Mood Disorder

Etiology

The brain areas responsible for controlling our feelings and emotions are the amygdala and orbitofrontal cortex. Patients with mood disorders have shown to have an enlarged amygdala on brain imaging, which substantiates the certainty that abnormalities in these areas lead to mood disorders. Ventricular expansion results from repeated episodes of mood disorders.[4]

Biological Factors

Neurotransmitters that play an important function in mood disorders are serotonin and norepinephrine, which are decreased in episodes of depression. Serotonin is the neurotransmitter most commonly associated with depression. Dopamine has also been implicated in mood disorders with research showing that it may be decreased in depression and increased in mania. 

Medical conditions which lead to mood disorders include:

• Brain tumors
• CNS syphilis
• Delirium
• Encephalitis
• Influenza
• Metabolic changes associated with hemodialysis
• Multiple sclerosis
• Q fever
• Cancer
• AIDS
• Hypothyroidism

There are certain drugs and medications, consumption of which lead to symptoms simulating a mood disorder. These are amphetamines, cocaine, procarbazine, and steroids.[5]

Genetic Factors

According to research based on twin studies, there are certain genes causing mood disorder.[6] Family and adoption studies have also indicated the heritability of mood disorders. People who have a strong positive family history of a mood disorder are more likely to develop mood disorders themselves. The parental mood disorder is a vital and constant risk factor for developing mood disorders in their children.[7]

Hormonal Factors

Increased HPA activity is associated with stress and depression. Increased TSH has been shown to be associated with depression.

Psychosocial Factors

Stressful life changes (death of significant other, parents, siblings, etc.) traumatic events and childhood abuse have been found to be major risk factors for the development of mood disorder later on in life, especially depressive disorder.[8] Personality traits or certain personality disorders like borderline and obsessive-compulsive disorder (OCD) are more frequently associated with depression. Attachment problems and early childhood adversity have been associated with depression.

Neuroimmunological Factors

Research shows that mood disorder leads to the altered release of neuroactive cytokines like IL-1beta, IL-6, and TNF-alpha.[9]

Recent research has found a crucial role of nitric oxide (NO) involved in causing the inflammatory process that leads to signs and symptoms of mood disorder. Altered levels of NO have also been found in patients suffering from mood disorders.[10]

Increased frequency of abnormal hyperintensities is seen in subcortical regions in depressive disorders and bipolar disorder.

Epidemiology

Major depression has a lifetime prevalence of about 5% to 17%. Women have almost twice the prevalence rate vs. men.[11] The annual prevalence rate of depression is 7.1% in U.S. adults, while the annual prevalence rate for bipolar disorder is 2.8%. The median age of onset of major depressive disorder is 32 years.[12]

Mood disorders are commonly seen in children and adolescents with an estimated rate of 15% suffering from any mood disorder, and 12% have a mood disorder with severe impairment.[13] Depression is prominent in children and adolescents, with rates as high as 18% to 22% in girls and 7% to 10% in boys by the age of 17. Research shows the prevalence of disruptive mood dysregulation disorder ranges from 0.8% to 4.3% in children.[14] The lifetime prevalence of bipolar disorder subtypes is 0.6% for bipolar I, 0.4% for bipolar II, and 2.4% for bipolar spectrum disorder (BPS).[15]

Pathophysiology

Depression is a complex neuropsychiatric disorder represented by severe anhedonia (a substantial incapacity to enjoy pleasurable activities), sad mood, feelings of guilt, suicidality, and cognitive impairment. One of the primary risk factors for the development of depressive disorders is chronic stress. The pathophysiology of constant stress results from overactivation of the hypothalamic-pituitary-adrenal (HPA) axis, which results in glucocorticoid cortisol level increase.[16] Neuronal plasticity also plays a significant role in the pathophysiology of mood disorder. Patients with poor social support show signs of impaired neuronal plasticity, predisposing them to mood disorders. Mild to moderate impairment of neuronal plasticity causes depression, while severe impairment results in mania.[17] 

Other symptoms of mood disturbances are decreased sleep and appetite. There could be increased (agitation) or decreased psychomotor activity. Increased agitation can be life-threatening as it can lead to muscle breakdown, followed by kidney failure (due to increased creatinine). In severe cases, the patient may develop psychotic symptoms of delusions and hallucinations. Neurocognitive changes with deficits in attention and concentration, recent and remote memory, and executive functions have been detected in cases of mood disorders. These signs and symptoms are due to an interplay of factors such as genetic vulnerability, positive family history, and social support systems.[18]

