MEDICINECONTINUING MEDICAL EDUCATION

Treatment of Depressive Disorders
Tom Bschor, Mazda Adli

SUMMARY
Introduction: A confusing variety of options are available
for the treatment of depressive disorders.
Method: Selective literature review under consideration ofcurrent guidelines.
Results: The treatment of depression can be divided into
acute, maintenance and prophylactic phases. The basic
forms of treatment are pharmacotherapy, psychotherapy,
and supportive strategies. The approximately 30 antidepressants currently on the market differ mainly withrespect to their side effect profiles. Of the specific types ofpsychotherapy, cognitive behavioral therapy, psychodynamic therapy, and psychoanalysis are funded by thestatutory health insurance providers in Germany. All
treatment strategies (except for sleep deprivation) showa latency of onset of several weeks and a nonresponse rateof about 30% to 50%. In clinical practice it is essential tofollow a stepwise procedure and to perform a standardized
evaluation of response after the latency period. In theevent of nonresponse, the next step of treatment should beinitiated.
Discussion: Depressive disorders have a good prognosis
provided one takes best advantage of the available treatment
options. Preconditions are continuation of treatment for an
appropriate length of time (for antidepressants ca. 4 to 6
weeks, for psychotherapy ca. 4 to 12 weeks) andstandardized evaluation of response thereafter.
Dtsch Arztebl Int 2008; 105(45): 782–92
DOI: 10.3238/arztebl.2008.0782
Key words: depression, antidepressants, stepwise antidepressant treatment, treatment algorithm, psychotherapy

Jüdisches Krankenhaus, Abteilung für Psychiatrie und Psychotherapie, Berlin:
PD Dr. med. Bschor
Klinik für Psychiatrie und Psychotherapie, Charité – Universitätsmedizin Berlin,
Campus Mitte: Dr. med. Adli

he diagnostic evaluation of depressive disorders
and their classification as mild, moderate, orsevere was presented a short while ago in an earlier issueof Deutsches Ärzteblatt (1). If depression has been correctly diagnosed, numerous effective treatment options
are currently available. The prognosis of a depressive
disorder is good if it is treated appropriately and consistently.

T

The learning aims of this article arec knowing the fundamentals of the treatment ofdepressive disorders (indication, setting, treatment
phases, treatment steps)
c learning the principles of establishment of thephysician-patient relationshipc acquiring basic knowledge about pharmacotherapy
with antidepressantsc acquiring knowledge about treating depression
with different forms of psychotherapy.
This continuing medical education article is based ona selective review of the literature, combined with theauthors' own extensive experience in the ambulatory
and in-hospital treatment of depressed patients. It presents
the current state of the therapy of depressive disorders,with an emphasis on treatments that can be provided bygeneral practitioners and family physicians.
Evidence of a depressive episode requiring treatment,
as opposed to appropriate grief, can include the following:c Duration of the depressive syndrome > 2 weeks
c Persistently depressed affect that cannot be lightenedeven by positive experiencesc A sense of paucity of emotion (the patient does notconsider himself or herself to be sad, but rather
feels "turned to stone" or "dead within")c Typical circadian fluctuations, with a morning low
and improvement toward eveningc Somatic symptoms without any organic cause

Prognosis
Depressive disorders have a favorable prognosis
if the available treatments are applied consistently
and thoroughly.

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c Inappropriate feelings of guilt, or even depressive
delusionsc Suicidality
c Previous episodes of severe depressionc A family history of severe depressive disorders.

The treatment setting
Depression is a very common condition (1). Therefore,
its diagnosis and treatment, at least in uncomplicatedcases, are tasks not just for the psychiatrist, but for thegeneral practitioner and family physician as well.
c The indications for referral to a psychiatrist are– diagnostic uncertainty– psychiatric comorbidity (e.g., addiction, dementia,
personality disorder)– severe depressive manifestations– delusional depression– depression in the setting of a bipolar affective
disorder (bipolar depression)– suicidality– chronified depression– intractability, i.e., nonresponse to one or two treatments that have been carried out appropriately– need for psychotherapy or for an intensity of carethat cannot be delivered in the setting of a family
practice.
c The indications for referral for inpatient psychiatrictreatment are– acute suicidality or other type of self-endangerment (e.g., refusal of food)– severe delusional or other psychotic manifestations– depressive stupor– the inability, because of illness or other causes, toparticipate in outpatient treatment on a regularbasis (e.g., because of a lack of drive)– imminent neglect of oneself because of the lackof an adequately supportive social network– external living conditions that would impair the
success of outpatient treatment, e.g., severefamilial conflicts– lack of response to outpatient treatment.

Phases and objectives of treatment
The treatment of depression is divided into three phases(2, 3). The goal of acute therapy is complete or nearcomplete remission of the depressive manifestations.
Because the speed of response of depressive disorders to

Depression—a common disorder
The recognition and treatment of depression, atleast in cases with an uncomplicated course,
is a task not just for psychiatrists, but for generalpractitioners as well.

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treatment varies, acute therapy may need to be given for
no more than a few weeks or for many months.
After the acute phase, maintenance therapy is given,
with the main goal of preventing an early relapse. Its
duration varies from 6 to 12 months. Maintenance therapy
is indicated during this period because there is a high chanceof relapse regardless of the form of treatment that was used
to induce remission in the acute phase (4). In general, theform of treatment that led to remission is continued
unchanged into the maintenance phase. A further goal of
maintenance therapy is complete functional recovery, i.e.,
the patient's complete return to his or her premorbid levelof function at home, in the workplace, and elsewhere.
Prophylactic therapy is indicated only in patients
whose illness has taken a recurrent course, depending on
the likelihood of recurrence in the individual case. The
latter can best be judged from the number of priordepressive episodes and from the intervals of time
between them. If prophylactic therapy is thought to be
indicated, it should be started without any temporal endpoint in view (4). This review article will mainly deal
with acute therapy.

