatment 
protocols use variable treatment parameters or more 
complex patterns of stimulus sequences that can be 
administered in much shorter treatment sessions (47). 
The most widely researched is theta burst stimulation 
(TBS), which regulatory agencies recently approved for 
clinical use after being compared with HF-rTMS in a 
noninferiority trial. Intermittent TBS of left DLPFC 
probably has the highest treatment efficacy in depres-
sion; however, the relative lack of data still precludes a 
specific recommendation (Strength of recommendation 
S) (47). For safety reasons, rTMS is also recommended 
as a possible first-line treatment for patients who can-
not take antidepressant medication for various reasons 
(Strength of recommendation C) (47,48). Transcranial 
direct current electrical stimulation (tDCS) techniques 
enhance activity in the left DLPFC with anodal stimula-
tion or reduce activity in the right DLPFC with cathodal 
stimulation. Currently, only anodal stimulation has suf-
ficient evidence of treatment efficacy to recommend it 
for non-treatment-resistant depression (Strength of rec-
ommendation B), whereas tDCS does not appear to be 
superior to a placebo for treatment-resistant depression 
(Strength of recommendation B) (49).
Electroconvulsive therapy (ECT) is the most effec-
tive short-term treatment for depression, with remis-
sion rates between 60-80% for non-treatment-resistant 
depression and 50% for treatment-resistant depression 
but with a very high relapse rate without maintenance 
therapy (50). ECT is used to treat severe depressive epi-
sodes (Strength of recommendation A), especially when 
psychotic features are present and in life-threatening 
conditions such as agitation, stupor, severe physical 
exhaustion due to refusal to eat, and high risk of suicide 
(50,51). Newer treatment protocols with unilateral ap-
plication and shorter pulse duration are similarly effec-
tive to standard procedures, with a lower risk of severe 
side effects such as cognitive impairment (Strength of 
recommendation B) (10,50,52).
ECT treatment is not currently offered in Slovenia, 
as various obstacles limit its availability. Patients who 
need this type of therapy are usually referred to treat-
ment centers in neighbouring countries such as Croa-
tia. Other brain stimulation methods, such as rTMS and 
tDCS, are only used on a case-by-case basis (53) or in 
research. Wider adoption of brain stimulation methods 
in clinical practice for depression treatment in Slovenia 
is currently limited due to the lack of available services 
and reimbursement by public health insurance (54).
3 Treatment of depression in children and 
adolescents
While there is a lack of quality RCTs with a high 
number of participants for all the treatments of depres-
sion in children and adolescents, the strengths of rec-
ommendation in the following recommendations are D. 
Cognitive-behavioral psychotherapy (Level of evidence 
II), interpersonal (Level of evidence II), and psycho-
dynamic psychotherapy are effective for the treatment 
of depression in adolescents, with brief psychosocial 
interventions showing similar effectiveness to individ-
ual CBT and psychodynamic psychotherapy (Level of 
evidence I) in some studies. Family-oriented therapies 
are more effective than individual therapies in treating 
depression in children (Level of evidence II), and group 
therapies (Level of evidence II) are effective in adoles-
cents in addition to individual therapies.
Treatment with antidepressants and/or psychothera-
py likely reduces suicidality, but in some children or ad-
olescents, treatment with SSRIs, in particular. increases 
suicide risk (55). Despite the lack of robust evidence, 
psychopharmacological treatment of depression in chil-
dren and adolescents is recommended because treat-
ment outweighs the risks of untreated depression (56). 
The combination of psychotherapy and treatment with 
antidepressants is more effective than either treatment 
alone.
The NICE guidelines (9) recommend that children 
and adolescents with moderate to severe depressive 
episodes are treated by a specialist in child and ado-
lescent psychiatry, whereas those with mild depressive 
episodes can be treated initially by a paediatrician. All 
should receive specific psychological interventions 
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with the possibility of concomitant use of psychotro-
pic drugs. For a moderate to severe depressive episode, 
psychotherapy is recommended first, to which fluox-
etine may be added. In children older than 12 years, 
fluoxetine may be added immediately; in younger chil-
dren, it may be added after at least four psychotherapy 
sessions have failed to produce adequate effects. In the 
case of ineffective initial treatment, TRD, psychotic or 
recurrent depressive disorder, fluoxetine, sertraline, cit-
alopram, or antipsychotic augmentation during inten-
sive psychotherapy are recommended. While sertraline 
or citalopram are recommended as second-line antide-
pressants, venlafaxine, paroxetine, or tricyclic antide-
pressants should not be prescribed because of signif-
icant side effects. In addition, treatment of depressive 
disorder at this developmental period should definitely 
include psychosocial assessment with appropriate in-
terventions, help with schooling, and assessment and 
treatment of a possible mental disorder in parents or 
guardians (9).
