The Pharmacotherapy of Mood Disorders

The Pharmacotherapy of Mood Disorders – Introduction

Mood Disorders are a large family of complex, chronic and relapsing disorders, affecting the general population, representing one of the world’s health emergencies (Murray & Lopez, 1996; WHO 2013). Among the mood disorders we identify various syndromes that impact on the patient’s emotional sphere, altering his mood, energy, volition, perception of pleasure, cognition and obviously affectivity. This is the most recent classification of Mood Disorders from the American Psychiatric Association present in the DSM-5 (APA, 2013):

• Depressive Disorders:
  1. Major Depressive Disorder. Characterized by low mood, loss of interest in activities usually performed, loss of hope, feelings of self-deprecation and guilt, sleep and appetite changes, tiredness, agitation or slowdown, difficulty concentrating, thoughts of death
  2. Persistent Depressive Disorder or Dysthymia. It is a chronically low mood that has lasted for at least 2 years.

• Disruptive Mood Dysregulation Disorder. Characterized by frequent angry outbursts that last for at least 1 year, onset between 6 and 18 years of age.

1. Premenstrual Dysphoric Disorder. Marked emotional lability, anger, depression or anxiety, with physical symptoms, changes in sleep, appetite, loss of interest in the week before the menstrual cycle.

• Bipolar Disorder and Related Disorders:
  1. Type I Bipolar Disorder.Characterized by the alternation of phases of depressed mood and manic phases (of euphoric or irritable mood), which may be accompanied by psychotic symptoms.
  2. Bipolar II Disorder. Characterized by the alternation of phases of depressed mood and hypomanic phases, which can be accompanied by psychotic symptoms.

• Cyclothymic Disorder. Alternation for at least 2 years of subthreshold depressive and hypomanic symptoms.

• Similar disorders, but induced by substances or by general medical conditions

The most widespread and disabling disorders among those listed, on which we will focus, are undoubtedly Major Depressive Disorder and Bipolar Disorder I and II, characterized by a multifactorial etiopathogenesis, which includes genetic vulnerability, environmental stress, alterations of the neurotransmission, impaired neuroplasticity and genetic expression (Li et al, 2012). According to WHO data, in 2015 about 322 million people in the world were affected by Depression, or 4.4% of the world population, with a prevalence of 5.1% in women and 3.6% in men. Between 2005 and 2015, the increase in the population affected by depression was 18%, parallel to the increase in the world population. The prevalence data relating to Bipolar Disorder are around 70 million affected people worldwide with a prevalence of 1% in the general population (Kessler et al, 2007), but most likely this is an underestimated figure, since it is relative exclusively to manifest episodes; the depressive polarities of bipolar disorder have probably been improperly included in the “Depression” category. Furthermore, a prevalence of subthreshold bipolar disorders was also calculated (Akiskal and Benazzi, 2005) estimated at 2.4% in the general population. the depressive polarities of bipolar disorder have probably been improperly included in the “Depression” category. Furthermore, a prevalence of subthreshold bipolar disorders was also calculated (Akiskal and Benazzi, 2005) estimated at 2.4% in the general population. the depressive polarities of bipolar disorder have probably been improperly included in the “Depression” category. Furthermore, a prevalence of subthreshold bipolar disorders was also calculated (Akiskal and Benazzi, 2005) estimated at 2.4% in the general population.

Both Depression and Bipolar Disorder very often have an incapacitating impact on the social and professional functioning of affected subjects, and it is no coincidence that depression has been found to be the most frequent cause of absenteeism from work in the United States (Kessler et al. 2006). By so severely affecting the quality of life, these disorders are also associated with an increased risk of committing suicide, which has a prevalence of 15% among the population with Mood Disorders.

The treatment of these disorders, which in the case of Unipolar Depression (Major Depression) showed a recurrence of 40% at 1 year and 58% at 5 years (Scapicchio, 2008) and in the case of Bipolar Disorder by 50% at 2 years and 70-90% at 5 years (Gitlin & Frye 2012), therefore has enormous significance in prognostic terms.