History and Physical

The evaluation for mood disorders mandates comprehensive and detailed history taking. Patients with bipolar disorder are easily diagnosed when they present with episodes of mania characterized by inflated self-esteem, grandiosity, impulsivity, irritability, increased psychomotor activity, delusions, or hallucinations. When the patients exhibit symptoms of depression such as sad mood, decreased concentration, guilt, decreased interest in pleasurable activities, ideas of self-harm, and suicide, it is crucial to differentiate unipolar from bipolar depression. Clinical features suggestive of bipolar depression are early age of onset, acute onset, recurrent episodes of depression (more than 5 episodes), positive family history of bipolar disorder, antidepressant-induced hypomania, depression with psychotic symptoms before the age of 25, postpartum depression, and depressive mixed state.[19] During history taking patients often ignore past hypomanic or manic episodes, so clinicians must explore periods with mood dysregulation associated with decreased need for sleep and increased energy in the past. A careful assessment of the risk of suicide and homicide is essential. 

Once the patient is stabilized, a formal mental status examination is mandatory. Patients suffering from depression show poor/limited eye contact during the interview, have a flat or blunted affect with decreased speech and increased reaction time. They appear disheveled with unkempt hair and poor hygiene. Psychomotor activity is markedly decreased. On the other hand, patients with mania have increased psychomotor activity, are agitated, irritable, hyper talkative, have pressured speech, tangentiality, decreased reaction time, and are difficult to interrupt. Patients with mania can sometimes have hallucinations, delusions, and paranoia. Occasionally, major depression can have psychotic features. 

Evaluation

A detailed longitudinal and in-depth family history, followed by a thorough mental status examination, is crucial for early diagnosis of mood disorders. Mood disorders secondary to substance abuse require a urine drug test. Specific rating scales are also available for the evaluation of mood disorders. Hamilton Rating Scale for Depression (HAM-D) and the Montgomery-Asberg Depression Rating Scale (MADRS) are for depression, and the Young Mania Rating Scale (YMRS) is for mania.[20]

• HAM-D is a 17 item depression rating scale administered by the clinician. It rates depressed mood, sleep difficulties, the ability to concentrate, guilt, suicidality, anxiety symptoms, and somatic symptoms on a 3 or 5 point scale. A score of 0 to 7 is considered normal, a score of more than 20 needs intervention.
• MADRS is a questionnaire administered by the clinician for the diagnosis of depression. It assesses sadness, inner tension, appetite, sleep, thoughts of self-harm, and suicide on a scale of 0 to 60. Scores between 0 to 6 are considered normal, 7 to 19 as mild depression, 20 to 34 as moderate depression, and score more than 34 is categorized as severe depression.
• YMRS is a clinician-administered scale for mania. It is an 11 item scale with 4 items (irritability, speech, thought content, and disruptive behavior) graded on a 0 to 8 scale and the remaining items (elevated mood, increase in motor activity, libido, sleep, appearance, and insight) are graded on a 0 to 4 scale. Scores less than 12 indicate remission, 13 to 25 as moderate, and 38 to 60 as severe mania.

Treatment / Management

Timely diagnosis and treatment of mood disorders can decrease the associated morbidity and mortality. The first step towards choosing an optimal treatment is a thorough assessment of the patient's safety and level of functioning. Distinct objectives of psychiatric management include solidifying and preserving a therapeutic alliance, educating the patient about signs and symptoms of mood disorders, reinforcing medication compliance, emphasizing the importance of regular sleep and appetite, foreseeing stressors, recognizing recurrences, and lessening social and functional impairment. 

Pharmacotherapy for Bipolar Disorder

1. If presenting episode is a manic episode with severe symptoms or is a mixed episode: Start with a mood stabilizer (lithium or valproic acid), and an atypical antipsychotic (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole). 
2. If the patient presents with a less severe episode: Monotherapy with lithium, an anticonvulsant, or an atypical antipsychotic. Alternatives to lithium or valproic acid are carbamazepine or oxcarbazepine. 
3. If presenting episode is a depressive episode: Prescribe quetiapine or lurasidone or Lamotrigine or a combination of olanzapine and fluoxetine.

