World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders in Primary Care

Figures & data

Table I.  Classification and criteria of major depressive disorder (DSM-IV) and depressive episode (ICD-10)

ICD-10^a (code)	DSM-IV^b (code)
Depressive episode mild (F32.0): at least two typical symptoms, plus at least two other common symptoms; none of symptoms intense moderate (F32.1): at least two typical symptoms, plus at least three other common symptoms; some symptoms marked severe (F32.2): all three typical symptoms, plus at least four other common symptoms; some symptoms severe with intensity Recurrent depressive disorder (F33): recurrent depressive episodes	Major depressive disorder single episode (296.2x) recurrent (296.3x)
Abridged criteria of depressive episode: Minimum duration of episode: about 2 weeksTypical symptoms: depressed mood loss of interest and enjoyment reduced energy, increased fatigability Other common symptoms: reduced concentration and attention reduced self-esteem and self-confidence ideas of guilt and unworthiness agitation or retardation ideas or acts of self-harm or suicide disturbed sleep diminished appetite.	Abridged criteria major depressive episode: Over the last 2 weeks, five of the following features should be present most of the day, or nearly every day (must include 1 or 2): depressed mood loss of interest or pleasure in almost all activities significant weight loss or gain (more than 5% change in 1 month) or an increase or decrease in appetite nearly every day insomnia or hypersomnia psychomotor agitation or retardation (observable by others) fatigue or loss of energy feelings of worthlessness or excessive or inappropriate guilt (not merely self reproach about being sick) diminished ability to think or concentrate, or indecisiveness (either by subjective account or as observed by others) recurrent thoughts of death (not just fear of dying), or recurrent suicidal ideation, or a suicide attempt, or a specific plan for committing suicide. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. The symptoms are not due to a physical/organic factor or illness (e.g., a drug abuse, a medication, a general medical condition). The symptoms are not better explained by bereavement (although this can be complicated by major depression).

^a4th Revision of the American Psychiatric Association's Diagnostic and Statistics Manual (American Psychiatric Association 1994).

^b10th Revision of the International Classification of Diseases (World Health Organization 1992).

Figure 1.  Stepped-care model (adapted version, original idea from NICE guideline (2004).

Figure 2.  Phases of disease and treatment (adapted version, original from Kupfer (1991)).

Table II.  Antidepressants: Mode of action and commonly used doses.

Generic Name^a (in alphabetical order)	Traditional structural classification^b	Classification according to neurochemical action^b	Starting dose^c (mg/day)	Standard dose^d (mg/day)	Plasma levels^e (therapeutic range) (ng/ml)
Agomelatine		MT agonist	25	25–50
Amineptine			100	200–300
Amitriptyline^f	TCA		25–50	100–300	80–200*
Amoxapine	TetraCA		50	100–400
Bupropion^g		NDRI	150	150–450
Citalopram^i		SSRI	20	20–40 (60)
Clomipramine^h,i	TCA		25–50	100–250	175–450*
Desipramine	TCA		25–50	100–300	100–300
Dibenzepine	TCA		120–180	240–720
Doslepine	TCA		75	75–150
Dothiepin	TCA		25–50	100–300
Doxepine^i	TCA		25–50	100–300
Duloxetine^k		SNRI	30–60	60–120
Escitalopram^i		SSRI	10	10–20
Fluoxetine^h		SSRI	20	20–60
Fluvoxamine^h		SSRI	50	100–200
Imipramine	TCA		25–50	100–300	175–300*
Isocarboxazid^i			20	20–60
Lofepramine	TCA		70	140–210
Maprotiline	TetraCA		25–50	150–225
Mianserin	TetraCA	§	30	60–120
Milnacipran		SNRI	50–100	100–200
Mirtazapine		Other$	15	15–45
Moclobemide		RIMA	150	300–600
Nefazodone			100	300–600
Nortriptyline	TCA		25–50	75–200	70–170
Paroxetine^h,i,j		SSRI	20	20–40 (60)
Phenelzine^i		MAOI	15	30–90
Protriptyline	TCA		10	20–60
Reboxetine		NARI	4–8	8–12
Sertraline^h,i,j		SSRI	50	50–150
Setiptiline	TetraCA		3	3–6
Tianeptine		Other#	37.5	37.5
Tranylcypromine^i		MAOI	10	20–60
Trazodone			50–100	200–600
Trimipramine^f,i	TCA		25–50	100–300
Venlafaxine^j		SNRI	37.5–75	75–375	195–400*
Viloxazine			100	200–500

