The “Selective Serotonin Reuptake Inhibitors” increase the supply of serotonin in the synaptic cleft and stimulate the serotonin receptors of the next cells, thereby regulating their sensitivity down in the long term. Overall, however, SSRIs promote proper transmission through serotonin. Unfortunately, they also stimulate subforms of the serotonin receptor, which are not necessary for therapy but cause temporary side effects such as restlessness, dizziness, nausea, headache. Suicidal ideation may rarely occur in patients younger than 24 years. The SSRIs are beneficial for cardiovascular problems. Unfortunately, sexual dysfunctions occur more often, which are difficult to distinguish causally from the depressive problem; a change of preparation may be necessary. Generic drugs (active ingredients) and corresponding drug names are Escitalopram/Cipralex®, Sertraline/Zoloft®, Paroxetine/Seroxat®, Fluoxetine/Fluctin® and Fluvoxamine/Fevarin®.
Norepinephrine and serotonin reuptake inhibitors include venlafaxine (Trevilor®) and duloxetine (Cymbalta®). They increase the supply of serotonin and norepinephrine, this is called dual mode of action. Probably more effective than SSRIs. Side effects are as with SSRIs, rarely dry mouth, weight gain, blood pressure increase, rarely urinary retention and constipation. Duloxetine also has an approval for pain in diabetic polyneuropathy.
The tri- and tetra-cyclic antidepressants, abbreviated TCAs, increase serotonin and norepinephrine to different proportions by inhibiting reuptake. They are known since 1957, well tested, well effective. As a side effect, they make calm and tired, but also unpleasant symptoms such as dry mouth, constipation and blurred vision.
Active ingredient and preparation names are amitriptyline (Saroten®), imipramine (Tofranil®), clomipramine (Anafranil®), doxepin (Aponal®), trimipramine (Stangyl®), maprotiline (Ludiomil®). They also differ somewhat in the individual patient in the profile of action on the transmitters and the side effects such as sedation or, for example, dry mouth.
The irreversible mono-amine oxidase inhibitors block an enzyme that breaks down serotonin, norepinephrine, and dopamine, even several weeks after discontinuation, until the enzyme is replicated. They are very effective against depression and indispensable in the therapy plan. However, the patient must follow a so-called MAO diet, otherwise severe and dangerous blood pressure crises may occur. The consumption of cheese and certain dairy products, beer and red wine, as well as yeast, meat extracts, salami and other foods is dangerous because they all contain the substance tyramine, which is converted in the body to a substance active in blood pressure and can then cause blood pressure crises and circulatory problems. The patient must be thoroughly informed about this diet and the possibility of a blood pressure crisis. Otherwise, MAO inhibitors are well tolerated, paradoxically tend to lower blood pressure and improve existing diabetes. The most common side effect is blood pressure lowering and dizziness, occasionally diarrhea and chills, rarely headache outside of blood pressure crises. The preparation name of the only MAO inhibitor available in Germany, tranylcypromine, is Jatrosom N®.
The reversible inhibitors of mono-amine oxidase are the “little brother” of the MAO inhibitors. They block only one type of enzyme, the effect fades after a few days, and the blockade is also never complete. No diet is needed, they are beneficial for heart and circulatory problems, but unfortunately they are not nearly as strong an effect as MAOH. In Germany, only the generic drug moclobemide is available as the preparation Aurorix® or Moclix®. Common side effects include dry mouth, dizziness, headache, sleep disturbances, and nausea.
Complicated dual mechanism of action, thus acts on serotonin and norepinephrine. The preparation name is Remergil®. Has some advantages by blocking a certain serotonin receptor (5-HT2): It makes somewhat tired, therefore promotes sleep well, calms quickly, does not make nausea and little sexual dysfunction. Problems are more often weight gain, sometimes individual severe fatigue, rarely disorders of blood count.
Selectively promotes only norepinephrine. Does not make you tired, no nausea, little sexual dysfunction, efficacy probably lower than SSRIs. The preparation name is Edronax®. Common side effects include insomnia, dry mouth, constipation, and sweating.
Well-established antidepressant in America. Probably promotes dopamine in addition to serotonin and especially norepinephrine. In Germany by the effect on motivation therefore first as a smoking cessation drug (Zyban®), only then under the name Elontril® as an antidepressant approved. Common side effects include insomnia, headache, dry mouth; rare but serious are changes in seizure threshold at high doses.
Mianserin (Tolvin®) and trazodone (Thombran®)
Rather weakly effective rarely prescribed preparations, but very well tolerated with different mechanisms of action. Both beneficial for heart and circulatory problems with a calming component. Mianserin is related to mirtazapine. Side effects of mianserin have been reported to include frequent drowsiness, involuntary movements, and low blood pressure, and rarely blood count disorders. Trazodone may cause cardiac arrhythmias and rarely blood count abnormalities in addition to fatigue, dizziness, and low blood pressure. The successor to trazodone was nefazodone (Nefadar®), but had to be withdrawn from the market in Germany due to cases of severe liver damage.
