Major depression/depressive disorder animal models

Francis PT, Pangalos MM, Bowen DM Animal and drug modelling for Alzheimer synaptic pathology. Prog Neurobiol 39 517-545, 1992 Frank E, Kupfer DJ, Perel JM, et al Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry 47 1093-1099, 1990 Frank E, Prien R, Jarrett RB, et al Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Arch Gen Psychiatry 48 851-855, 1991... 

Extensive studies on bupropion, including animal models of depression, have demonstrated that the desired inhibition of dopamine and norepinephrine reuptake resides mainly with radafaxine (that is the (S,S)-enantiomer, 2a). Furthermore, these studies confirmed that the (R,R) -enantiomer, 2b, is associated with a number of the known related undesirable side effects. Hence, development of radafaxine hydrochloride was undertaken for the treatment of Major Depressive Disorder (MDD) as a stand-alone New Chemical Entity (NCE). Furthermore, owing to the undesirable side effects associated with the (R,R)-enantiomer 2b, levels of this compound were to be controlled to <0.5% to minimize these effects. 

In the learned helpless model, animals (usually rats) are subjected to a brief (l-2h) inescapable shock. Subsequently, they are tested in a task in w hich they can terminate the shock by an operant response. Animals w ith prior inescapable shock exposure do not perform as w ell in the test (Maier and Watkins, 2005). Advantages of the learned helplessness model include its use in studies of neurochemical changes, and that it responds to repeated, rather than acute, antidepressant drug adminish ation. Disadvantages of the model include its dependence on acute stress adminish ation, suggesting it may better model posthau-madc stress disorder than major depressive disorder. 

In summary, many animal of models depressive disorders have been developed, each w ith relative advantages and disadvantages (Nestler et al., 2002). The validity of these models for human depressive disorders continues to be the subject of debate. Probably, this reflects the lack of comprehensive data on the molecular pathophysiology, genetic etiology, and relation to stress in human major depressive disorder. 

Bipolar disorder is characterized by episodes of mania or hypomania, which include hyperactivity, decreased need for sleep, and a euphoric or irritable mood. Additionally, persons with bipolar disorder may have episodes of depression similar to those seen in major depressive disorder. The lifetime prevalence of severe bipolar disorder is about 1% and 3-5% if milder cases are included, afflicting men and women equally. Both bipolar disorder and major depressive disorder tend to be episodic, and in the periods of time between episodes, persons may experience few or no symptoms. The etiology of bipolar disorder is predominately genetic, with a 70% concordance in monozygotic twins. The neurobiology of bipolar disorder is less well understood, and few animal models have been developed. Treatment of bipolar disorder usually involves mood stabilizer medications, including lithium, and the anticonvulsants valproate and carbamazepine. At times, antidepressant and antipsychotic medications are also used. 

The above project represents a novel approach and a possible new treatment for psychiatric disorder. The possibility that neuronal discharge short of total brain convulsion may have psychiatric effects would be a major advance in understanding the action of ECT. Moreover, a possible substitute treatment for ECT would be a major clinical breakthrough. TMS might allow us to stimulate deep brain regions without convulsions, pain, or known hazards. Before one widens the use of TMS in humans, further evaluation of the effectiveness of TMS in animal models for depression is necessary. Our hypothesis is that ECT exerts its therapeutic effects by stimulation of specific brain regions. We suggest that TMS may exert therapeutic effects without need for total brain convulsion. 

The inability to gain pleasure from normally pleasurable experiences was a concept first identified in the 1890s, then ignored before being more recognized from the 1980s as a major symptom of depression and other disorders. There are now animal models of anhedonia reported. (See http //www.biopsychiatry.com/anhedonia.html)... 

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