The primary goal of Mood Disorder therapy is now not only to resolve the acute phases, but to prevent future episodes, through the use of long-term treatments. In fact, it is now established that the risk of relapse is directly proportional to the number of episodes of disease subsequent to the first, which however have worsening symptoms (Greden JF, 2003), while the risk of relapse is reduced with the phases of euthymia (well-being ).

Treatment of Major Depression

The drug options currently present are:

• Antidepressants Serotonin Reuptake Inhibitors ( SSRIs). Introduced in the 1990s, they are currently considered the first line of treatment for Depression (Olfson et al, 2002), for Dysthymia and Premenstrual Dysphoric Disorder, but also for many anxiety disorders (Thase & Denko, 2008). SSRIs have drastically replaced tricyclic antidepressants. The first to be marketed was Fluoxetine ; today Sertraline, Paroxetine, Fluvoxamine, Citalopram and Escitalopram were added. They are not completely overlapping, since they have more or less sedative profiles depending on the histaminergic component. The dosage should be adjusted according to the age, weight and metabolism of each individual. Therapeutic efficacy is usually visible about 15 days after starting treatment. The most common side effects are nausea and diarrhea, headache, tremor, insomnia or sleepiness, decreased libido or anorgasmia. They are not considered to be among the most dangerous drugs to take during pregnancy, but there are studies that show that untreated depression can be more harmful than exposure of the fetus to SSRI (Hendrick & Altshuler 2002). In some cases, subjects being treated with SSRIs may experience a state of restlessness and psychomotor activation, with worsening of suicidal ideation. Treatment of Major Depressive Episode with SSRIs should not be prolonged beyond 6 months to 1 year, after which maintenance therapy at a lower dose and then gradual tapering may be considered to avoid withdrawal symptoms and paradoxical flare-ups of anxiety and depressed mood.
• Antidepressants Serotonin and Norepinephrine Reuptake Inhibitors ( SNRI). Also called dual drugs, in Italy we know Venlafaxine and the more recent Duloxetine , very suitable also in the treatment of anxiety and in the case of Duloxetine of neuropathic pain. They are drugs widely used in clinical practice, they have a mechanism of action partly common to the old tricyclics, which generates some side effects such as: dry mouth, tachycardia and hypertension. Venlafaxine is more complex scaling, unlike Duloxetine which should not be administered to subjects with hepatic impairment.
• Norepinephrine and Dopamine Reuptake Inhibitor. It is Buproprion, the only non-serotonergic antidepressant, also approved for weaning from smoking (Foley et al, 2006). It differs from other classes in the absence of sexual symptoms and is often associated with SSRIs in resistant depressions. Useful in the treatment of anxious depression and with hypersomnia.
• Serotonin receptor blockers. The Mirtazapineis a blocker of serotonin and a powerful histaminergic, and then with a strong sedative effect, therefore useful in the treatment of depressions with insomnia. In addition to the sedation itself, it has as a side effect an important increase in the sense of hunger. It can be useful in the elderly, depressed, with poor appetite and insomnia.
• Tricyclic Antidepressants(TCAs). They are serotonin and norepinephrine reuptake inhibitors. The precursor born in the 1960s was Impiramine (Klerman and Cole, 1965). Today Amitriptyline, Clomipramine, Nortriptyline are still used. The antidepressant effect of TCAs does not appear for 15-20 days and usually also shows good efficacy on anxiety. The Clomipramine is a great coverage for acute intravenous, for the most rapid and effective, as long as you constantly monitor your blood pressure. Amitriptylineinstead it has more sedative properties. The therapeutic dosage of TCAs must be maintained for a variable period (2-8 months) after the remission of symptoms. After this has been achieved, the doses should be gradually reduced. Side effects are mostly related to the anticholinergic (atropine-like) activity of these drugs. Recall: urinary retention, dry mouth, constipation, tachycardia, orthostatic hypotension, fine tremors in the upper limbs, delayed ejaculation, decreased libido. They are contraindicated in heart patients (especially in the case of arrhythmias), closed angle glaucoma, prostatic hypertrophy.
• Monoamine oxidase inhibitors(MAOIs). They were among the first antidepressants to be discovered (Youdim and Bakhle, 2006), while showing a high therapeutic efficacy, they are almost no longer used due to important interactions between this class of drugs and some foods (aged cheeses, red wine) or other drugs (containing sympathomimetic amines). Selegiline has been reformulated as a transdermal patch, being able to avoid the aforementioned interactions and therefore the induction of tachycardia and hypertension.
• Other “atypical” antidepressants. Trazodoneis a low dose serotonin antagonist, a high dose agonist. It has a powerful sedative effect so it is used in the treatment of depressions with insomnia and also has a good effect on anxiety. Initially used in the elderly patient for the few side effects, then orthostatic hypotension was found. Today it is used in alcoholic detoxification of the depressed subject. Agomelatineon the other hand, it is a melatonin receptor agonist approved for Major Depression, but it has shown greater efficacy in stabilizing the circadian rhythm than in controlling depressive symptoms. It has no effect on the sexual sphere or on weight, but it is absolutely contraindicated in case of liver failure. The newest of the antidepressants is Vortioxetine, a multimodal antidepressant (acts on serotonin receptors from time to time as an antagonist, agonist and partial agonist) approved by the FDA in 2013 for Major Depressive Disorder that has shown similar efficacy to SSRIs and SNRIs, with a good tolerability profile (absence of effects on weight and on the sexual sphere) (D’Agostino et al, 2015). It has the advantage of not needing the 15-day action window, but of giving immediate benefit. The most common and disabling side effect is nausea.
• II generation antipsychotics. These drugs find space in treatment-resistant depressions (Papakostas et al. 2007) in addition to antidepressant therapy. In the USA the association between Fluoxetine and Olanzapine is approved , but the addition of Aripiprazole has also given good results, which the FDA has approved as an adjuvant treatment in resistant depression (Berman et al. 2007). The use of low-dose Amisulpride is also widespread . Among the side effects, akathisia (restlessness) is common, especially when taken concomitantly with SSRIs.
• They have anxiolytic, muscle relaxant and hypno-inducing action, which is why they are very often associated with the above treatment, for the resolution of anxious symptoms and for insomnia. Among the most used of the many molecules with a short half-life are Alprazolam and Lorazepam, Clonazepam with a medium half-life, Delorazepam and Diazepam with a long half-life.
• Electroconvulsive Therapy(ECT). The guidelines suggest the indication for the use of ECT in treatment-resistant patients at high risk of suicide and in pregnant women with severe depressive symptoms. As you know, confusion and memory loss are among the most common side effects.
• Transcranial Magnetic Stimulation(TMS). The FDA approved the use of TMS in Major Depression in 2008. In recent years it has given some positive results as an adjuvant therapy. No side effects were highlighted, apart from slight pains in the place where the magnet was placed. It appears to be a tolerable and safe technique, which will be further investigated (Agarkar et al, 2011).