Principles of treatment
The three main types of treatment for depression arec pharmacotherapy,
c psychotherapy, andc supportive measures.
Because of the considerable rate of spontaneous
remission, particularly in milder cases of depression(untreated episodes last for an average of 6 to 8 months),
the physician and the patient may agree on a two- tofour-week period of "watchful waiting" before anytreatment is given (5).
The initial treatment of mild or moderate depression
should consist of monotherapy, either with a single
medication or with psychotherapy, depending on availability and on the patient's preference. In severe, recurrent,
or chronified depression, as well as for elderly depressed
patients, a primary combination of these two treatment
modalities may be advantageous.

Basic treatment strategy
The foundation of any treatment for depression, including
but not restricted to specific forms of psychotherapy, isconversation with an empathic and understanding physician in the framework of a stable therapeutic alliance.
The patient should sense the physician's acceptance of
his or her worries and fears and should feel relieved as a

The basis of treatment
The treatment of depression is based on conversation with an empathetic and understanding
physician and on a stable therapeutic alliance.

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result of the therapeutic interview, particularly with respect to feelings of guilt and inadequacy. The physician
should inspire optimism by assuring the patient that
depression is treatable and has a good prognosis. To thisend, it often helps to instruct patients with a biologicalmodel of their condition, making it possible for them—
particularly in the acute stage—to understand theirdepressive manifestations as the expression of an illness
and thus as a legitimate, temporary dispensation fromthe duties of everyday life. A biological explanation canoften also take away the inexplicable and threatening
character of depression. Chronically depressed patients,on the other hand, need stepwise activation and promotion of their individual responsibility and initiative.
Over-challenged family members often react withreproaches, trivializations ("everything will be OK soon
enough, it's not really so bad"), or exhortations to "pullyourself together." All of these are unhelpful, yet they
underscore the necessity of educating the patient's family,
too, about depression as a treatable illness and of enlisting them in the effort to bring about recovery. Patientsand their families can be motivated to participate in aself-help or family group (see German Internet addresses
listed at the end of this article). Written patient information can be useful as well (see Internet addresses).
A special danger of depressive disorders is suicidality.
3% to 15% of persons suffering from depression commit
suicide (e1), while 40% to 70% of suicide victims had
suffered from depression (6).
The issue of suicidality should always be addressed
repeatedly over the course of treatment. Patients almost
always feel relieved when this topic is discussed. For
concrete management, see the article by Rudolf et al.
(1). Most suicides are announced beforehand in someway, either directly or indirectly.
Important steps to be taken for suicidal patients are
the following:c The immediate commencement of a psychotherapeutic crisis intervention. A stable physician-patient
relationship is the most effective protective factor;
thus, the family physician plays a central role insuch situations.
c Referral to a specialized psychiatristc Short-term follow-up at close intervals and clear,
unambiguous agreement on the time and place ofthe next session—no vague offers such as, "give mea call if things are not going well."c A concrete, 24-hour offer of help: telephone numberof the psychiatric crisis service or rescue center

Suicidality
A special danger of depressive disorders issuicidality. 3% to 15% of persons suffering fromdepression commit suicide, while 40% to 70% of
suicide victims had suffered from depression.

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c Obtain the patient's agreement to put off any
thoughts of harming himself or herself and havethe patient commit to an anti-suicide pact. The
latter is an agreement between the physician andthe patient in which the patient promises not toharm himself or herself within a specified periodof time.
c Inpatient referral or involuntary commitment, if
necessary, in accordance with the relevant lawsc For acute suicidality, give benzodiazepine whenindicated.
Because there is no single treatment method towhich all patients will respond, depression is treated,
as a rule, in sequential therapeutic steps (7). The
duration of each step should be long enough to givethe method used a chance to be effective, yet also
short enough to avoid treating the patient ineffectively
for any longer than necessary. Four weeks (or six, forelderly patients) has generally been found to be an
appropriate period for treatment with antidepressant
medications, four to twelve weeks for specific formsof psychotherapy.
At the end of this period, the patient's response totreatment should be evaluated in a standardized fashion.
To this end, a detailed documentation of the patient's
disease manifestations at the outset of the treatment stepis essential. The established, easy-to-use depression
severity scales are also helpful—both external assessment scales (e.g., the Hamilton Depression Scale [8])and self-assessment scales (e.g., the Beck Depression
Inventory [9]). A "response" in terms of these scales isgenerally said to have occurred when the overall scorehas gone down by at least half during the treatment stepin question (10). If this is the case, further treatment
should be aimed at a complete remission of the disease
manifestations. In case of nonresponse, on the other
hand, a transition should be made to the next treatment
step.

Pharmacotherapy
Antidepressants
The antidepressants play a central role in the pharmacotherapy of depression. Approximately 30 substances inthis class are approved for use in Germany. All are about
equally effective (5), with a nonresponder rate of onethird to one-half. All antidepressants have a similar
latency until the onset of their therapeutic effect: forpractical clinical purposes, a latency of two to fourweeks can be assumed (EBM level A [Ia]).

The treatment of depression
As a rule, depression should be treated insuccessively applied therapeutic steps, because
not all patients respond to every kind of treatment.