^aAvailability on the market differs considerably across countries.

^bAbbreviations see below.

^cLower starting doses may be needed for older adults (>60) or patients with co-morbid medical illness (especially cardiovascular conditions; see text).

^dStandard doses are generally lower in Japan.

^eOnly given for those antidepressants with well established therapeutic range (Perry et al. 1994).

*Recommended therapeutic range is the sum of the drug and the active metabolite

Other indications than depression (approved in some countries) or common uses: ^fchronic pain; ^gsmoking cessation; ^hobsessive-compulsive disorder (OCD); ⁱanxiety disorders (panic disorders, PTSD, social phobia); ^jgeneralized anxiety disorder; ^kdiabetic and peripheral neuropathic pain, stress urinary incontinence.

Abbreviations: MAO-I, irreversible inhibition of monoamine oxidase (MAO); MT agonist, agonist of the melatonine receptor (MT1 und MT2); NARI, noradrenaline reuptake inhibition; NDRI, noradrenaline and dopamine reuptake inhibition; Other, other types of receptor or transmitter profile; RIMA, reversible inhibition of monoamine oxidase A (MAO-A); SNRI, selective serotonine and noradrenaline reuptake inhibitors; SSRI, selective serotonine reuptake inhibitors; TCA, tricyclic antidepressant. TetraCA, tetracyclic antidepressant.§Noradrenaline reuptake inhibion plus presynaptic α2-blockade; $α2-antagonist; #5-HT reuptake enhancer.