Treatment of Bipolar Disorder

(Hypo) manic polarity : the treatment of these phases is mainly aimed at stabilizing mood in acute, impulse control, psychomotor agitation and acceleration and crowding of thought. In the presence of psychotic symptoms (delusions and / or hallucinations) acute treatment should also include an antipsychotic and delirolytic attack properly.

The indicated pharmacotherapy will therefore be based on:

• Mood stabilizers:
  1. The most suitable in these phases will be Valproateand Carbamazepine , which act biologically as stabilizers of cell membranes and which are administered to reduce euphoric / dysphoric peaks, acceleration of thought and psycho-physical agitation, as well as to sedate the internal tension. They have a hepatic metabolism and should therefore be used with caution in cases of moderate to severe hepatic insufficiency. Valproate can be offered to women of childbearing age only after evaluating other treatments.
  2. Salts of lithium. Discovered as effective normotimizers already in the 1950s, they are still the first choice drug for the normalization of mood swings in the (hypo) manic phases and for the prevention of relapses, as well as suicidal ideation. They need blood tests of the therapeutic dosage. They should be administered with care in those who suffer from dystyroidism or have kidney failure. They can cause fine tremor especially in the upper limbs. They provide a daily water intake of about 1.5 liters / day for correct absorption, which often also normalizes the tremor.