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With very few exceptions, all available antidepressants
work mainly by raising the synaptic concentration ofserotonin and/or noradrenaline in the central nervous
system. They differ only in the precise mechanism bywhich they do this (11) (table 1).
Phytotherapy (St. John's wort)
Phytotherapy with St. John's wort preparations is very
popular in Germany in particular. The scientific evidencewith regard to the efficacy of this agent is mixed at present,with many studies fraught with severe methodologicaldeficiencies. A current meta-analysis (5) comes to theconclusion that St. John's wort is probably effective forthe treatment of mild and moderate depression. The morethan 40 St. John's wort preparations that are now available
on the German market contain extremely variable concentrations of more than 400 individual chemical
substances (5).
It is not widely known, yet highly clinically relevant,that St. John's wort carries with it a major risk of interactions with other medications: by inducing isoenzymesof the cytochrome P450 system, it can weaken the effectof many medications, including oral contraceptives,
anticoagulants, digoxin, theophylline, other antidepressants, cyclosporine, and anti-HIV agents. Likewise,
when a patient stops taking St. John's wort, the serum
concentrations of these drugs will rise.
Benzodiazepines
Benzodiazepines have no antidepressant effect in the strict
sense of the term, yet they have an acute sedative andanxiolytic effect and their use may thus be indicated forseverely depressed and suicidal patients for a period nolonger than 14 days. Such treatment is often needed
because of the long latency of effect of the antidepressants,
which was already mentioned above. The risks and contraindications of the benzodiazepines must, however, betaken into account. For instance, a history of addiction
may be a risk that contraindicates benzodiazepine use.

TABLE 1
The mechanism of action of antidepressantsMechanism

Pharmacological group

Inhibition of serotonin and/or
noradrenaline reuptake

c Tri- and tetracyclic
antidepressants (TCA)c Selective serotonin and noradrenaline
reuptake inhibitors (SNRI)c Selective serotonin reuptake
inhibitors (SSRI)
c Selective noradrenaline reuptake
inhibitors (reboxetine)

Inhibition of monoamine oxidasesc Reversible monoamine oxidase
inhibitorsc Irreversible monoamine oxidase
inhibitors

Inhibition of presynaptic autoreceptors

c Presynaptic receptor antagonists

Weekly injections of fluspirilene should not be given
because of the risk of tardive dyskinesia.
Lithium
So-called lithium augmentation plays a role in the acutetreatment of depression that has not responded to antidepressants (12). Furthermore, lithium as monotherapy
is effective for prophylactic treatment in recurrent
depression. Treatment with lithium requires special
knowledge and precautionary measures and should thus
be prescribed only by experienced physicians.

The course of pharmacotherapy

Neuroleptics
Neither the older nor the newer neuroleptics have beenshown to be effective as monotherapy for unipolar
depression. Neuroleptics are indicated only for the treatment of delusional depression and should only be prescribed by a psychiatrist. Studies have shown that someof the atypical neuroleptics are effective when given in
addition to an antidepressant (augmentation therapy),
but neuroleptics have not been approved for this indication.

Patient education and shared decision-making
Thorough patient instruction about the effect, duration,and possible side effects of treatment is an integral component of pharmacotherapy. Patients must also be informed that maintenance therapy will be needed after
the acute phase of treatment. When discussing thesematters with the patient, the physician must address
widespread misgivings and ungrounded fears, e.g., ofaddiction or a change of personality. Patient compliancewith psychiatric medication is often inadequate but canbe improved by informing the patient about the latencyof the antidepressant effect and by describing possible
side effects in advance. Shared decision-making (13)means that the well-informed patient should be able todecide for or against taking any proposed antidepressant
medication in tandem with the physician. Letting the

St. John's wort
St. John's wort is likely to be effective for thetreatment of mild or moderately severe depression.
The available preparations are, however, of variable
composition and can lower the effectiveness ofmany types of concomitantly taken medications.

Patient education and shared decision-making
A thorough orientation of the patient about the effect,
duration, and possible side effects of treatment is an
integral component of pharmacotherapy. Patients
must also be informed that maintenance therapy will
be necessary after the acute phase of treatment.

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TABLE 2
Antidepressants

Substance group,
substances

Initialdose(mg/d)

Tricyclic antidepressants:
amitriptyline, clomipramine,
desipramine, doxepine,
imipramine, lofepramine,
nortriptyline, trimipramine
Tetracyclic
antidepressant:maprotiline
MAO inhibitors:
Irreversible: tranylcypromine
Reversible: moclobemideStandard
dose(mg/d)

High
dose*1(mg/d)Side effect, risk, and interaction profile(selected)

Neurochemical
properties

Anticholinergic effects (dry mouth, constipation,
impaired accommodation, urinary retention, delirium,
cognitive impairment); orthostatic hypotension;
sedation, increased appetite, weight gain
(esp. with amitriptyline, doxepine, and trimipramine);heart block, cardiac arrhythmia;
potentially lethal toxicity with overdose:
beware of accidental (impaired memory)or suicidal overdoses

Inhibition of serotonin andnoradrenaline reuptake; also,
blockade of muscarinic
acetylcholine receptors,
histamine1 receptors,
and α1-adrenergic receptors

For tranylcypromine, pay close attention to drug
information (a low-tyramine diet is necessary—bewareof hypertensive crises! Danger of serotonin syndrome
when combined with serotonergic medications, or given
at too short an interval before or after them!). Side effects:
sleep disturbance, orthostatic hypotension, dry mouth.

Tranylcypromine: irreversible
MAO-A and MAO-B inhibition;
Moclobemide: reversible
MAO-A inhibition

Nausea, inner unrest, sleep disturbance, sexual
dysfunction, SIADH*2. With fluoxetine, paroxetine,
and fluvoxamine, beware of the major risk ofinteractions with many other drugs because
of inhibition of cytochrome P450 isoenzymes!

Selective inhibition of serotonin
reuptake

Nausea, inner unrest, sexual dysfunction,rise in blood pressure (esp. venlafaxine),
SIADH*2, dry mouth, diaphoresis

Selective inhibition of serotonin
and noradrenaline reuptake

Sedation, increased appetite, weight gain; mianserin:risk of changes in blood count (check periodically!)

Blockade of presynaptic
autoreceptors and thus inhibitionof negative feedback

Sedation, sleep disturbance, increased appetite,weight gain, orthostatic hypotension, priapism(inform patient!)

