Therapy of Depressive Illness

The term “depression” is used for a variety of states that are characterized by downswings in mood varying from slight to most severe. The principal types are:

Endogenous depression, ranging from its severe form (major depression) to lighter cases (minor depression)

Dysthymia (neurotic depression)

Reactive depression as (overshooting) reaction to psychic insults or somatic illness

Endogenous depression generally follows a phasic course with intervals of normal mood. When mood swings do not change direction, unipolar depression is said to be present. Bipolar illness designates an alternation between depressive states and manic episodes. Besides devitalizing melancholia with its attendant burden of suffering, the behavior of patients in depression may vary from strongly inhibited to anxious, agitated, guilt-ridden, presuicidal, and so on. Depressive states are frequently associated with somatic symptoms; the patients project their mood disturbance into a physical ailment. Accordingly, many depressive patients initially visit a family physician or internist.

The pharmacotherapy of depression is a dif cult undertaking. At the outset, it is necessary to determine the type of depression. For instance, in neurotic depression, psychotherapy may be suf cient. A reactive mood disorder calls for attempts to establish the causal link. In either condition, temporary use of antidepressants may be warranted. The proper indication for thymoleptics is endogenous depression. However, even for this endogenous psychosis, it is dif cult to evaluate the effectiveness of this drug class. One fundamental reason is the lack of experimental animal models of depression: the ef cacy of drugs cannot be tested in experiments on animals. Moreover, depression is periodic in nature; spontaneous remission nearly always occurs. Intensive psychological support may also sometimes be effective in improving the condition of patients. Ac-

cording to some estimates, one-third oftherapeutic success in moderately severe depression can be attributed to a placebo effect, one-third to intensive support, and the remaining one-thirdto use ofantidepressant agents. In severe depression, pharmacotherapy may achieve somewhat more favorable results. Because objective documentation of therapeutic success is extraordinarily dif - cult, it is hardly surprising that no specific antidepressant has proved superior in comparison with others. About 30% of patients are resistant to currently available drug treatments. A workable general rule would be to prescribe tricyclic compounds (and venlafaxine) for severe depression, and selective serotonin reuptake inhibitors (SSRI) for moderately severe to mild cases. No scientifically convincing evidence is available for the “alternative” phytomedicinal, St. John’s wort (Hypericum perforatum), although drug interactions are well documented.

It would be a major therapeutic error to administer a drive-enhancing drug such as amphetamine to a depressed patient with psychomotor inhibition (A). Suicide would be an expected consequence.

The antidepressant effect of thymoleptics manifests after a prolonged latency; usually 1–3 weeks pass before subjective or objective improvementbecomesnoticeable (A). In contrast, somatic effects are immediately evident; specifically, the interference with neuronal transmitter/modulator systems (norepinephrine, serotonin, acetylcholine, histamine, dopamine). Reuptake of released serotonin, norepinephrine, or both is impaired († elevatedconcentration in synaptic cleft) and/or receptors are blocked (example in A). These effects are demonstrable in animal studies and are the cause of acute adverse effects.

The importance of these phenomena for the antidepressant effect remains unclear. Presumably, adaptation of receptor systems to altered concentrations or actions of transmitter/modulator substances plays a role.

Deficient drive

Normal mood

Normal drive

Week 3

Week 5

Week 7

Week 9

Imipramine

CH2 CH2 CH2 N

CH3

5 HT or NA

Amphetamine Immediate

The thymoleptic mechanism of action remains to be elucidated.

Antidepressants can be divided into four groups:

1.Tricyclic antidepressants (A), such as desipramine, amitriptyline, and many analogue substances, possess a hydrophobic ring system. The central 7-membered ring increases the annelation angle between the outer flanking rings. This moiety can also be tetracyclic (e.g., maprotiline). The ring system bears a side chain with a secondary or tertiary amine that can be protonated depending on its pKa value. These substances can thus take on an amphiphilic character, permitting insertion into lipid membranes and enrichment in cellular structures. The basic structure of tricyclic antidepressants also explains their af nity for receptors and transmitter transport mechanisms. Receptor blockade is the chief cause of the adverse effects in this drug group, including: tachycardia, inhibition of glandular secretion (dry mouth), constipation, dif culty in micturition, blurred vision, and orthostatic hypotension (A upper). Asedative action probably arising from antagonism at CNS H1 histamine receptors, as obtained with amitriptyline, can be desirable.

2.Selective serotonin reuptake inhibitors (SSRI). These substances (e.g., fluoxetine) also possess a protonatable nitrogen atom and, instead of a larger ring system, contain simpler aromatic moieties. They also have amphiphilic character. Because their af nity for receptors is much less (no blockade of acetylcholine or norepinephrine receptors), acute adverse effects are less marked than those of tricyclic thymoleptics. Blockade of reuptake is confined to serotonin (5-HT). Antidepressant potency is equal to or slightly inferior to that of tricyclics. Fluoxetine has a long duration of action. Together with its active metabolite, it is eliminated with a half-life of several days. The SSRI group includes several other substances

such as citalopram, paroxetine, sertraline and fluvoxamine. Besides depression, these substances are also marketed for various other psychiatricindications, including anxiety disorders, posttraumatic stress, and ob- sessive-compulsive disorder.

Labeling of most drugs in this group was recently revised to include a warning statement concerning a worsening of depression and treatment-emergent suicidality in both adult and pediatric patients.

3.Inhibitors of monoamine oxidase A (thymeretics). Moclobemide is the only representative of this group. It produces a reversible inhibition of MAOA, which is responsible for inactivation of the amines norepinephrine, dopamine, and serotonin (A). Enzyme inhibition results in an increased concentration of these neurotransmitters in the synaptic cleft. Moclobemide is less effective as an antidepressant than as a psychomotor stimulant. It is indicated only in depressions with extreme psychomotor slowing and is contraindicated in patients at risk of suicide.

Tranylcypromine causes irreversible inhibition ofthe twoisozymesMAOA and0$2% Therefore, presystemic elimination in the liver of biogenic amines, such as tyramine, thatare ingestedin food(e.g.,in aged cheese and Chianti) is impaired (with danger of a diet-induced hypertensive crisis). The compound is obsolete in some countries.

4.Atypical antidepressants represent a heterogeneous group comprising agents that interfere only weakly or not at all with monoamine reuptake (trazodone, nefazodone, bupropion, mirtazapine), preferentially block reuptake of norepinephrine (reboxetine), or act as dual inhibitors of 5-HT and norepinephrine reuptake (venlafaxine, milnacipran, duloxetine). Venlafaxine appears to be as effective as tricyclic antidepressants in severe depression.