Augmentation strategies in depression has also been shown to enhance synaptic availability of approximately 4000 depressed patients will begin treatment noradrenaline using in vivo extracellular unitary recordings with citalopram at doses up to 60 mg per day. If there is an (Szabo and Blier 2002). Many atypical antipsychotics also inadequate response, they will be randomly assigned to a possess 5-HT1A receptor agonist properties. It is possible variety of treatment options: alternative SSRIs (sertraline), that this characteristic may play a role especially when SNRI (venlafaxine), cognitive therapy alone, or continuation associated with an increase in the release of noradrenaline citalopram with the addition of cognitive therapy, buspirone, and dopamine in the prefrontal cortex when antipsychotics or bupropion augmentation. In case of no response, the next are combined with the SSRIs (Papakostas et al 2004). Conclusion Approximately, eight classes of antidepressants acting by distinct pharmacological mechanisms including over 20 compounds are available to the clinician for the treatment of depression. The potential combination of any two compounds is therefore high, which makes for a very impressive armamentarium to treat depressed patients who do not respond to antidepressant monotherapy. The exact nature of the depressive disorder and the type of symptoms can guide the clinician in choosing the first treatment. The use of an algorithm can also provide help for adapting and managing the best combination for a given individual. Certain combinations such as a MAOI with a drug that blocks serotonin reuptake should never be used because of the high risk of inducing a serotonin syndrome (Bijl 2004). Unfortunately, some combinations and most augmenting strategies are often based on case reports, very small, open pilot trials, or even anecdotal findings, which would merit replication in larger controlled trials. A summary of combinations and augmentations presented here is given in Table 2. Lithium, thyroid hormone, and buspirone, which have been used for a long time, have been the three most studied combinatory agents. Some of the newer compounds are promising since they provide ways of boosting neurotransmission or reducing negative adverse effects allowing increased doses of the accompanying anti- depressant. The increased use of this panoply of drug combinations will hopefully make it easier for clinicians to overcome the treatment-resistant depression and reach full recovery in a larger number of patients. The problem is that there is a lot of rather unstructured data suggesting benefit from various approaches, but there are very few comparisons between these approaches. The National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression (STAR*D) program is an ambitious research initiative that is intended to generate a much needed treatment algorithm (Lavori et al 2001; National Institute of Mental Health 2003; Rush et al 2004). In this study, step of therapy will include switching to nortriptyline or mirtazapine, or augmentation with lithium or thyroid hormone. A final phase for ultimate nonresponders will be random assignment to either tranylcypromine or combined venlafaxine and mirtazapine. Hopefully, this program should provide good comparative data and make the clinician’s choice easier. References Agid O, Lerer B. 2003. Algorithm-based treatment of major depression in an outpatient clinic: clinical correlates of response to a specific serotonin reuptake inhibitor and to triiodothyronine augmentation. Int J Neuropsychopharmacol, 6:41–9. Alpert JE, Papakostas G, Mischoulon D, et al. 2004. S-Adenosyl-L- methionine (SAMe) as an adjunct for resistant major depressive disorder: an open trial following partial or nonresponse to selective serotonin reuptake inhibitors or venlafaxine. J Clin Psychopharmacol, 24:661–4. Altshuler LL, Bauer M, Frye MA, et al. 2001. Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Am J Psychiatry, 158:1617–22. Andrade L, Caraveo-Anduaga JJ, Berglund P, et al. 2003. The epidemiology of major depressive episodes: results from the International Consortium of Psychiatric Epidemiology (ICPE) Surveys. Int J Methods Psychiatr Res, 12:3–21. [APA] American Psychiatric Association. 1994. Diagnostic and statistical manual of mental disorders. 4th ed. Washington: APA. Appelberg BG, Syvalahti EK, Koskinen TE, et al. 2001. Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind, placebo wash-in study. J Clin Psychiatry, 62:448–52. Artigas F, Celada P, Laruelle M, et al. 2001. How does pindolol improve antidepressant action? Trends Pharmacol Sci, 22:224–8. Artigas F, Nutt DJ, Shelton R. 2002. Mechanism of action of antidepressants. Psychopharmacol Bull, 36 Suppl 2:123–32. Ballesteros J, Callado LF. 2004. Effectiveness of pindolol plus serotonin uptake inhibitors in depression: a meta-analysis of early and late outcomes from randomised controlled trials. J Affect Disord, 79: 137–47. Barbee JG, Conrad EJ, Jamhour NJ. 2004. The effectiveness of olanzapine, risperidone, quetiapine, and ziprasidone as augmentation agents in treatment-resistant major depressive disorder. J Clin Psychiatry, 65:975–81. Barbosa L, Berk M, Vorster M. 2003. A double-blind, randomized, placebo- controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes. J Clin Psychiatry, 64:403–7. Bauer M, Adli M, Baethge C, et al. 2003. Lithium augmentation therapy in refractory depression: clinical evidence and neurobiological mechanisms. Can J Psychiatry, 48:440–8. Neuropsychiatric Disease and Treatment 2005:1(4) 307