Bipolar disorder (BD) has a complex and variable clinical picture which is characterized by many different phacets and phases and as a result its therapeutical options are also complex and often unsatisfactory. Typically the so-called "mood stabilizers" are used in the treatment of BD and in this class lithium and specific antiepileptics are included. The present study aimed to systematically review the literature concerning the presence of randomized double blind clinical trials of 'non conventional' pharmaceutical treatment options. The present systematic review utilized the PRISMA method and searched the MEDLINE through January 1st 2015 with the use of appropriate key words. In order to identify randomized controlled trials- RCTs a combination of the words "bipolar", "manic", "mania", "manic depression" and "manic depressive" with "randomized" was used. Webpages with lists of trials were also searched including http://clinicaltrials.gov and http://www.clinicalstudyresults.org as well as the official webpages of all pharma companies with products marketed in the treatment of BD. The reference lists of various review papers were also searched. The MEDLINE was searched with the combination of the words "guidelines" or "algorithms" with "mania", "manic", "bipolar", "manicdepressive" or "manic depression" in order to identify articles with treatment guidelines. The reference list of these articles were also scanned. From 3,284 papers which were initially traced, only 47 papers were included in the present study. From those agents studied in acute mania, tamoxifen is efficacious as monotherapy and as combination therapy with lithium and other mood stabilizers, however its safety profile is relatively poor. Allopurinol manifests efficacy in combination with lithium but not with other agents and its safety profile is satisfactory. Methoxyprogesterone is efficacious in combination with mood stabilizers and its safety profile is very good. In acute bipolar depression the combinations of FEWP with carbamazepine and ketamine, modafinil, pramipexole, pregnenolone and maybe armodafinil with mood stabilizers are efficacious. The safety profile of these combinations is medium. The use of celecoxib, lisdexamfetamine and memantine have negative data. Concerning the maintenance treatment, the data are negative for memantine and for Nacetylcysteine. Although most of the data concerning the usefulness of "non-conventional" pharmacotherapeutic agents in the treatment of bipolar disorder are negative, it is encouraging that those agents who have been proven efficacious probably exert their therapeutic effect through pathways which differ from usual and probably different from those classically considered in most biological models of bipolar illness. In this way there constitute new paradigms and open new horizons in the understanding of the disease.