Agitated Depression

Agitated depression is a form of depression characterized by agitation and restlessness.

The disease is related to the following processes:  mental and has an incidence of about  143 / 100.000.

Overview

Agitated depression is a subtype of depression with significant features of agitation and restlessness [1] [2]. As in other forms of major depressive disorder, the causative factors remain unclear, although it is thought that both environmental stressors and genetic influences play an important role. In particular, adolescent and adult onset major depressive disorder have stronger genetic links than prepubertal depression.

Agitated depression occurs more commonly among middle-aged and elderly individuals. Affected patients usually have a history of psychiatric hospitalization and have received psychiatric evaluations at a later age than individuals with other forms of major depressive disorder. The pathophysiologic processes underlying depression, in general, remain unclear, although scientists now understand more about the neurochemical and neurological changes that are involved in the disorder. Serotonin deficiency is thought to play a particularly prominent role, in combination with changes in neural networks critical for mood and emotional regulation. Neuroimaging studies report changes in the frontostriatal pathway, the orbitofrontal cortices, the amygdala, and the hippocampus.

Patients with agitated depression present with severe agitation along with features common to major depressive disorder. Psychomotor retardation along with a tendency to complain and to express a feeling of being misunderstood are characteristic. More specific features include racing thoughts, hand-wringing, continuous speech, as well as motor agitation. Workup is directed at excluding organic causes and should comprise laboratory tests and sometimes neuroimaging studies, in cases when neurological dysfunction is suspected. Important organic causes that are present on the differential diagnosis are vitamin deficiencies, hypopituitarism, infectious disorders and cerebrovascular lesions. Other diagnostic modalities that may need to be performed include a spinal tap and urine studies. Patients are treated with a combination of pharmacotherapy and psychotherapy. A number of agents can be used, such as antidepressants, antipsychotics, sedatives, anticonvulsants and sometimes stimulants. Patients usually require more time to recover from an episode in comparison to those affected with other forms of major depressive disorder, although long-term prognosis is similar.

Etiology

The causes for agitated depression remain unknown and involve both genetic and environmental factors. This is common to the majority of psychiatric disorders. Nonetheless, some evidence suggests that depression is more strongly related to psychological stressors during childhood than to genetic influences [3]. This pattern, however, varies with the type of depression. Adolescent and adult onset depression tend to be more heritable than the depression with a pre-pubertal onset, although all forms involve a complex interaction between genes and environment.

Epidemiology

The incidence of major depressive disorder has been increasing in the last 70 years, according to two major studies by Klerman and Gershon et al. [4] [5]. In particular, an incidence is increasing among relatives and the age of onset is getting smaller in successive generations. The Center for Disease Control and Prevention (CDC) estimated the prevalence of current depression to be 9% on a sample of 235,067 adults in a time range of 2 years (2006-2008). 3.4% of this sample were clinically diagnosed with major depression. Currently, a lifetime incidence of major depressive disorder is thought to be 12% in men and 20% in women, with a point prevalence reaching 10% for individuals in a medical environment.

An incidence of depression increases with age, due to the connection of the disorder with illness and institutionalization. Nonetheless, depression in the elderly tends to be atypical and sometimes escapes clinical diagnosis as major depressive disorder. Affected individuals are usually diagnosed with dysthymic disorder.

On the other hand, agitated depression often occurs in middle-aged or older individuals. Patients have usually suffered more psychiatric hospitalizations and were much older at the time of the first psychiatric evaluation.

Sex distribution
Age distribution

Pathophysiology

The pathophysiology of depression remains unclear. Serotonin is thought to play an important role, although other neurotransmitters such as norepinephrine (NE), dopamine (DA), glutamate and brain-derived neurotrophic factor (BDNF) are also involved [6]. Evidence for the involvement of serotonin includes response to selective serotonin reuptake inhibitors (SSRIs) and studies on human subjects showing that depletion of tryptophan, the precursor for serotonin, can lead to the relapse of the illness. In addition to serotonin depletion, receptor regulation, gene expression, and intracellular signaling play an important role.

Depression can also be caused by vascular lesions, leading to disturbances in the neural networks that regulate emotions [7]. The affected network comprises the dorsal and anterior cingulate cortices, in addition to the dorsolateral prefrontal and orbitofrontal cortices. The amygdala and the hippocampus have also been involved.