Table III.  Side effect profiles of antidepressants.^a

Generic name (in alphabetical order)	Anticholinergic^b	Nausea/gastrointestinal	Sedation	Insomnia/agitation	Sexual dysfunction	Orthostatic hypotension	Weight Gain	Specific adverse effects	Lethality in overdose
Agomelatine	−	+	−	−	−	−	−		Low
Amineptine	−	+	−	+ +	+	+	+	Risk of abuse (amphetamine-like effects)	Low
Amitriptyline	+ + +	−	+ + +	−	+	+ + +	+ + +	ECG changes^c; may lower seizure threshold	High
Amoxapine	+ + +	−	+	+ +	+	+	+	hyperprolactinemia	High
Bupropion	+	+	−	+	−	−	−		Low
Citalopram	−	+ +	−	+ +	+ +	−	−		Low
Clomipramine	+ + +	+	+	+	+ +	+ +	+ +	ECG changes^c; may lower seizure threshold	Moderate
Desipramine	+	−	−	+ +	+	+	+		High
Dibenzepine	+	−	+	−	+	+	+		Moderate
Doslepine	+ +	−	+ +	−	+	+	+		High
Dothiepin	+ + +	−	+ + +	−	+	+ + +	+ + +		High
Doxepine	+ + +	−	+ + +	−	+ +	+ + +	+ +		High
Duloxetine	−	+ +	−	+ +	+	−	−		Low
Escitalopram	−	+ +	−	+ +	+ +	−	−		Low
Fluoxetine		+ +		+					Low
Fluvoxamine	+	+ + +		+	+				Low
Imipramine	+ +	−	+	+ +	+	+ +	+ +	ECG changes^c; may lower seizure threshold	High
Isocarboxazid	+	+	−	+ +	+	+ +	+	Hypertensive crisis^e; risk of serotonin syndrome^f	High
Lofepramine	+	−	+	+ +	+	+	+	ECG changes^c; may lower seizure threshold	Low
Maprotiline	+ +	−	+ +	−	+	+ +	+ +	Increased seizure risk	High
Mianserin	+	−	+ +	−	−	+	+	Blood dyscrasia (rare)	Low
Milnacipran	−	+ +	−	+ +	+ +	−	−		Low
Mirtazapine	−	−	+ +	−	−	+	+ +		Low
Moclobemide	+	+	−	+	−	−	−		Low
Nefazodone	+	+	+ +	−	−	+	+	Inhibitory effects on CYP3A4^d	Low
Nortriptyline	+	−	+	+	+	+	+	ECG changes^c; may lower seizure threshold	High
Paroxetine	+	+ +	−	+ +	+ +	−	+	Inhibitory effects on CYP2D6^d	Low
Phenelzine	+	+	+	+ +	+ +	+ +	+	Hypertensive crisis^e; risk of serotonin syndrome^f	High
Protriptyline	+ + +	−	+	+ +	+	+ +	+	ECG changes^c; may lower seizure threshold	High
Reboxetine	−	+	−	+ +	+	+ +	−		Low
Sertraline	−	+ +	−	+ +	+ +	−	−		Low
Setiptiline	+	−	+ +	−	+	+	+		Moderate
Tianeptine	+	+	−	+	−	−	−	ECG changes^c; may lower seizure threshold	Low
Tranylcypromine	−	+	−	+ +	+	+ +	−	Hypertensive crisis^e; risk of serotonin syndrome^f	High
Trazodone	−	+	+ +	−	+ +	+	+	Priapism (rare)	Low
Trimipramine	+ +	−	+ + +	−	+	+ +	+ +	ECG changes^c; may lower seizure threshold	High
Venlafaxine	−	+ +	−	+ +	+ +	−	−	Hypertension	Low
Viloxazine	−	+	−	+ +	−	−	−		Low

Categories of side effect strength: + + +, high/strong; ++, moderate; +, low/mild; −, very low/none.

^aThese side effect profiles of antidepressants are not comprehensive and are for rough comparison only. Details of drugs used and potential cautions and interactions should be looked up in textbooks/reviews (e.g., Bezchlibnyk-Butler and Jeffries 1996, Benkert and Hippius 2005; Kent 2000), the primary literature or the complete prescribing information available in the package insert of the drug.

^bThese refer to symptoms commonly caused by muscarinic receptor blockade including dry mouth, sweating, blurred vision, constipation and urinary retention.

^cConduct delays.

^dOnly those inhibitory effects on hepatic CYP450 enzymes are shown that are clinically relevant; for details see Brøsen (1998) and Kent (2000).

^eIncreased risk with high tyramine containing food and sympathomimetic drugs.

^fIn combination with serotonergic drugs.

Figure 3.  Flow Chart: Therapeutic options in partial and nonresponders¹ to initial treatment with an antidepressant in major depressive disorder. ¹Partial response: 26–49% decrease in baseline symptom severity; nonresponse:≤25% decrease in baseline symptom severity. ²See Table II. ³Caution with combining irreversible MAO inhibitors (see 2.1.8.2). ⁴For indications see 2.3.

Table IV.  Factors associated with increased risk for recurrence in major depressive disorder.

Three or more episodes of major depression High prior frequency of recurrence (e.g., two episodes within 5 years) Previous episode in the last year Residual symptoms during continuation phase treatment Residual subsyndromal symptoms at remission Concurrent dysthymic disorder (“double depression”) Severity of episodes (includes suicidality and psychotic features) Longer previous episodes Relapse after medication withdrawal Concurrent coexisting substance abuse Concurrent coexisting anxiety disorders Family history of major depressive disorder in first-degree relatives Onset prior to age 30 Age of 60 or 65 and older

Table V.  Possible interaction of antidepressants with comedications.