Treatment of depression in children and adolescents 
requires careful and fully informed shared decision 
making between the child, parent/guardian, and cli-
nician. Information about the current availability and 
waiting times for psychological support services should 
be included in the decision-making process, as well as 
the expected effects and side effects of the various forms 
of treatment and the risks associated with not treating 
the disorder (9,56).
In Slovenia, the current accessibility to child and 
adolescent psychiatry services is extremely poor, with 
waiting times for the first non-urgent examination 
exceeding one year, and psychotherapeutic treatment 
is almost inaccessible in public health care (57). Cur-
rently, the only readily accessible psychiatric services 
for children and adolescents are emergency outpatient 
clinics, which have seen a remarkable increase in the 
number of admissions in recent years (58). As a result, 
we see a 43.3% increase in the use of antidepressants 
prescribed to under-19s, even though guidelines do not 
recommend this. In girls aged 15-19 years, antidepres-
sants account for 69.5% of all drugs prescribed for the 
treatment of mental and behavioural disorders (59).
4 Treatment of depression in the elderly
Depressive disorders in the elderly often present 
with concomitant physical illness or impaired higher 
nervous system abilities and cognitive decline, mak-
ing them difficult to recognize and treat (8). Com-
pared with depressive episodes that begin at other ages, 
depressive disorders with onset later in life have a poor-
er prognosis. They are more likely to be chronic, with 
a higher risk of illness relapse and mortality (8,60). In 
terms of treatment choice, similar principles apply as 
described for the general population. The advantages 
and disadvantages of a particular treatment should be 
carefully weighed when selecting a drug, as there is an 
increased risk of treatment side effects at this age (61).
Choice of antidepressant based on The Canadian 
guidelines for the treatment of a depressive episode (8) 
recommend the selection of an antidepressant in the 
following order: the first choice duloxetine, mirtazap-
ine, nortriptyline (Level of evidence I), bupropion, 
citalopram/escitalopram, desvenlafaxine, sertraline, 
venlafaxine, vortioxetine (Level of evidence II); the 
second choice: replacement with nortriptyline (Level 
of evidence I), moclobemide, phenelzine, quetiapine, 
trazodone (Level of evidence II), bupropion (Level of 
evidence III) combination with aripiprazole, lithium 
(Level of evidence I), methylphenidate (Level of evi-
dence II); the third choice: replacement with amitrip-
tyline, imipramine (Level of evidence II), combination 
with SSRI or SNRI with bupropion, SSRI (Level of ev-
idence III).
A clinical pharmacist is a relatively new profession 
in Slovenia. Services include a review of pharmaco-
therapy to optimise the number of medications and 
drug-drug interactions to improve the quality of life of 
patients with depressive disorders in the geriatric pop-
ulation (62).
5 Treatment of perinatal depression
A Slovenian study from 2014 showed that 21.7% 
of pregnant women experienced depressive episodes 
during pregnancy (63). There are no RCTs for the treat-
ment of perinatal depression. The prescription of psy-
chotropic drugs to women of childbearing age should be 
guided by the latest evidence on the risks to pregnancy 
and the fetus. Treatment decisions should include the 
use of nonpharmacologic methods such as psychoed-
ucation, psychotherapy, and other modalities (medita-
tion, relaxation techniques, mindfulness, hypnosis, oc-
cupational therapy), as well as balancing the effects of a 
depressive episode on pregnancy and the fetus against 
possible adverse effects of medication (Table 6).
General recommendations are as follows (64):
1. Patients with a history of depressive disorder should 
be encouraged to plan pregnancy when they are in 
remission.
2. The Edinburgh Postnatal Depression Scale (EPDS) 
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Legend: AD – antidepressant; SSRI – serotonin reuptake inhibitor; SNRI – serotonin and norepinephrine reuptake inhibitor .