Neuroimaging studies have improved our knowledge of the neural processes underlying depression. Researchers have found increased metabolism in the limbic system and decreased metabolism in the neocortex [8]. Furthermore, a meta-analysis found significant changes in the following regions: the thalamus, the basal ganglia, the gyrus rectus, the hippocampus, the frontal lobe, the ventricles and the orbitofrontal cortex [9]. Sacher et al. also report changes in glucose metabolism in the right subgenual and pregenual anterior cingulate cortices, the dorsal frontomedian cortex, the right paracingulate cortex and the amygdala. Other relevant findings include decreased activity in the prefrontal cortex, in a region with strong connections to other areas responsible for dopamine and serotonin regulation [10].

Prognosis

Agitated depression tends to follow a more severe course than non-agitated depression. Patients usually require more than 12 weeks on average to recover from an episode, in comparison to 9 weeks in patients with non-agitated depression. Furthermore, antidepressant drugs may worsen symptoms in up to 23% of patients, relative to 8.7% of patients with non-agitated depression. Nonetheless, outcomes for patients were similar for agitated and non-agitated depression after 5 years of diagnosis. Patients with agitated depression scored on average 10.7 on the Strauss-Carpenter Outcome Scale in comparison to 11.0 in patients with non-agitated depression [11].

Presentation

Agitation is the defining characteristic of agitated depression. Patients may not be able to sit still for a considerable time range. They usually feel that they are not being properly understood and tend to complain about a number of things. Psychomotor retardation is an important objective characteristic of the disease, and at least two of the following must be met for diagnosis: racing thoughts, hand-wringing, pacing, trouble in explaining problems, continuous talking, inner tension that is intense, motor agitation, tearing of clothes, pulling on hair, clothing or skin, shouting outbursts and a stream of baseless thoughts.

Agitated depression can also occur in the context of bipolar 1 disorder. It can be part of psychosis or not, and in general is classified into the following 3 subtypes: psychotic agitated depression (proposed to be referred to as melancholia), non-psychotic agitated depression and anxious depression (with a provisional name of "psychic agitation and racing or crowded thoughts").

Diagnosis of agitated depression is difficult to establish because of the overlap of symptoms with other disorders. Some clinicians believe it is not an independent disease category and, indeed, it is now thought of as a form of depression. Others, however, believe it should be part of bipolar disorder given the frequent presence of mood swings. The right classification is not only useful for diagnostic purposes but has major therapeutic consequences. One study in 2004 by Italian researchers Benazzi, Koukopoulos and Akiskal found that individuals with features of both depression and agitation who were diagnosed with major depression had worse outcomes because the therapy ignored the presence of irritability [12]. This lead to a worsening of the symptoms for the patient.

On the other hand, drugs can also lead to the occurrence of agitated depression, especially those used to treat major depression. Furthermore, because of the associated restlessness and agitation, patients tend to not follow direction and use medication as prescribed, leading to worsened symptoms.

Workup

Workup of symptoms of agitation is broad, and the physician may need to request a number of tests to establish a relevant differential diagnosis and rule out organic disorders. These include laboratory blood tests to exclude certain vitamin deficiencies, an infectious process or hormonal disturbances. A spinal tap, neuroimaging studies, and urinalyses may also be necessary.

Patients who do not show outward neurologic signs usually do not require neuroimaging procedures. Suspicion in hypopituitarism or some specific neurologic brain disease should prompt the clinician to consider computerized tomography (CT) or magnetic resonance imaging (MRI) scanning. Positron emission tomography (PET) may also be useful, as it enables to assess the binding of molecules to certain receptors in the brain. Nonetheless, its use is not encouraged among children and adolescents because of the presence of radiation. Single photon emission computed tomography (SPECT) imaging, on the other hand, has shown important brain differences between adolescents diagnosed with depression and healthy subjects. In particular, studies have shown decreased regional blood flow to the left temporal cortex and the left anterofrontal regions in addition to a higher level of asymmetry in blood flow between the right and left cerebral hemisphere [13].

The DSM-III-R has defined the following criteria for agitated depression: a major depressive episode and two of motor agitation, crowded or racing thoughts and intense inner tension or psychic agitation. These criteria correspond to major depressive episode but not to a mixed bipolar disorder.

Treatment

Several agents can be used in the treatment of agitated depression. They include sedatives, antipsychotics such as aripiprazole, clozapine or olanzapine, antidepressants and anticonvulsants like divalproex. Paradoxically, stimulants can also be used, as in the case of attention deficit disorder (ADD). A combination of medication and psychotherapy is considered the optimal treatment for agitated depression. It is important to fine tune the pharmacotherapy according to the response and the side effects of the drugs, based on the personal needs of every patient. Sometimes, several months are needed to witness clinical improvement in conjunction with the absence of significant drug side effects. Resistant cases can be treated with electroconvulsive therapy (ECT).