Comedication	Interaction
TCAs
α1-Adrenoreceptor antagonists (prazosine)	Heightened decrease of blood pressure
Anesthetics/muscular relaxants (halothane, pancuronium, gallamine)	Heightened risk for arrhythmia
Antazids, adsorbants	Possibly lower AD blood levels
Antiarrhythmics (chinine, lidocaine, disopyramide, procainamide, propafenone)	Prolonged intracardiac conduction times, decreased myocardial contraction up to insufficiency
Anticoagulants (warfarin, maybe phenprocoumon)	Heightened effect of anticoagulation with longer bleeding times
Anticonceptives	More side effects of TCAs, lower plasma levels of TCAs observed, therefore lower antidepressive effect possible
Antidiabetics, oral	Higher plasma levels with increased blood sugar decreasing effect
Antimycotics (fluconazole, ketoconazole)	Higher plasma levels of TCAs with more side effects
β-Blocker	Heightened decrease of blood pressure, increase of plasma levels of propranolol and TCAs, therefore more side effects, with propranolol possible worsening or induction of depression
Calcium antagonists (diltiazem, verapamil)	Higher plasma levels of, e.g., imipramine, therefore more side effects
Carbamazepine	Risk of lower plasma level of TCAs because of induction of enzymes (CYP)
Cimetidine	Higher plasma levels with more side effects
Cisapride	Higher plasma levels of antidepressant with higher risk of side effects
Diuretics	Heightened decrease of blood pressure
Insuline	Possibly increased blood sugar decreasing effect
Nicotine, smoking	Lower blood levels of TCA possible
Omeprazole	Possibly higher plasma levels of TCA with more side effects
Rifampizine	Lower plasma levels of TCAs, therefore lower antidepressive effect possible
SSRIs	Risk of higher plasma levels of TCAs because of inhibition of enzymes (CYP)
SSRIs
Antiarrhythmics (propafenone, flecainide)	Inhibition of metabolisation with potentially higher plasma levels of antiarrythmics
Anticoagulants (phenprocoumon, warfarin)	Fluvoxamine may increase levels of warfarin. Increased bleeding may result.
Antidiabetics, oral	Potentially increased blood sugar decreasing effect of antidiabetics
Antihistaminics (terfenadine, astemizole)	Prolongation of intracardiac conduction times and arrhythmias
β-Blocker	Inhibition of metabolisation of paroxetine, therefore potentially higher plasma levels with higher risk for side effects
Carbamazepine	Risk of higher plasma level of carbamazepine
Cimetidine	Inhibition of metabolisation of paroxetine, therefore potentially higher plasma levels with higher risk for side effects
Cisapride	Higher plasma levels of antidepressant with higher risk of side effects
Digitoxine	Potenial lower plasma levals of digitoxine with lower efficacy
Immunosuppressants	Higher plasma levels of immunosuppressants with fluvoxamine and fluoxetine
Theophyllin, coffein	Inhibition of metabolisation of theophyllin with fluvoxamine, therefore higher risk of theophyllin side effects
Tramadole	Risk of central serotonine syndrome
Venalafaxine
β-Blocker	Inhibition of metabolisation, therefore potentially higher plasma levels with higher risk for side effects
Carbamazepine	Risk of lower plasma level of venlafaxine because of induction of enzymes (CYP)
SSRIs	Risk of higher plasma levels of venlafaxine because of slower metabolisation
Tramadole	Risk of central serotonine syndrome
MAO inhibitors
Serotonergic drugs (especially SSRIs)	Potentiation of effects and risk of central serotonergic syndrome
Sympathomimetic drugs (epinephrine and other catecholamines, ephedrine)	Risk of hypertensive crisis

Figure 4.  Flow chart: therapeutic options for maintenance treatment of major depressive disorder. CBZ, carbamazepine; MT, maintenance treatment; Li, lithium. *Maintenance electroconvulsive therapy (ECT) is an option for patients responding to ECT in the acute-phase treatment or who fail two or more maintenance medication treatments. **Additional course of psychotherapy may also be considered.

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