• Antiepileptics + Lithium Salts. In severe manic phases, the association of the two principals is often necessary for the resolution of the episode.

• Antipsychotics:
  1. Second generation or “atypical” antipsychoticsare drugs that are weakly or selectively blocking dopamine receptors and antagonists of serotonin. Today the most used to treat psychotic symptoms that can arise in the manic phase or in mixed mood states are:  Amisulpride, Aripiprazole, Asenapine, Clozapine, Quetiapine, Paliperidone, Risperidone, Olanzapine. The dosage and formulation (immediate or prolonged oral release or intramuscular for the drugs that supply it) depend on the severity of the symptoms, the adherence to the treatment, the body weight, the coexistence of internal pathologies in progress. Among the side effects in some cases there is weight gain, parkinsonism (tremors, rigidity, motor slowdown similar to those present in Parkinson’s disease), akathisia (motor restlessness) albeit with a much lower frequency than typical antipsychotics. Amisulpride, Paliperidone, Risperidone and Quetiapine can cause an increase in prolactin values ​​which must be monitored and corrected. Clozapine, the most complete of the drugs in this family, requires frequent control of the blood count, to monitor for any changes in white blood cell counts. All of the above drugs require ongoing electrocardiography checks to monitor QTc length.
  2. I generation or “typical” antipsychoticsare the first drugs created for the management of psychotic symptoms, they have a more powerful blocking action on dopamine receptors and therefore have greater efficacy and rapidity of action in delirolytic action and in management agitation, but are much more frequently associated with side effects, such as: parkinsonism, weight gain and metabolic syndrome (diabetes, hypercholesterolemia and hypertriglyceridemia), akathisia. The most commonly used are: Haloperidol, Chlorpromazine, Clotiapine, Levomepromazine, Promazine, Flufenazine, Zuclopentixolo. The use of “atypical” antipsychotics should always be preferred when possible, but if necessary a short-term use of “typical” ones can be considered for the resolution of manifest symptoms of the acute phase. All of the above drugs need regular electrocardiographic checks during treatment to monitor QTc length.
• They have anxiolytic, muscle relaxant and hypno-inducing action, which is why they are very often associated with the above treatment, for the resolution of the acute phase of the (hypo) manic episode to treat the symptoms of agitation and insomnia. Among the most used of the many molecules with a short half-life is Lorazepam, Clonazepam with medium half-life, Delorazepam and Diazepam with a long half-life. In case of agitation and the need for immediate sedation, the intramuscular or intravenous route of some of these devices may be preferred.

Depressive polarity:

• Mood stabilizers:
  1. The most suitable in these phases will be Lamotrigineand secondarily Valproate, Carbamazepine, Topiramate, Pregabalin, which act biologically as cell membrane stabilizers and which are administered to stabilize depressive states with mixed mood characteristics or with anxiety, as well as quell internal tension. Mostly they are used in combination with atypical antipsychotic drugs or antidepressants. They have a hepatic metabolism and should therefore be used with caution in cases of moderate to severe hepatic insufficiency. Lamotrigine can lead to a skin rash, in which case it should be stopped. Valproate can be offered to women of childbearing age only after having preferred other treatments.
  2. Salts of lithium. Also in the depressive phase they are used for the normalization of mood swings typical of bipolar depressions with mixed characteristics and for the prevention of relapses, as well as for suicidal ideation. Mostly, an atypical antipsychotic, Lamotrigine, or an antidepressant accompanies the treatment. They need blood tests of the therapeutic dosage. They should be administered with care in those suffering from dystyroidism or having kidney failure. They can cause fine tremor especially in the upper limbs. They provide a daily water intake of about 1.5 liters / day for correct absorption, which often also normalizes the tremor.

• Lamotrigine + Lithium Salts. It is an association that has shown excellent results in the treatment of acute symptoms of bipolar depression (Ghaemi et al, 2006) and in rapid cyclicals.