Blockade of serotonin2 receptors
and presynaptic autoreceptors,
moderate inhibition of serotonin
reuptake
Inhibition of dopamine andnoradrenaline reuptake

25–50

150

300

10
150

10–30
300–600

80
900

SSRI:
Citalopram, fluoxetine,paroxetine
Escitalopram
Fluvoxamine, sertraline

20
10
50

20–40
10–20
50–150not
indicated

SNRI:
Venlafaxine
Duloxetine

75
60

150–225
60

375
120

Autoreceptor blockers:
Mianserine
Mirtazapine30
15

60–120
15–45

180
80

Other:
Trazodone

50–100

200–400

600

Bupropion

150

150–300

450

Unrest, sleep disturbance, headache,rise in blood pressure, dry mouth

Reboxetine

8

8

10

Tachycardia, orthostatic hypotension, inner unrest, sleep Selective inhibition of
disturbance, dry mouth, diaphoresis, urinary retention
noradrenaline reuptake*1High-dose treatment requires more frequent monitoring, sometimes on an inpatient basis, and will predictably result in a higher rate of undesired effects.
*2SIADH, syndrome of inappropriate ADH secretion

patient's family take part in this process also improvescompliance.
The choice of antidepressant
The choice of an antidepressant for acute treatment islargely based on the side-effect profile, as the agentsused for acute treatment are all comparably effective(table 2). If a particular antidepressant has already been

The choice of antidepressant
The choice of an antidepressant for acutetreatment is largely based on the side-effectprofile, as the agents used for acute treatment are
all comparably effective.

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used effectively to treat a previous episode, then thisagent should be preferred.
Sedation is a side effect that may be either undesiredor beneficial if the patient suffers from sleep disturbance.
Tricyclic antidepressants should be avoided in a number of situations (5):c In prostatic hyperplasia, glaucoma, cognitive impairment/dementia, constipation, and co-medication

EffectivenessThe effectiveness of antidepressants can only beassessed after they have been given for two tofour weeks in standard doses.

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with other anticholinergically active substances,because of their anticholinergic side effects;
c In patients with pre-existing heart disease, because
they may cause cardiac conduction abnormalities
or arrhythmias;c In suicidal or cognitively impaired patients (risk ofdeliberate or accidental overdose), because of theirgreater overdose toxicity compared to other antidepressants.
A reasonable and well-established practice is to give,
during the maintenance phase, the same antidepressantthat led to remission in the acute phase (4), even thoughvenlafaxine is the only substance officially approved inGermany for maintenance pharmacotherapy. Either
antidepressants or, alternatively, lithium can be used forprophylactic therapy in recurrent depression.
DosingEach antidepressant has a minimal effective dose; thesestandard doses are listed in table 2, as are the differing
starting doses of preparations that must be given initially in a slowly increasing dose. For elderly patients,
but for no others, lower than standard doses may
already be effective and may, indeed, be indicatedbecause they cause fewer complications. The sameantidepressant dose should be prescribed in the maintenance phase of treatment that induced a remission in
the acute phase (4). It is very difficult to recommend
specific doses for prophylactic treatment at present
because of the limited data that are currently available.
For prophylactic treatment, too, the standard doseused for acute treatment is probably more effective
than a lower dose.
Monitoring
In the first four weeks of acute therapy, the patient
should be seen in follow-up at least once a week. At eachfollow-up appointment, the patient's toleration of the
medication should be evaluated, and any concerns on
the patient's part should be addressed. The response
should be evaluated after four weeks of treatment.
The following tests are recommended for follow-up:
c Before treatment with an antidepressant, complete
blood count and transaminases
c If a tricyclic antidepressant (TCA) is used, an ECG
as wellc If a TCA or selective serotonin and noradrenaline
reuptake inhibitor (SNRI) is used, blood pressure
measurement

For acute therapy
In the first four weeks of acute therapy,
the patient should be clinically reassessedat least once per week.

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c Over the course of treatment, repeated complete
blood count and transaminases, as well as (in thesituations mentioned above) ECG and bloodpressure measurement, particularly if the dose israisedc If selective serotonin reuptake inhibitors (SSRI) areused, then the serum electrolytes should be measured
over the course of treatment because of the risk ofhyponatremia, particularly in elderly patients.

What to do in case of nonresponse
If the patient's disease manifestations do not respond totreatment with antidepressants in adequate doses for anadequately long trial period, the treatment strategy
should be changed. In this situation, a number of options
are available.
A reasonable first step consists of measuring theserum concentration of the antidepressant being used.
This is called therapeutic drug monitoring (TDM) and isa helpful check on patient compliance as well as a meansof detecting any metabolic particularities that may cause
an inadequate serum level in the individual patient when
taking a standard dose. Blood must be drawn before themedication is taken. For many newer antidepressants,
however, there is still no reliably established connection
between a therapeutic serum level and a clinical response;
thus, TDM is mainly recommended if the agent being
used is either a tricyclic antidepressant or venlafaxine.
More information on therapeutic levels, the degree of
evidence upon which they are based, and the laboratories
that measure them can be found on the Internet (please
see list of German-language websites at the end of thisarticle).
A common strategy after nonresponse to initial antidepressant treatment is to switch to another antidepressant; choosing an agent from another antidepressantclass is usually recommended. There is, however, no
scientific evidence for the effectiveness of this strategy(14). Thus, the antidepressant should not be changed
more than once in the acute phase, and, if the second
antidepressant also fails to bring about a response, another strategy should be used.
High-dose antidepressant treatment (table 2) is asensible option for most antidepressants (15). The
SSRIs are an exception: these agents have no clear
dose-response relationship, so dose escalation of
SSRIs lacks a theoretical basis (15). Antidepressantsgiven in high doses can be expected to produce more
severe side effects. ECG checks at closer intervals are

In case of resistance to treatmentc measure the serum concentration ofantidepressantc change the antidepressant (no more than once)c give the antidepressant in a high dose(exception: SSRI)

