The lifetime prevalence for major depressive disorders that require treatment falls within 12 – 17 %. Therefore, every clinically active physician will come in contact with patients suffering from symptoms of depression or taking in antidepressant medication. For this reason, it is important to know the indications, adverse effects and interactions of antidepressants and to not shy treatment.

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sad man

Image: “Ohne Titel” von Viktor. Licence: CC BY 2.0


Definition

Antidepressants, also known as thymoleptic, are a class of chemically different drugs used for the treatment of depressive disorders, anxiety disorders, obsessive-compulsive disorders and chronic pain and are very different from each other concerning their profile. Their effect is based on re-elevating mood and activation on the psychomotor drive, leading to the subsiding of physical symptoms of depression. There is no risk of dependency.

Note: In mentally healthy individuals, antidepressants do not show effects – excluding vegetative side effects and slight sedation.

The first antidepressant was Imipramine, which was discovered in 1957 by swiss psychiatrist R. Kuhn. Before that, depressive patients were treated with Opium or Somnifen with barbiturates to induce dorm. Since Imipramine discovery, numerous other tricyclic, tetracyclic and novel antidepressants have been introduced to the market. They are divided into 8 classes:

  • Classic Tricyclic antidepressants

  • Tetracyclic and modified Tricyclic antidepressants

  • Selective serotonin reuptake inhibitors (SSRIs)

  • Norepinephrine reuptake inhibitors (NRIs/NERIs)

  • Serotonin-norepinephrine reuptake inhibitors (SNRIs)

  • Irreversible and reversible Monoamine oxidase inhibitors (MAOIs)

  • Atypical antidepressants

  • Herbal antidepressants

Pharmacology and Biochemistry

The mode of action of antidepressants has been essential for the understanding of the development of depressive disorders. It was shown that antidepressants raise the concentration of neurotransmitters norepinephrine and serotonin in the synaptic gap. This happens either by inhibiting their reuptake or inhibition of the enzymatic breakdown.

Studies have shown, that in some depressive patients the neurotransmitters norepinephrine and serotonin are dysbalanced or lowered. In long-term applications of antidepressants, sensitivity of postsynaptic receptors is changed: β-receptors are regulated down, 5-HT-receptors are regulated up. This could explain the effect latency of antidepressants. The connection between the influenced receptor system and the immediate effect is not always apparent. Imipramine seems to inhibit the reuptake of norepinephrine and by this activating drive.

Amitriptyline, however, inhibits the reuptake of serotonin, what could be the cause of its sedative effect. Fluoxetine, on the other hand, is a selective serotonin reuptake inhibitor but is not sedating.

Tricyclic antidepressants

The name tricyclic antidepressants are based on their hydrophobic, three-membered ring system. Tri- and tetracyclic antidepressants do not show any affinity to a certain neurochemical transmitter system, but exert influence on the norepinephrine and serotonin system by other means. Also, they bind to peripheral acetylcholine and histamine receptors. Typically, they are classified according to their clinical-therapeutical effect.

Kielholz scheme

Imipramin

Imipramin

Amitriptyline-type: Substances are sedating and suitable for therapy of agitated-anxious depression.

Imipramine-type: They do not affect drive and are solely mood-elevating. They are suitable for agitated depression and psychomotor retardation.

Desipramine-type: These antidepressants raise interest in activities and are used for the treatment of melancholic depression.

Note: Desipramine is the natural metabolite of Imipramine. Desipramine has a significantly shorter half-life, so within a few days, treatment with Imipramine is transformed to treatment with Desipramine.

Like neuroleptics, tricyclic antidepressants show two distinctive effects. First, the immediately occurring effect that is characterized by sedation, sleepiness, and reduction of mental and physical activity. This effect is also observed in mentally healthy individuals. The antipsychotic effect, that solely occurs after long-time use, is only detected in patients with pathologically lowered mood.