• Lithium— It is the primary mood-stabilizer. The mechanism of action of lithium is to inhibit the hydrolysis of inositol 1 phosphate by inositol monophosphatase. As a result, the supply of free inositol for the regeneration of membrane phosphatidyl–inositides, which are the sources of inositol triphosphate and diacylglycerol, is reduced. It also inhibits enzyme glycogen synthase kinase, and the hyperactive neurons involved in manic states are preferentially affected because the supply of inositol from extracellular sources is compromised.

Dosage recommendation— In adults, the starting dose is 300 milligrams of the regular release formulation two-three times a day. In elderly persons with renal impairment, the starting dose is 300 milligrams once or twice daily. At a dose of 900 to 1200 milligrams, the plasma concentration of the drug is 0.6 - 1.0 milliequivalents/liter, which is effective in treating bipolar disorder. At a dose of 1200 to 1800 milligrams, the plasma concentration is 0.8 - 1.2 milliequivalent/liter.

Adverse effects—Gastrointestinal upset, fine tremors, polyuria, and polydipsia-reduction in urinary concentrating capacity leading to nephrogenic diabetes insipidus, hypothyroidism, hyperthyroidism, increased risk of hyperparathyroidism, and cognitive impairment. Check sodium, calcium, phosphorus, electrocardiogram, creatinine, urinalysis, complete blood count, thyroid function test, renal function test, and a pregnancy test. Lithium has a narrow therapeutic index; therefore, it requires monitoring of blood levels.

• Sodium valproate— It blocks voltage-gated sodium channels and boosts the inhibitory transmission of gamma-aminobutyric acid (GABA).

Dosage recommendation—For patients having acute mania, oral loading is 20 to 30 milligram/kilogram/day. Therapeutic plasma concentration is attained on a dosage between 1,200 and 1,500 milligrams/day given in divided doses. Sodium valproate can also be given as an intravenous (IV) infusion to stabilize a patient who comes with agitated behavior rapidly.

Adverse effects— Weight gain, gastric irritation, hair loss, thrombocytopenia, leucopenia, red cell hypoplasia, tremor, menstrual irregularities, polycystic ovaries, hyperandrogenism, hirsutism, obesity, insulin resistance, fatal hepatotoxicity, pancreatitis, hyperammonemia-induced encephalopathy.

• Carbamazepine, oxcarbazepine— These are anticonvulsant medications. These act by blockade of the sodium channels.

Dosage recommendation—The target dose for antimanic activity is 1,200 mg a day.

Adverse effects are dizziness, diplopia, drowsiness, ataxia, nausea and headache, dry mouth, edema, hyponatremia, and sexual dysfunction. Preliminary workup should include a CBC, liver function tests (LFTs), electrolytes, and ECG.

• Lamotrigine— It acts by blockade of voltage-sensitive sodium channels, which in turn modulate the release of glutamate and aspartate and a slight effect on calcium channels.

Dosage recommendation— 50 to 200 milligrams per day is used for bipolar depression. It is usually started at 25 mg daily, and the dose is titrated upwards gradually to reduce the risk of Stevens-Johnson syndrome.

Adverse effects— Increased risk of rash (Stevens-Johnson syndrome /toxic epidermal necrolysis), which is associated with the speed of dose titration. The appearance of any kind of rash necessitates sudden discontinuation of the Lamotrigine regimen.

Other anticonvulsants which can be used as a mood stabilizer are riluzole, topiramate, zonisamide, gabapentin, pregabalin, and levetiracetam. Of these, topiramate is used most commonly and is associated with renal stones.

• Benzodiazepines acting as anxiolytic, sedative-hypnotic, anticonvulsant is a valuable adjunctive to a mood stabilizer. These can be useful adjunctive treatment as anxiety and panic disorder is significantly comorbid with bipolar disorder.

• Thyroid hormone: Triiodothyronine may stabilize mood in some bipolar patients. It is important to stabilize hypothyroidism with levothyroxine as thyroid abnormalities are associated with rapid-cycling bipolar disorder.

 Pharmacotherapy for Unipolar depression or dysthymia: 

• Selective serotonin reuptake inhibitors (SSRIs): Sertraline, fluvoxamine, fluoxetine, citalopram, escitalopram, and paroxetine.