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obligatory when tricyclic antidepressants are given inhigh doses; with venlafaxine, the blood pressuremust be checked at close intervals. The possible
response to high-dose therapy should be evaluated no
sooner than about four weeks after it has been initiatedbecause of the known latency until the treatment
effect sets in.
A further reasonable treatment strategy after nonresponse to antidepressant monotherapy is combination
therapy with two antidepressants. The effectiveness of
combination therapy, however, has only been documented
for one specific type of combination, namely that of a
reuptake inhibitor (tricyclic antidepressant or SSRI)
together with a presynaptic autoreceptor blocker (mirtazapine, mianserin, or trazodone) (16).
Lithium augmentation is the administration of lithiumin addition to an antidepressant that has been usedhitherto for monotherapy without effect. Adding onlithium can bring about a response in a considerable
number of patients, as has been shown in numerous
studies and meta-analyses (12).

FIGURE

Psychotherapy
The effectiveness of various forms of psychotherapy indepression has been well documented. Most of thetherapeutic effect seems to be due to common, nonspecific factors that may also be at work in medical careoutside the specifically psychotherapeutic setting. The
most important among these factors is a systematicallyestablished therapeutic relationship with an accepting,actively listening, and empathetic physician. The physician himself or herself thereby becomes a potent "therapeutic agent," whose importance can scarcely be underestimated.
Most psychotherapeutic approaches to the treatment
of depression involve the following strategies:c Resource activation (identification and reinforcement of the patient's current abilities)
c Problem actualization (directed addressing of particular areas of conflict)c Problem coping (supporting the patient with emotional, cognitive, or active solution strategies)c Motivational clarification (recognition of problematic modes of perception and behavior and dysfunctional cognitions).
As in pharmacotherapy, patients should be regularly
re-evaluated for the possible emergence of side effects,
and therapeutic efficacy should be assessed after anadequate period of treatment.

Psychotherapy in the treatment
of depressionc Resource activationc Problem actualizationc Problem copingc Motivational clarification

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Algorithm-based flowchart for stepwise treatment of depression. The flowchart shows thethree arms of the algorithm study of the German Competence Network on Depression, because
neither the result of the study (supported by the German Federal Ministry of Education andResearch) nor the relevant literature permits any definite recommendation to be made.
Whether the patient goes on to the next step in any of the three algorithms is a function of thedecision procedure. The severity of depression is assessed at the end of each step with the
Hamilton Depression Rating Scale (HAM-D, 21-item version).
T3, triiodothyronine• HAM-D < 9: remission Þ clinical reassessment in 2 weeks to confirm remission, if confirmedÞ transition to maintenance therapy, if not confirmed Þ next step
• HAM-D decreased by at least 8 points (and overall score > 9): partial response Þ prolongation of the current step by 2 weeks (no more than once per step)• HAM-D decreased by less than 8 points: non-response Þ next step

Algorithm-based stepwise treatment
There are a number of different stepwise algorithms
for the treatment of depression. The current stateof the data does not permit any definite
recommendation to be made.

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Specific psychotherapeutic techniques
Psychotherapy for depression can be carried out in an
outpatient or inpatient setting, individually or in groups,
and with or without the participation of the patient's
family. In Germany, the statutory health insurance carriers
currently reimburse ambulatory behavioral therapy anddeep psychology–based and analytic psychotherapy as
so-called guideline techniques.
Cognitive behavioral therapy
Cognitive behavioral therapy (CBT) is based on theassumption that dysfunctional cognitions can lead to
disturbed emotions and behavior, and vice versa. A lackof positive reinforcement owing to depression worsens
the patient's depressive manifestations. CBT thus involves
both cognitive and behavioral approaches. Its treatment
strategies aim at overcoming the patient's lack of positive
reinforcement, social withdrawal, and conviction of hisor her own helplessness. The "cognitive errors" that areoften identified among depressed patients include inappropriate generalizations, personalization, emotional
thinking, and black-and-white thinking. Etiologicalimportance is also attached to "depressiogenic" cognitive
schemata that are learned early on in life and may bereactivated by critical life events; a typical example isthe so-called "cognitive triad" of automatic negative
assumptions about oneself, the environment, and thefuture. Cognitive therapy aims to correct these dysfunctional cognitions with structured and directed shortterm therapy consisting of an average of 20 sessions.
The efficacy of ambulatory CBT against depression has
been very well studied and has also been confirmed bymeta-analyses (17, e2–e4).
Deep psychology–based and psychoanalytic psychotherapy
Classical psychoanalytic treatment is performed withthe patient lying on a couch, several times weekly, overa long period of time. Deep psychology–based psychotherapy is based on central fundamental assumptions
and principles of psychoanalysis, but it is usually performed with the patient sitting in a chair, only once per
week, and over a shorter period of time. Both of thesetypes of psychotherapy are based on the assumption that
depressive disorders are largely due to unconscious processes whose roots typically lie in the patient's childhood. Depressed persons, in particular, often suffer fromuncertainties in their relationships and a negative bondingstyle with increased vulnerability to losses and affronts.
More than in other types of psychotherapy, the therapist-

Cognitive behavioral therapy
The effectiveness of cognitive behavioral therapy
in the outpatient setting has been very wellstudied and has also been confirmed by metaanalyses.

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patient relationship itself becomes an object of treatment,
because the patient's typical relationship pattern andanxieties are reproduced in this relationship and can beaddressed within it.
The currently available data from controlled studies
of efficacy are less extensive than for CBT. More structured, short-term deep psychological psychotherapy inmildly or moderately depressed patients has been the typemost frequently studied (e5). Other studies and metaanalyses have involved patients with a mixture of diagnoses, so that it is difficult to draw any specific conclusions about the effectiveness of these types of treatment
for depression (e6, 18).
Interpersonal psychotherapy (IPT)
IPT is a type of short-term psychotherapy that wasdeveloped specifically for the treatment of depression. It
consists of 12 to 20 hours of semi-structured psychotherapy, generally in weekly sessions, and focuses on
the psychosocial and interpersonal aspects of depressive
disorders. Thus, it places particular emphasis on copingwith grief, role switching, life changes, and interpersonal
conflicts.
Although much evidence for the efficacy of IPT isavailable from controlled studies and meta-analyses(19), in which it was used alone or in combination withantidepressants, IPT is currently not reimbursed by thestatutory health insurance carriers in Germany.