Substances: Amitriptyline, Doxepin, Imipramine, Nortriptyline, Desipramine, Trazodone

Tetracyclic antidepressants

The antidepressant effect of this group is based on inhibition of central α2- and 5-HT2-receptors. Their mood-elevating effect is accompanied by a sedating component. They are indicated in patients with agitated depression.

Substances: Maprotiline, Mianserin

Selective serotonin reuptake inhibitors (SSRIs)

By selective inhibition of the serotonin transporter, the reuptake of serotonin from the synaptic gap of the serotonergic neuron into the presynaptic neuron is prevented. Unlike in TCAs, these drugs do not block histamine and muscarinic receptors, so that typical adverse effects are missing.

It is observed that SSRIs can lead to bleeding tendency. This is attributed to the inhibition of the serotonin reuptake into the platelets with following lowered capability to aggregate.

Substances: (Es-)Citalopram, Fluoxetine, Paroxetine, Sertraline

Norepinephrine reuptake inhibitors (NRIs)

Similar to the mechanism in SSRIs, in SNRIs, the reuptake of norepinephrine into the presynaptic neuron is inhibited. They are suitable for treatment of mild depression.

Substances: Reboxetine

Antidepressants with dual mechanism of action: e.g. Serotonin-norepinephrine reuptake inhibitors (SNRIs)

reboxetin

Image: “Strukturformel Imipramin” by Jü. Licence: CC BY-SA 3.0

In this class, substances are summarized based on their acting through inhibition of serotonin and norepinephrine reuptake, a norepinephrine-serotonin-specific mechanism or a dual-serotonergic mechanism.

Venlafaxine inhibits the reuptake of serotonin, norepinephrine, and dopamine. Interestingly, at lower doses, there is mainly a serotonin reuptake inhibition followed by an additional norepinephrine reuptake inhibition in higher doses. Hence, Venlafaxine is suitable for treatment of depression in combination with anxiety disorders.

Mirtazapine, on the one hand, inhibits central α2-norepinephric receptors leading to an indirect amplification of norepinephrine and serotonergic neurotransmission. On the other hand, a postsynaptic serotonin-receptor-antagonistic effect trigger increased serotonin release. Mirtazapine is typically taken before sleep because of its sedating and hence sleep-rhythm-regulating effect.

Substances:

SNRIs: Venlafaxine

Serotonin-norepinephrine-specific antidepressants: Mianserin, Mirtazapine

Duloxetine is taking a special position among SNRIs.

Duloxetine is intended to be used for a particular indication, namely, stress urinary incontinence in depressive women. The effect is based on the influence on the Onuf nucleus located in the sacral region of the spinal cord. It is the origin of the pudendus nerve´s motor neurons.

Monoamine oxidase inhibitors (MAOIs)

Monoamine oxidase catalyzes the breakdown of neuro-active and vaso-active amines. MAO A deaminates norepinephrine, serotonin, and dopamine. A distinction is made between irreversible non-selective and reversible selective monoamine oxidase inhibitors.

Non-selective MAOIs inhibit MAO A and B and have many side effects, what makes them second-choice drugs.

Furthermore, ingestion of tyramine has to be restricted to avoid serotonin hyper function syndrome or irritation syndrome, which entails fever, muscle twitching, hypertensive crisis, sweating, nausea, and hallucinations. Foods rich in tyramine are among others chocolate, red wine, bananas and ripened cheese, that is why it is also referred to as cheese-effect.

In reversible MAOIs, the reactions induced by tyramine are not observed, because they solely inhibit monoamine oxidase A.

MAOIs act mainly drives enhancing – not mood elevating, hence they are called thymeretics. Their use is limited to treatment of interest deprived depression and late-life depression.

Substances:

irreversible, non-selective MAOIs: Trancylpromine (obsolete),

reversible MAOIs: Moclobemid.

Note: MAO inhibitors are the only substances that are contraindicated in endogenous depression because they only enhance drive and do not elevate mood.