SSRIs are the first-line treatment option for depressive disorder, as they are tolerated better with lesser side effects. They normally take 4 to 5 weeks to display full effects. When on SSRI, it is important to monitor for suicidal thoughts, especially in young adults. The commonly seen adverse effects are nausea, vomiting, diarrhea, dizziness, loss of appetite, reduced sexual desire, anxiety, and insomnia.

•  Serotonin-norepinephrine reuptake inhibitors (SNRI): venlafaxine, desvenlafaxine, duloxetine, milnacipran, and levomilnacipran

These are the next in line medication for the treatment of depression after SSRIs. This category of the medication has a dual-action and found to be beneficial in cases with comorbid pain. The common side effects include nausea, dry mouth, hypertension, fatigue, loss of appetite, insomnia, sweating, and anxiety.

•  Atypical antidepressants: bupropion and mirtazapine. Agomelatine is another atypical antidepressant, but it is unavailable in the United States. 

Mirtazapine also acts as a second-line medication for depression. Side effects include somnolence, increased appetite, and weight gain. Bupropion lowers the seizure threshold and is contraindicated in cases with epilepsy, and in eating disorders.

•  Tricyclic antidepressants (TCA): desipramine, nortriptyline, imipramine, and amitriptyline.

This category of medications can be effective, but no longer used as primary agents for depression due to the various side effects and toxicity due to overdose. Common side effects include weight gain, somnolence, orthostatic hypotension, increased heart rate, constipation, giddiness, and urinary retention.

•  Serotonin modulators: nefazodone, trazodone, vilazodone, and vortioxetine. 

Serotonin modulators act as antagonists and agonists at postsynaptic serotonin receptors and inhibit the reuptake of postsynaptic serotonin. Nefazodone is contraindicated in liver disease. Priapism may be seen with trazodone. 

•  Monoamine oxidase inhibitors (MAOIs):

These include tranylcypromine, phenelzine, and selegiline. These are scarcely used due to their particular dietary regulations to avoid the hypertensive crisis and serotonin syndrome. Commonly seen side effects include orthostatic hypotension and decreased sleep.

Phototherapy (bright light therapy) is used in the treatment of seasonal affective disorder (SAD).

• Newer medications such as intravenous and intranasal ketamine (esketamine) have shown positive results in the treatment of mood disorders. Ketamine has also shown utility in rapidly reducing suicidal ideation though effects require repeat treatments and are not long-lasting. 
• Somatic treatments like vagal nerve stimulation are used for patients with treatment-resistant depression.[11] 
• Antipsychotics like aripiprazole can be used for the adjunctive treatment of depression.

Psychotherapy

Apart from pharmacotherapy, patients suffering from depression and other mood disorders benefit from several types of nonpharmacological therapies.

1. Mindfulness-based cognitive therapy (MBCT) and acceptance and commitment therapy (ACT): These seem to be beneficial in ameliorating mood symptoms and in curbing relapse.
2. Interpersonal psychotherapy: It recognizes interpersonal problems and role transitions.
3. Cognitive-behavioral therapy: It improves dysfunctional cognitions and attitudes that are considered to sustain depression. Amongst psychotherapies, CBT is the most extensively studied therapy for depression.
4. Dialectical behavioral therapy: It is a form of CBT that involves mindfulness, distress tolerance, and emotional regulation.

CBT, interpersonal therapy, and behavioral activation are considered important psychological treatments for depression. Behavioral activation involves encouraging depressed patients to be involved in activities that uplift mood like exercise, new skills, chores, etc.

 Brain Stimulation Therapy

1. Repetitive transcranial magnetic stimulation (rTMS) has shown promising results in treating mood disorders. rTMS is a technique that utilizes a pulsed magnetic field to facilitate alteration in brain activity. Repeated cortical stimulation can enhance or lessen regional brain activity. rTMS procedure includes about 5 sessions delivered over a period of four to six weeks. The patient does not need a general anesthetic while undergoing rTMS, and it can be administered in the outpatient unit. Dissimilar to ECT, it does not cause cognitive side effects. The major adverse effects are headache and scalp discomfort at the site of administration.[21]
2. Electroconvulsive therapy is used in treatment-resistant cases, in severe depression when patients refuse to eat/drink, in pregnancy, and highly suicidal patients. Side effects include headache, cognitive deficits, and memory( both anterograde and retrograde) impairment is of chief concern to the patients while undergoing ECT.[22]

 Healthy Lifestyles

1. Diet and mental health: Research has demonstrated that following a 'healthy' diet routine is correlated with decreased risk of mood disorders.
2. Exercise and yoga: Regular exercise and yoga are protective against the development of mood disorders. People who are physically inactive are at a greater risk for the development of depressive disorders. A likely mechanism behind this seems to be the effect of regular workouts on brain-derived neurotrophic factor (BDNF).
3. Smoking: Smoking cessation is related to an increased optimistic mood and quality of life and fewer chances of getting anxious and depressed compared with regular smoking.
4. Omega-3 fatty acids: The antidepressant effects of omega 3 fatty acids are due to the regulation of neurotransmitters (serotonin, dopamine), and its anti-inflammatory and antioxidant effects. 