Supportive measures
The importance of involving the patient's family has
already been mentioned more than once. The only
treatment for depression that has an immediate
therapeutic effect is sleep deprivation, which can bedone on an inpatient or outpatient basis. The patient isrequired either to do without sleep for an entire night(complete sleep withdrawal) or simply to get up
between 1 a.m. and 2 a.m. (partial sleep deprivation),
without making up for the missed sleep either inadvance or afterward. It is crucial for the success of
this treatment that the patient should not take even a
short nap during periods of wakefulness. About 60%
of patients so treated have a marked improvement ofmood the day after.
The main disadvantage of sleep deprivation treatment is that its beneficial effect lasts no more than 1 or 2days in about 80% of patients. If the treatment is effective, it can be repeated once every 3 to 4 days. An absolutecontraindication is a history of epileptic seizures; relative

Supportive measures
Roughly 60% of patients undergoing sleep
withdrawal therapy experience a marked
improvement of mood for 1 to 2 days thereafter.

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contraindications include bipolar or psychotic forms ofdepression.
The effectiveness of light therapy with special apparatus has been unequivocally documented only forseasonal depression (winter depression) (e7). Physicalactivity probably has a beneficial effect on the resolutionof depression and can be recommended as a supplementary treatment, even though the scientific data to support
this are as yet inadequate (e8). Treatments that are currently under investigation include aerobic training andendurance training (treadmill running) (20).
The most effective of all treatments for depression isprobably electroconvulsive therapy (ECT), for which
the current main indication is treatment-resistantdepression (21, 22). Because of the specialized personnel
and apparatus that this form of treatment requires, andalso because of persistent, widespread misgivings about
it, ECT is used only when multiple previous therapeuticattempts have failed, or when the patient explicitly
requests it. Its beneficial effect typically appears after
one to three weeks of treatment with three ECT sessions
per week. Its major clinical drawback is the high rate ofearly recurrences in the first 16 weeks—up to 75% of
patients who are not subjected to continuing treatment.
With good maintenance therapy, the percentage of earlyrecurrences can be reduced to about 35%, but suchrecurrences cannot be eliminated.

Conclusion
Depression can be treated effectively at present because
multiple forms of treatment are available that complement
each other or can be given in combination. Most of them
have been well documented as effective in properly
designed, controlled studies. No single form of treatment can be considered superior to all of the others, anda relatively high nonresponder rate is a common featureof all of them. Thus, the art of treating depression consists of a methodical and exhaustive use of the available
therapeutic options within the framework of an algorithm-based stepwise treatment regimen (figure), in
which each sequential step of treatment is carried out foran adequate length of time and is then evaluated for
effectiveness in standardized fashion. Randomized
comparative studies have shown that stepwise treatment
leads to more frequent and more rapid treatment responses
than unstructured treatment, while simultaneously reducing the amount of psychoactive medication thatmust be prescribed as well as the frequency of changes
in treatment strategy (7).

Conflict of interest statement
Dr. Adli has received research grants from the German Federal Ministry of
Education and Research and from the following companies: Pharmacia, Pfizer,
Lilly, Janssen Cilag, and Wyeth as well as honoraria from Astra Zeneca, Lilly,
Boehringer Ingelheim, GlaxoSmithKline, Pfizer, Sanofi Aventis, Wyeth, andCyberonics. PD Dr. Bschor has received lecture honoraria from Sanofi Aventis,
Lilly, esparma, GlaxoSmithKline, Pfizer, and Astra Zeneca.
Manuscript received on 4 June 2006; revised version accepted on 20 August
2008.
Translated from the original German by Ethan Taub, M.D.

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medizinische Fortbildung: Diagnostik depressiver Störungen. Dtsch
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4. Bauer M, Bschor T, Pfennig A, Whybrow PC, Angst J, Versiani M,
Möller HJ, WFSBP Task Force on Unipolar Depressive Disorders:World Federation of Societies of Biological Psychiatry (WFSBP)
Guidelines for Biological Treatment of Unipolar Depressive Disordersin Primary Care. World J Biol Psychiatry 2007; 8: 67–104.
5. AkdÄ – Arzneimittelkommission der deutschen Ärzteschaft: Empfehlungen zur Therapie der Depression. 2. Auflage. Arzneiverordnung in der Praxis (Therapieempfehlungen), Juli 2006;
Band 33, Sonderheft 1.
6. Wolfersdorf M, Mäulen B: Suizidprävention bei psychich Kranken.
In: Wedler H, Wolfersdorf M, Welz R, Hrsg.: Therapie bei Suizidgefährdung. Ein Handbuch. Regensburg Roderer 1992: 175–97.
7. Adli M, Bauer M, Rush AJ: Algorithms and collaborative-care systems
for depression: are they effective and why? A systematic review. Biol
Psychiatry 2006; 59: 1029–38.
8. Hamilton M: A rating scale for depression. J Neurol Neurosurg
Psychiatry 1960; 23: 56–62.
9. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J: An inventory formeasuring depression. Arch Gen Psychiatry 1961; 4: 561–71.
10. Bschor T: Definition, klinisches Bild und Epidemiologie therapieresistenter Depressionen. In: Bschor T, Hrsg.: Behandlungsmanual
therapieresistente Depression. Pharmakotherapie -somatische
Therapieverfahren – Psychotherapie. Stuttgart: Kohlhammer 2008:
11–6.
11. Bschor T: Behandlung mit Antidepressiva. Pharmakologie, Therapieabschnitte. In: Bschor T, Hrsg.: Behandlungsmanual therapieresistente
Depression. Pharmakotherapie – somatische Therapieverfahren –Psychotherapie. Stuttgart: Kohlhammer 2008: 28–39.
12. Bschor T, Bauer M: Efficacy and mechanisms of action of lithium augmentation in refractory major depression. Curr Pharm Des 2006; 12:2985–92.
13. Loh A, Simon D, Kriston L, Härter M: Shared Decision-Making in Medicine. Dtsch Arztebl Int 2007; 104(21): A 1483–8.
14. Bschor T, Baethge C: Wechsel des Antidepressivums. In: Bschor T,
Hrsg.: Behandlungsmanual therapieresistente Depression. Pharmakotherapie – somatische Therapieverfahren – Psychotherapie. Stuttgart:
Kohlhammer 2008: 48–56.