Herbal antidepressants

ypericum_perforatum

Image: “Hypericum perforatum” by: Superior National Forest. Licence: CC BY 2.0

St. John´s Wort, lat. Hypericum perforatum is an option for the treatment of mild depressive episodes. Responsible for the antidepressant effect is the inhibition of the serotonin, norepinephrine and dopamine reuptake by hyperforin, which is contained in St. John´s Wort. It has to be taken into consideration that an agent with sufficient concentration of hyperforin is necessary because of the minimal daily dose of 900mg.

Ketamine

Ketamine, a Glutamate-NMDA-receptor antagonist with a quick effect, has proved to be successful in the treatment of emergencies in danger of suicide. A single dose leads to significant improvement of depressive symptoms for at least 7 days. Also, regular use contributes to raised mood and better reception and sleep.

Practical Application

Antidepressants are used in everyday clinical practice due to their drive-enhancing or sedating effect. Their efficiency, compared to unspecific therapeutic measures such as talking therapy and placebos, is all the more visible the heavier the depression is.

Therefore, combining psychotherapeutic and psychopharmacological treatment is the method of choice today. The aim of the therapy is a reduction of symptoms, improvement of patient´s functionality in everyday life and relapse prevention.

Further indications are anxiety disorders, obsessive-compulsive disorders, chronic pain, and bulimia.

Agents should be applied in slowly increasing doses, the onset of antidepressant effects can be expected after one or two weeks. When prescribing drive-enhancing drugs, it has to be taken into consideration that the drive-enhancing effect precedes the mood-elevating effect. In suicidal patients, that is the reason for increased frequency of suicide attempts in the first two weeks.

In most cases, tranquilizers like benzodiazepines or neuroleptics are prescribed as co-medication to reduce the risk of suicide in the first few weeks. In addition, close supervision and prescription of small package sizes are advisable. The first sign of recovery is normalization of sleep. A fluctuating course is typical over a longer period of time until complete remission.

If no improvement is observed after several weeks of treatment with adequate dosage, therapy can be changed to another antidepressant after confirmation of the diagnosis. For patients, the change is highly demanding because the recommended change to another substance class is accompanied by side effects such as nausea.

In principle, only one antidepressant should be prescribed. Augmentation with lithium is possible. The drug should be chosen in dependence of main and secondary diseases. In obsessive-compulsive disorders, serotonergic antidepressants proved to be effective, while in elder patients newer antidepressants are used because of the noticeably less pronounced anticholinergic side effects compared to tricyclic antidepressants.

In mild depression, hyperforin contained in St. John´s Wort can be used in sufficient dosage. It should be considered that St. John´s Wort is a strong cytochrome P450 Cyp3A4 inducer and leads to lowered effects of countless other drugs, e.g. HIV protease inhibitors, anticoagulants, and immunosuppressants. There have been deaths because of transplant rejection after use of St. John´s Wort.

The duration of the treatment has to be considered individually. In single depressive episodes, a six-month-long therapy with a focus on remission must be sought, followed by a gradual phasing out.

It is absolutely necessary to avoid abrupt withdrawal since abnormal reactions or even suicidal thoughts could arise. This is called rebound. Have there already been multiple episodes of sickness, a 5-year-long prophylaxis with antidepressants should be taken into account. A longer period is possible if there are no major complications. In bipolar disorder, lithium can be used as a mood stabilizer.

A therapy-resistant depression is one where symptoms remain, even though treatment was done with two correctly chosen and correctly dosed antidepressants successively over a period of three weeks each. In such cases, infusion therapy has proved to be effective because of the higher plasma levels, compliance and the positive psychodynamic influence of the infusion therapy.

During the intake of medication, including antidepressants, regular medical examinations are necessary to check for blood count, kidney and liver values. Furthermore, blood pressure,ECG and EEG checks are recommended.

For instance, Valdoxan is a relatively new antidepressant with the active substance Agomelatine, a melatonin analog. Its effect is based on regulation the rhythm of sleep and wake. In 2012, Arzneitelegramm, an online database for practitioners and pharmacists, advised against usage of that antidepressant. Not only was no effect proved, but also hepatotoxicity with raised values of transaminases three times higher than reference values.