One of the major challenges in the treatment of agitated depression is the trouble patients usually have in following medical advice and taking the medication as they are prescribed. Thus, patients need very close supervision by medical personnel.

Prevention

No preventive measures are known, although a good sleep hygiene and a consistent exercise program can be helpful. Compliance to therapy is also important in preventing recurrence of the illness. This includes both compliance to drug treatment and attending therapy sessions.

Patient Information

Agitated depression is a form of major depressive disorder characterized by significant agitation and restlessness. It is thought to be caused by a combination of genetic and environmental factors and tends to afflict middle-aged and elderly individuals. Major depressive disorder is a very common illness. Around 20% of women and 12% of men will suffer an episode of clinically diagnosed depression in their lifetime. Patients with agitated depression tend to complain a lot and show several specific signs and symptoms such as racing thoughts, hand-wringing, shouting outbursts, pacing or hair pulling. To correctly diagnose the disorder, the physician may perform several laboratory and imaging tests to rule out organic causes for the agitation and the depression. Vitamin deficiencies, hormonal imbalances, abnormalities in the vessels of the brain and infectious diseases can also cause similar symptoms. Neuroimaging studies have been very helpful in delineating certain abnormalities in the brain associated with agitated depression and major depressive disorder in general, but their clinical use remains limited. Treatment of agitated depression is best performed through a combination of drugs and psychotherapy. A number of medication agents can be used, such as antidepressants, sedatives and other drugs used to treat seizures and psychotic episodes (a psychotic episode is defined as an episode characterized by a detachment of the patient from surrounding reality). Individuals affected from agitated depression need more time to recover than patients diagnosed with an episode of non-agitated depression, although both groups have similar outcomes after 5 years of initial diagnosis. It is important to note that patients should do their best to adhere to the medication regimen proposed by the physician. This is often difficult because of the associated agitation and restlessness, thus requiring close supervision from medical staff.

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References

  1. Mohr P, Volavka J. Ladislav Haskovec and akathisia: 100th anniversary. Br J Psychiatry. 2002 Dec;181:537.
  2. Akiskal HS, Benazzi F, Perugi G, Rihmer Z. Agitated "unipolar" depression re-conceptualized as a depressive mixed state: implications for the antidepressant-suicide controversy. J Affect Disord. 2005 Apr;85(3):245-258.
  3. Rice F. Genetics of childhood and adolescent depression: insights into etiological heterogeneity and challenges for future genomic research. Genome Med. 2010 Sep 20. 2(9):68.
  4. Klerman GL. The current age of youthful melancholia. Evidence for increase in depression among adolescents and young adults. Br J Psychiatry. 1988 Jan. 152:4-14.
  5. Gershon ES, Hamovit JH, Guroff JJ, Nurnberger JI. Birth-cohort changes in manic and depressive disorders in relatives of bipolar and schizoaffective patients. Arch Gen Psychiatry. 1987 Apr. 44(4):314-319.
  6. Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry. 2007 Mar. 64(3):327-337.
  7. Alexopoulos GS. Depression in the elderly. Lancet. 2005 Jun 4-10. 365(9475):1961-1970.
  8. Mayberg HS, Liotti M, Brannan SK, et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry. 1999 May. 156(5):675-682.
  9. Kempton MJ, Salvador Z, Munafò MR, et al. Structural neuroimaging studies in major depressive disorder. Meta-analysis and comparison with bipolar disorder. Arch Gen Psychiatry. 2011 Jul. 68(7):675-690.
  10. Sacher J, Neumann J, Fünfstück T, Soliman A, Villringer A, Schroeter ML. Mapping the depressed brain: A meta-analysis of structural and functional alterations in major depressive disorder. J Affect Disord. 2011.
  11. Mario M, Raffaele P, Lorenza M, Luca B. Agitated Depression in Bipolar I Disorder: Prevalence, Phenomenology, and Outcome. The American Journal of Psychiatry. 2003; 2134-2140.
  12. Benazzi F, Koukopoulos A, Akiskal HS. Toward a validation of a new definition of agitated depression as a bipolar mixed state (mixed depression). Eur Psychiatry. 2004;19(2):85-90.
  13. Tutus A, Kibar M, Sofuoglu S, Basturk M, Gönül AS. A technetium-99m hexamethylpropylene amine oxime brain single-photon emission tomography study in adolescent patients with major depressive disorder. Eur J Nucl Med. 1998;25(6):601-606.

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