High nonresponder rate
The treatment of depression must make thoroughuse of all of the currently available therapeutic
options in accordance with a stepwise treatment
algorithm.

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15. Adli M, Baethge C, Heinz A, Langlitz N, Bauer M: Is dose escalation ofantidepressants a rational strategy after a medium-dose treatment has
failed? A systematic review. Eur Arch Psychiatry Clin Neurosci 2005;
255: 387–400.
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Bschor T, Hrsg.: Behandlungsmanual therapieresistente Depression.
Pharmakotherapie -somatische Therapieverfahren – Psychotherapie.
Stuttgart: Kohlhammer 2008: 86–101.
17. Gloaguen V, Cottraux J, Cucherat M, Blackburn IM: A meta-analysis of
the effects of cognitive therapy in depressed patients. J Affect Disord
1998; 49: 59–72.
18. Leichsenring F: Are psychodynamic and psychoanalytic therapies effective? A review of empirical data. Int J Psychoanal 2005; 86: 841–68.
19. de Mello MF, de Jesus Mari J, Bacaltchuk J, Verdeli H, Neugebauer R: A
systematic review of research findings on the efficacy of interpersonal
therapy for depressive disorders. Eur Arch Psychiatry Clin Neurosci
2005; 255: 75–82.
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randomized, controlled study on the effects of a short-term endurance
training programme in patients with major depression. Br J Sports Med
2007; 41: 29–33.
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in depressive disorders: a systematic review and meta-analysis. Lancet
2003; 361:799–808.
22. Folkerts H, Remschmidt H, Saß H, Sauer H, Schäfer M, Sewing K-Fr:
Stellungnahme zur Elektrokrampftherapie (EKT) als psychiatrische Behandlungsmaßnahme. Dtsch Arztebl 2003; 100(8): A 504–6.
Corresponding author
PD Dr. med. Tom Bschor
Jüdisches Krankenhaus Berlin
Abteilung für Psychiatrie und Psychotherapie
Heinz-Galinski-Str. 1
13347 Berlin, Germanybschor@jkb-online.de@

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For e-references please see:www.aerzteblatt-international.de/ref4508
For a case illustration relating to this article,
see the following website:www.aerzteblatt-international.de/0812
German-language websites for further information:– Self-help and family groups:
www.nakos.de– Written information for patients:
www.akdae.de/45/Depression.pdf
www.kompetenznetz-depression.de– Information about therapeutic serum levels of antidepressants and grades of supportive evidence:www.agnp.de ÞArbeitsgruppen ÞAG Therapeutisches
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Please answer the following questions to participate in our certified Continuing Medical Education
program. Only one answer is possible per question. Please select the answer that is most appropriate.
Question 1
What is the objective of maintenance therapy for depressive
disorders?
(a) Phase prophylaxis(b) Remission(c) Response(d) Relief of symptoms(e) The prevention of an early relapse

Question 2
In what respect do the roughly 30 antidepressants that are currently
available in Germany differ from one another most markedly?
(a) Their side-effect profiles(b) Their nonresponder rates(c) Their addictive potential(d) Their latency of onset(e) Their potency

Question 3
A 68-year-old woman in whom you have diagnosed moderately
severe depression will only accept St. John's wort as the sole
pharmacotherapeutic agent against depression. What should be
your particular concern if you prescribe her a preparation
containing this substance?
(a) The potential for morbid obesity(b) The ECG(c) Any medications she is concomitantly taking(d) Renal function(e) Possible addiction

Question 4
A 59-year-old bus driver presents to you with a history of depressionthat began two months ago. You are considering treatment witha tricyclic antidepressant. Which of the following comorbidities
would lead you not to prescribe a drug of this type?
(a) Bronchial asthma(b) Gout(c) Prostatic hyperplasia(d) Psoriasis(e) Rheumatoid arthritis

Question 5
What is the most rapidly acting treatment for depression?
(a) Depression-specific psychotherapy(b) Electroconvulsive therapy (ECT)(c) Light therapy(d) Pharmacotherapy with antidepressants(e) Sleep deprivation

Question 6
According to the theory underlying psychotherapy based on deep
psychology, what psychological phenomenon is more common in
depressed people?
(a) Borderline personality structure(b) Latent homosexuality in a parent

792(c) Penis envy(d) Increased vulnerability to loss(e) Documented above-average intelligence

Question 7
Which of the following antidepressive treatments has been
well documented to be effective by multiple controlled
studies and meta-analyses?
(a) Physical activity(b) Neuroleptic monotherapy(c) High-dose SSRI treatment(d) Outpatient cognitive behavioral therapy(e) Changing the antidepressant in case of nonresponse