Adverse Effects and Contraindications

In treatment with tricyclic antidepressants, vegetative-anticholinergic adverse effects are prominent. Among them are orthostatic hypotension, obstipation up to paralytic ileus, xerostomia, tremor, and tachycardia.

Often, because of their low rate of side effects, SSRIs are first-choice drugs. Especially in the beginning of the therapy, nausea, and vomiting, as well as inner restlessness, may occur. For some time now, the s-enantiomer of Citalopram named Escitalopram is on the market, showing even fewer side effects.

Note: At the beginning, driving motor vehicles and using machines is not recommended.

It is important to differentiate adverse effects from symptoms of a major depressive disorder. Adverse effects typically occur in the first days of therapy, hence the slowly increasing application. In major, mainly endogenous, depressions intolerance is rare even with high doses.

SSRI-caused sexual dysfunction is one of the main reasons for the lack of compliance and a premature termination of treatment. Symptoms are reduced libido, anorgasmia, and genital numbness. Studies showed that up to 60 % of all patients taking SSRIs are affected and it is assumed that the symptoms remain even years after drug treatment has ended. In this case, it is referred to as post-SSRI-sexual dysfunction.

Substance (class)

Most important adverse effects

TCAs

Voiding disorders, accommodation disorders, tremor, xerostomia, dizziness, cardiac conduction disorders, unrest, weight gain, loss of libido, erectile dysfunction, edemas, exanthema

SSRIs

Nausea, unrest, sexual dysfunction, headache, tremor

NRIs

Unrest, urinary retention, tachycardia

Venlafaxin

Nausea, hypertension, withdrawal symptoms

Mirtazapin

Fatigue increased appetite, edemas, arthralgia

MAOIs

Unrest, sleep disturbance

Hyperforin

Photosensitization, allergic reactions

Various agents have proved to be effective in the treatment of side effects. Dihydroergotamine is used for orthostatic dysregulation and hypotension. A low-dosed β-blocker reduces tremor.

Intoxication with antidepressants

Intoxication mainly occurs with tricyclic antidepressants. In most cases, these are suicide attempts or accidents in children. For instance, 100mg of Amitriptyline are deadly for children. Considering the standard dose of 25mg, only four pills can be fatal. Typical symptoms are unconsciousness, chorea-like athetotic condition, spasms, and arrhythmia. In case of intoxication, cholinesterase inhibitors like physostigmine are used to oppose the anticholinergic effect of antidepressants.

Contraindications

Contraindications in tricyclic antidepressants are angle closure glaucoma, pyloric stenosis, prostatic hypertrophy and status post-acute myocardial infarction.

Selective serotonin reuptake inhibitors must not be prescribed along with MAOIs, L-Tryptophan, and triptans to avoid serotonin hyperfunction syndrome.

Review Questions on Antidepressants

The correct answers can be found below the references.

1. A 34yr old woman presents herself for the first time in your general practitioner´s office. She reports that she has felt joyless and tired for a few weeks. Before that, she used to exercise or go out with friends after work. Now, she has to lay down in bed immediately, her dishes pile up in the kitchen because she lost motivation to do so. She never had such a low mood before. You assume that she has a mild to the medium depressive episode and prescribe an antidepressant. What substance is your first choice?

  1. Valdoxan
  2. St. John´s Wort
  3. Venlafaxine
  4. Reboxetine
  5. Citalopram

2. What is the antidote in acute intoxication with amitriptyline?

  1. Physostigmine
  2. Atropine
  3. Naloxone
  4. Acetylcysteine
  5. Methylene blue

3. Typically, what of these is no adverse effect of tricyclic antidepressants?

  1. Dependency
  2. Orthostatic dysregulation
  3. Sexual dysfunction
  4. Voiding disorders
  5. Mouth and nose dryness
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