• Atypical or second generation antipsychotics. The most commonly used are : Aripiprazole, Asenapine, Quetiapine, Paliperidone, Olanzapine not only in the presence of psychotic symptoms (delusions of ruin, unworthiness), to exploit the dopaminergic blocking effect, but also for the serotonergic action (especially at medium dosage – low) which guarantees an antidepressant and anxiolytic effect, without the risk of a (hypo) manic switch. The Quetiapinareceived FDA indication for use as monotherapy in bipolar depression (Calabrese et al, 2005). Among the side effects in some cases there is weight gain, parkinsonism (tremors, rigidity, motor slowdown similar to those present in Parkinson’s disease), akathisia (motor restlessness), hyperprolactinemia.
• International guidelines do not suggest its use as a first-line drug for the risk of (hypo) manic switch, irritability, aggression and suicidality (Pacchiarotti et al, 2013). They are used in combination with a mood stabilizer or an atypical antipsychotic, in case of resistant depression. SSRIs and Bupropion are preferable to Tricyclics, MAOIs, dual (Venlafaxine, Duloxetine) or multimodal (Vortioxetine) drugs.
• Electroconvulsive Therapy(ECT). The guidelines suggest the indication for the use of ECT in treatment-resistant patients with psychotic symptoms, high risk of suicide and in pregnant women with severe depressive symptoms. As you know, confusion and memory loss are among the most common side effects.
• Transcranial Magnetic Stimulation(TMS). Approved in Major Depression, there is still little evidence of its use in bipolar depression. No side effects were highlighted, apart from slight pains in the place where the magnet was placed. It appears to be a tolerable and safe technique, which will be further investigated (Agarkar et al, 2011).

The resolution of the acute (hypo) manic or depressive phases does not have a predetermined time, each organism will respond differently to the treatment depending on its ability to metabolise the drugs administered, the severity of the episode, the duration of the disease, the number of episodes suffered , comorbidity with other disorders, adherence to treatment and as a consequence of proper hygiene of life ( adequate night rest for quantity and quality; reduction in the use of stimulants for the nervous system, such as caffeine, theine and nicotine; food; proper hydration; total abstention from the consumption of substances for abuse and alcohol ).

Long-term treatment:

Once stabilization of the acute phase is achieved, the continuation phase takes place , the primary objective of which is to reduce relapse rates in terms of frequency and severity of relapses and to resolve inter-episodic symptoms. This phase lasts about 3-6 months in which drug dosages can be reduced by adjusting them to the clinical status and any antidepressants, administered in case of bipolar depression, suspended. After this phase, the maintenance phase takes over, which is extremely delicate due to the risk of decreased adherence to the treatment. Among the drugs used in the maintenance phase we still find antiepileptics and lithium salts and atypical antipsychotics. The choice to use the new monthly intramuscular formulations of atypical antipsychotics available (Aripiprazole, Paliperidone palmitate, Risperidone and Olanzapine) called LAI has recently been increasing.(long-acting intramuscular) precisely in order to reduce the relapse rates associated with the loss of adherence to treatment. Relapses during maintenance treatment, according to the guidelines, should be treated by adjusting the dosage of the drugs already taken: in the case of the (hypo) manic episode by increasing the dosage of the antiepileptic or bringing the lithemia to 0.8-1 mmol / L or adding an atypical antipsychotic and clearly discontinuing any antidepressant; in the case of a depressive relapse, the need for the use of atypical antipsychotics, Lamotrigine and antidepressants will be evaluated. Lithium salts remain the only ones to show evidence of preventing depressive relapses, albeit less than they do with manic relapses (Goodwin et al, 2016).

Mood Disorders Pharmacotherapy – Conclusions

While there is no long-term treatment for Major Depressive Disorder, prophylactic treatment for Bipolar Disorder is absolutely necessary to limit the risk of relapses, which are still possible. It is an extremely complex process, so it requires continuous attention from the clinician, but also from the affected subject, who must be sufficiently aware of their disease and the implications of stopping a treatment. A solid therapeutic alliance and a valid psychoeducational path aimed at achieving a good awareness of the disease are essential requirements for an effective treatment.