St. John’s wort (Hypericum)
So called natural remedy from the plant St. John’s wort. Exact active substance cannot be determined, as mixed extract. Only high doses possibly effective, yet the best-selling antidepressant in Germany. Has quite side effects to be considered such as allergic reaction and light sensitization, gastrointestinal discomfort as well as interactions with other medications. If therapy fails, the stepwise plan should be followed further.
The 20-year development of esketamine as an antidepressant has now led to approval. The effect can often occur in hours, the application is done initially under medical supervision several times a week, then weekly.
Non-drug apparative therapies
In therapy-resistant cases, electroconvulsive therapy remains as another therapeutic option as the most effective therapeutic method against depression. With modern methodology under general anesthesia, according to available studies, no harm is to be feared, ECT even has a nerve growth promoting effect. After six to twelve treatments over 2 to 4 weeks, complete freedom from symptoms is possible in half of the cases in previously severely therapy-resistant cases.
High-frequency transcranial magnetic stimulation (rTMS) involves stimulating nerve centers with magnetic fields at, say, 10 Hz and 1000 pulses in 20 to 30 minutes, about 15 to 20 times over 3-4 weeks. The necessary strength of stimulation is determined individually. Side effects are mildly unpleasant irritation of skin and head muscle nerves and rarely headache, in very rare cases epileptic seizures were induced. The procedure is still being tested, certainly effective in some cases.
Vagus nerve stimulation / deep brain stimulation
Vagus nerve stimulation involves implanting a pacemaker on the vagus nerve. The procedure, which originated in epilepsy treatment, is still being tested at university hospitals. Also still under development is deep brain stimulation, in which electrodes are inserted into the brain in a similar way to those used in Parkinson’s disease.
Sleep deprivation therapy
Applied e.g. 2 times/week, an “old home remedy”, can accelerate healing, with the patient sleeping for about 4 hours and then staying awake from 2am until the next evening.
1 x per day 30 to 90 minutes with special white light can be helpful in the treatment of so-called winter depression (= seasonal depression).
Other drug therapies currently being tested
High-dose therapy with thyroid hormones
Thyroid hormone given above normal blood levels improves treatment-resistant depression in many cases. Side effects resemble artificial hyperthyroidism. Should be used only in specialized centers.
Stimulant substances, amphetamine is subject to narcotics law, in resistant cases often improvement of permanent drive weakness and sensory disturbance.
such as omega-3 fatty acids, folic acid, SAMe, etc. can be purchased over the counter, but their effect is not assured, see the chapter on dietary supplements.
Treatment, step by step plan
The treatment is carried out according to a defined step-by-step plan. Selection is based on expected side effects, prior treatment, and specific symptoms such as agitation, anxiety, or insomnia. Since the onset of the antidepressant effect takes 2-3 weeks, tranquilizers are used in combination to calm and relieve anxiety. In severe depressive states with delusional misperception or severe agitation and brooding mental narrowing to unpleasant content, neuroleptics are very effective in combination. Lithium in combination with antidepressants has a good acute effect even in purely depressive courses. In cases of mania known from previous history, i.e. bipolar disorder, a mood stabilizer must be given at the same time, otherwise the triggering of mania is to be feared. Every 2-3 weeks, a detailed examination with so-called rating scales and interviews is carried out to check whether the onset of an effect can be foreseen. If this is not the case, the strategy is changed. Complete remission/recovery of symptoms takes at least 6-8 weeks.
If this is not successful at first go, patients and their doctors have to be very patient and tenacious, since quick, ill-considered changes of medication do not promise success and lead to unnecessary early resignation.
Often, as with psychoses, a long recovery period must be accepted. Risky therapies must be weighed up, as must the threat of suicide on the part of the patient. It should never be forgotten that the natural course alone can spontaneously end the disease completely even after years.
Many clinical pictures such as anxiety, panic, phobia, disorders with abnormal bodily sensation, chronic pain, trauma sequelae, chronic fatigue or compulsions occur frequently together with depression and respond favorably to treatment with antidepressants.
Both purely depressive illnesses and manic-depressive illnesses can recur, observed over decades. Unipolar patients (only depressive phases) have an average phase every 5 years, bipolar patients (manic and depressive phases) every 3 years. Overall, over 50% of unipolars and 90-100% of bipolars relapse at least once.
Preventive treatment of unipolar patients is done by continuing the same strategies as in the acute phase (“What makes you well keeps you well”). After the first episode, the patient should take the antidepressant for 6-12 months. If risk factors are present, such as genetic burden, severity of the disease, or lack of improvement, continuous therapy should be given for many years after the second episode, and at the latest after the third episode.
Drugs that act by influencing the stress axis, via the melatonin system and immunological mechanisms are being tested. In the far future, mechanisms inside the cell, the messenger substances there and also cell growth and the reading of the genes are to be investigated.