 CHOICE OF THERAPEUTIC TREATMENT IN PREGNANCY AND POSTPARTUM PERIOD
Clinically stable depression in remission (6 months), 
low probability of relapse:
Psychoeducation, psychotherapy, sometimes 
medications are required
Currently symptomatic or asymptomatic with a high 
probability of relapse:
• Mild to moderate depressive episode: 
psychoeducation, psychotherapy, sometimes 
medication is required.
• Moderate to severe depressive episode: 
medication usually required, in addition to 
psychoeducation, psychotherapy.
PHARMACOLOGICAL TREATMENT
Before and 
during 
pregnancy
• The AD can be discontinued before pregnancy if 
there is little chance of relapse.
• If AD cannot be discontinued, continued use of AD 
is advisable only if the benefit of taking it outweighs 
the risk and the drug is not contraindicated during 
pregnancy.
• If the current AD is effective, continued treatment 
is advisable if the benefits of taking it outweigh the 
risk and if the drug is not contraindicated during 
pregnancy.
• If the AD is needed, an SSRI is prescribed as the 
first choice (not paroxetine or fluoxetine in the first 
trimester) and an SNRI as the second choice.
During birth A therapeutic dose of the same AD is maintained.
After birth • The currently effective AD is continued, and the dose may need to be adjusted.
• If an AD is needed, an SSRI that allows breastfeeding is prescribed.
• After remission of the first depressive episode, the AD should be taken for 6-12 months (or at least 2 years after 
the second depressive episode).
Table 6: Recommendations for treating perinatal depressive disorder. Adapted from Williams J, 2014 (70).
is the most commonly used instrument for screen-
ing postpartum depression (65).
3. The patient should be informed about the benefits of 
treatment, possible side effects, and the consequenc-
es of changing or discontinuing treatment during 
pregnancy.
4. Abrupt medication discontinuation because of 
pregnancy without consultation with a psychiatrist 
is not recommended and may lead to relapse (66).
5. If a woman is taking an effective antidepressant at 
the start of pregnancy, treatment should be contin-
ued with the same antidepressant if the benefit of 
taking it outweighs the risk and it is not contrain-
dicated during pregnancy. Antidepressants with 
higher risk (e.g., paroxetine, fluoxetine) are replaced 
with a lower risk antidepressant.
6. Psychotropic medications cross the placenta. 
During pregnancy, we prescribe those medications 
that have not shown teratogenic or other significant 
effects on the fetus and pregnancy.
7. The drug with the least risk and at the lowest effec-
tive dose should be prescribed, but subtherapeutic 
doses are ineffective. Whenever possible, monother-
apy should be used.
8. The drug dose may need to be adjusted during preg-
nancy due to altered absorption and protein bind-
ing. Higher doses are often required in the third 
trimester because plasma volume increases by one-
third (67).
9. During lactation, sertraline and paroxetine are less 
likely to be excreted into milk (68). When taking 
medications during lactation, it is advisable to con-
sider the percentage of the mother’s dose that the 
infant absorbs in milk (relative infant dose - RID), 
which allows an estimate of the infant’s exposure to 
the drug. The online database LactMed (Drugs and 
lactation database) can be helpful.
When introducing an antidepressant in pregnancy, 
previous response to antidepressants, the pregnancy 
term, the drug’s reproductive safety, and the potential ef-
fects on the newborn must be considered. In pregnancy, 
SSRIs are the antidepressants of choice, with sertraline 
being the most commonly prescribed medication. The 
FDA has used the ABCDX risk categories for safety in 
pregnancy. Since 2015, a description of the risks and 
clinical dilemmas of taking the drug during pregnancy 
and lactation, as well as the effects of the drug on fer-
tility, has been available as Lactation Labeling Rules 
(PLLR). The teratogenic influence is important during 
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organogenesis in the first trimester (69). Benzodiaze-
pines and hypnotics are avoided in the postpartum pe-
riod, except for short-term treatment of severe anxiety 
and agitation. Long-acting benzodiazepines should not 
be prescribed before delivery. Atypical antipsychotics 
may be prescribed in low doses to enhance antidepres-
sant effects (70).
Conflict of interest
None declared.
Acknowledgements
The paper was supported by Slovenian Research 
Agency grants P5-0110 and J3-1763.
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