Differential Diagnosis

Differential diagnosis: According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) following are the differential diagnosis of mood disorders.[18]

• Generalized anxiety disorder, panic disorder, posttraumatic stress disorder (PTSD), or other anxiety disorders: A comprehensive history taking is required to distinguish generalized anxiety disorder from a mood disorder, as anxious ruminations can be misunderstood as racing thoughts. Actions to decrease anxiety may be comprehended as aggressive behavior seen in the manic episode. Likewise, signs and symptoms of PTSD, including anger and aggression, should be differentiated from bipolar disorder.
• Substance/medication-induced mood disorder: Substance use disorders may present with symptoms suggestive of mania/ depression that needs to be differentiated. A primary diagnosis of a mood disorder must be ascertained based on symptoms that continue once the patient stops consuming the substance. Certain medications (steroids and alpha-interferon) can induce manic or depressive symptoms. Clinical judgment and a thorough history are required to distinguish these symptoms from mood disorders.

• Attention-deficit/hyperactivity disorder (ADHD): Commonly seen in adolescents and children, this disorder can be mistaken for bipolar disorder. Symptoms such as increased psychomotor activity, difficulty to interrupt speech, distractibility, and decreased need for sleep overlap with symptoms in a manic episode. The episodic nature of bipolar disorder can be valuable in differentiating mania from ADHD.

• Personality disorder: Symptoms of certain personality disorders like borderline personality disorder may have a significant overlap with bipolar disorders. Labile mood, impulsivity, delusions, and hallucinations are commonly seen in both disorders. These symptoms must appear in episodes with a marked increase over baseline, to be categorized as bipolar disorder.

• Schizophrenia spectrum and other related psychotic disorders: Bipolar disorder and severe depression with psychotic symptoms must be differentiated from psychotic disorders. Schizophrenia and other related psychotic disorders are all defined by intervals of psychotic symptoms. Important criteria to distinguish these two are delusions, and hallucinations in psychotic disorders are seen in the absence of any mood symptoms. Other valuable considerations constitute the concurrent symptoms, the chronology of symptoms, and the longitudinal course.

• Delirium, catatonia, and acute anxiety: It is crucial to distinguish symptoms of mania from hyperactive delirious symptoms, excited catatonia, and impulsivity/aggression associated with acute anxiety.

Prognosis

In the first year of follow-up, the patients who had a childhood-onset mood disorder, delay in the diagnosis, and longer duration of untreated illness exhibited quite considerable severity of the disorder, the larger number of episodes, additional days depressed, additional ultradian cycling, and limited days of euthymia.[23] About one-third of mood disorders recur, one-third of the patients develop psychotic disorders, and another one-third develop a lifetime anxiety disorder. Thoughts of dying (80.8%) and thoughts of suicide (69.5%) were continuous, and specific suicidal plans were more frequent in females during follow-up.[24] There are higher chances of comorbid lifelong anxiety, substance abuse disorder, absenteeism from work, and family discord leading to poor quality of life.[25] It is also associated with increased direct and indirect health care expenditures because of the longer duration of hospital stay.

Complications

Findings suggest a possible association between a longer duration of illness and a worse outcome in mood disorder, especially in terms of self-harm/suicide.[26] Mood disorders, especially bipolar disorders might be undiagnosed or misdiagnosed for as long as 10 years. A late diagnosis of bipolar disorder has serious outcomes. It leads to several forms of substance abuse. Anxiety disorder was amongst the most frequent lifetime comorbidity associated with mood disorders. Attention deficit-hyperactivity disorder, oppositional defiant disorder, and conduct disorders were also frequently seen. Mood disorders can cause serious functional impairment, for example, inability to work and problems in sustaining emotional relationships with family and friends.[27]