Question 8
What is meant by an algorithm-based stepwise treatment
regimen for depression?
(a) Alternation between psycho- and pharmacotherapeutictechniques until a remission occurs(b) Choice of treatment according to the classification of thepatient's depression as mild, moderate, or severe, on the basisof a systematic evaluation(c) Treatment of depression with monotherapy or with a combinationof two, three, or four therapeutic methods, depending on thesystematically assessed degree of resistance to treatment(d) Determination of the treatment plan with the aid of treatment
software that processes the data of the individual patient on
the basis of a response probability matrix(e) Determination of a multi-step treatment plan at the beginningof treatment with a standardized response evaluation at theend of each step, whose results determine the transition to thenext treatment step

Question 9
Which of the following is a basic assumption of cognitive
behavioral therapy?
(a) Placing the overwhelming emphasis on cognition, rather thanemotion, is a central element in the pathogenesis of depression.
(b) Depressive disorders are based to a large extent on
unconscious processes.
(c) Dysfunctional cognitions lead to disturbed emotions andbehavior.
(d) Cognitive ego-splitting lies at the heart of depressive disorders.
(e) Excessive positive reinforcement in the consumer society is themain cause of depression.

Question 10
What tests are advisable before the beginning of treatment
for depression and regularly over the course of treatment?
(a) Stress ECG for sertraline treatment(b) Blood pressure checks for venlafaxine treatment(c) EEG for citalopram treatment(d) Metabolizer status checks for amitriptyline treatment(e) Serum level determinations for treatment with reboxetine Dtsch Arztebl Int 2008; 105(45): 782–92
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CONTINUING MEDICAL EDUCATION

Treatment of Depressive Disorders
Tom Bschor, Mazda Adli

E-REFERENCES
e1. Bostwick JM, Pankratz VS: Affective disorders and suicide risk:
A reexamination. Am J Psychiatry 2000; 157: 1925–32.
e2. Dobson KS: A meta-analysis of the efficacy of cognitive therapy for
depression. J Consult Clin Psychol 1989; 57: 414–9.
e3. Gaffan EA, Tsaousis I, Kemp-Wheeler SM: Researcher allegianceand meta-analysis: the case of cognitive therapy for depression.
J Consult Clin Psychol 1995; 63: 966–80.
e4. DeRubeis RJ, Gelfand LA, Tang TZ, Simons AD: Medications versus
cognitive behavior therapy for severely depressed outpatients: megaanalysis of four randomized comparisons. Am J Psychiatry 1999;
156: 1007–13.
e5. Leichsenring F: Comparative effects of short-term psychodynamic
psychotherapy and cognitive-behavioral therapy in depression: ameta-analytic approach. Clin Psychol Rev 2001; 21: 401–19.
e6. Crits-Christoph P: The efficacy of brief dynamic psychotherapy: ameta-analysis. Am J Psychiatry 1992; 149: 151–8.
e7. Golden RN, Gaynes BN, Ekstrom RD, Hamer RM, Jacobsen FM,
Suppes T, Wisner KL, Nemeroff CB: The efficacy of light therapy inthe treatment of mood disorders: A review and meta-analysis of theevidence. Am J Psychiatry 2005; 162: 656–62.
e8. Lawlor DA, Hopker SW: The effectiveness of exercise as an intervention in the management of depression: systematic review and metaregression analysis of randomised controlled trials. BMJ 2001; 322:
763–7.

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CONTINUING MEDICAL EDUCATION

Treatment of Depressive Disorders
Tom Bschor, Mazda Adli

Case

now continually worried about the possible implications of his current three-day absence for his job security and the family's financial future.

Treatment of Depressive Disorders

The addiction history and past psychiatric history
were negative. There was, however, a positive family
history: the patient's paternal grandfather hadcommitted suicide, for unknown reasons.

A 46-year-old office worker went to his family physician, accompanied by his wife, complaining of
persistent headaches. When questioned more closely,
he described a dull pressure in the entire head that
had been present continuously, though at varying
intensity, for approximately the past four weeks. His
chronic back pain had worsened in the same period.
Because of these problems, he had first stopped
attending his weekly chess night and then stopped
going on his usual weekend excursions with hisfamily. Over the course of time, he had stopped performing any tasks at all for his family and household.
He had stayed home from work for the past threedays. A thorough physical examination revealed noabnormality.
Only on directed questioning did the patient statethat he had felt exhausted and bereft of energy all thetime for the past few weeks, that he had lost interest in
his usual activities, and that he no longer enjoyed thethings that used to give him pleasure. His food nolonger tasted good to him, and he had already lost 2.5
kg of weight. Most recently, he had begun to havedifficulty falling asleep and to wake up every morning
between 4 and 5 a.m.; he attributed this to the headaches. His wife, on directed questioning, said that her
husband often seemed sad and that she had seen tears
in his eyes for no apparent reason on multiple occasions. Nor could she understand why her husband,
who was normally very conscientious about his work, Dtsch Arztebl Int 2008; 105(45)
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The family physician diagnosed a first depressive
episode, informed the patient and his wife of her
diagnosis in two separate interviews, and stressedboth the nature of the symptoms as a disease and thegood prognosis for recovery.
She declared him unable to work for two weeks andurged him to take a one- to two-hour walk each morning, but to take on no further tasks or activities. The
patient was able to accept the temporary, passive roleof an ill person only when acute depression was
explained to him through an analogy to acute pneumonia. The patient and his family physician agreed that hewould take antidepressive medication; she prescribed
nortriptyline (150 mg/day), an agent with both serotonergic and noradrenergic properties, because suchagents can be expected to have an additional beneficial
effect in pain. Other than dry mouth, the medication
was well tolerated. The patient and his family physician
saw each other weekly. Three weeks after the onset oftreatment, the patient came for the first time without
his wife accompanying him and reported that he hadjust begun working in the garden again on his own
initiative. After a total of five weeks of treatment, he
was practically free of symptoms and returned towork. The patient and his family physician agreed that
he would continue taking nortriptyline for six
months as maintenance therapy.

I