A lot of experience has been gathered relating to the use of medication in the treatment of bipolar disorder (BD), both in handling acute mania and depression, and in the prophylactic of affective relapses in this illness. Research into the mechanisms behind the drugs efficacious in the therapy of various phases of bipolar disorder have prompted the search for new agents with similar effect, which could be used in the treatment of this illness. New medication may be also developed based on our better knowledge of pathogenetic mechanisms. This paper presents a review of some of the medication, which can be useful in the future, in the treatment of various phases of bipolar disorder, i.e. acute depression, acute mania and prevention of relapses of affective episodes. Although the treatment of depression in bipolar disorder varies from the therapy of unipolar depression, any progress in the treatment of depression has direct implications for the therapy of this phase of BD.
One of the most important events relating to the pharmacological treatment of depression in the recent years was the discovery of rapid antidepressant effect of a single ketamine infusion. Ketamine is a derivative of phencyclidine, used to induce anesthesia, the so-called "dissociative anesthesia", and it acts as an NMDA (N-Methyl-D-aspartate) glutamatergic receptor antagonist. The first observations of the efficacy of ketamine in the treatment of depressive episodes were reported in 2000; four patients with depression benefited from its rapid antidepressant effect, which was maintained for approximately two weeks, after receiving ketamine in a 40-minute intravenous infusion, at a dose of 0.5 mg/kg of body weight (Berman et al., 2000). Six years later Zarate et al. (2006) conducted another trial using a double-blind placebo-controlled method in a group of 17 patients with drug-resistant depression, and observed a remission of symptoms in 29% of patients and reduction of symptoms in 71% of patients, within 24 hours after the ketamine infusion. Around 35% of patients maintained the state of clinical improvement after 1 week. It was also proven that the ketamine infusion reduced suicidal thoughts and intent. The effect appeared after a few hours and was maintained up to 10 days (Price et al., 2009; Larkin and Beautrais 2011). Diazgranados et al. (2010) used a ketamine infusion in a double-blind placebo-controlled sample of 15 patients suffering from depression in BD, additionally to mood stabilisers (lithium and valproate). 71% of patients showed improvement maintained up to the fourteenth day. The difference with the placebo group was already demonstrated on the second day after the infusion. These results were replicated by Zarate at al. (2012), who demonstrated an improvement in 12 out of 15 patients (79%), maintained up to the fourteenth day after the ketamine infusion.
The results of the first Polish research into the effects of a single ketamine infusion have been also published recently, investigating 25 patients (21 women, 4 men), aged 27 to 67 with depression in the course of bipolar depression. They all received at least one first or second generation mood stabilizer (Rybakowski 2007), and had been previously unsuccessfully treated with antidepressants. Once antidepressants were discontinued for at least 7 days, a single ketamine infusion (0.5mg/kg of body weight) was administered. A psychometric evaluation was carried out with the use of 17-item Hamilton Depression Rating Scale (HDRS) immediately before the infusion, and also after 6, 12 and 24 hours and 3, 7, 10 and 14 days after the infusion. Average severity of depression before ketamine infusion was at 21 ± 5 points (HDRS scale); 6 hours after the infusion it was reduced to 19 ± 8, on day 2 to 16 ± 9, on day 7 to 12 ± 7, and day 14 to 11 ± 7 points. The improvement of mental condition (reduced HDRS score by ≥ 50%) occurred in 1 patient after 6 hours, in 25% of patients after 24 hours and in 52% of patients after 7 and after 14 days. Four patients reached remission (≤7 points in HDRS) on the second day after the infusion, eight patients after seven days and twelve after 14 days. Ketamine infusion was altogether well tolerated (Permoda-Osip et al., 2012).
In the recent years attempts have been made to use multiple ketamine infusions to achieve more permanent improvement (Rasmussen et al., 2013), alongside the research into clinical and biochemical factors which determine the effectiveness of a single ketamine infusion. American researchers demonstrated better effects of ketamine treatment in depression which occurs in bipolar disorder in the case of patients whose family history revealed the presence of alcoholism. (Luckenbaugh et al., 2012). We have also confirmed the presence of such correlation in our sample (Permoda-Osip et al., 2013). Among the biological factors associated with the effect of single ketamine infusion in bipolar depression, we have managed to determine its relationship with the changes in the serum levels of brain-derived neurotropic factor - BDNF (Rybakowski et al., 2012) and with initial serum vitamin B12 level (Permoda -Osip et al., 2013).
Efforts have been also made to utilise drugs of a profile similar to ketamine. Traxoprodil an NMDA receptor, NR2B subunit selective antagonist has demonstrated neuroprotective, analgesic and anti-Parkinsonian effects in animal studies. Research into the use of traxoprodil effect in the treatment of depression has revealed similarities with the effect of ketamine. Preskorn et al. (2008) reported rapid improvement of patients with depression, previously treated with poor results with serotonin reuptake inhibitors, after a traxoprodil infusion. In fact, one third of their patients displayed symptoms of remission on the fifth day after the infusion. So far there has been no other data available on replication of this effect. Some Italian authors suggest using a similar substance, metoxidine, which apart from blocking NMDA receptors, acts on the reuptake of neurotrasmitters, opioid receptors and sigma receptors (Coppola and Mondola 2013).
Memantine is an uncompetitive NMDA receptor antagonist and a neuroprotective agent. It has been used for a few years now in the pharmacological treatment of Alzheimer's disease. In their recent review Lu et al. (2012) discussed the pharmacological properties of memantine and clinical experience with it so far, and indicated that it could be useful in the treatment of bipolar disorder, especially type two (BD-II). There is also a corresponding pre-clinical research in which memantine yielded antimanic results in animal studies (Gao et al., 2011). In 2006, Brazilian researchers reported on two patients with drug resistant bipolar disorder, whose treatment, enriched with memantine, produced rapid antidepressant and pro-cognitive effect (Teng and Demetrio 2006). Koukopoulos et al. (2012) added memantine in 10-30mg doses to treatment with mood stabilisers of 40 patients with drug resistant bipolar disorder. The annual follow-up showed a significant improvement in mood stabilization in 73% of patients, even in those with rapid change of phases. Also noteworthy is a recent study by American authors, in which they claimed the potentiation of lamotrigine, used in bipolar depression, by memantine (Anand et al., 2012).
Structurally close to memantine is amantadine which, apart from blocking the NMDA, has anti-Parkinsonian action (stimulation of the dopaminergic system) and antiviral properties. Researchers from a Polish Krakow-based centre demonstrated its efficacy in potentiating the effect of imipramine in patients with treatment-resistant depression (Rogóż et al., 2007).
Tamoxifen is primarily used in the treatment of breast cancer because of its impact on the estrogen receptor. It is also a specific inhibitor of protein kinase C (protein kinase C - PKC), an enzyme associated with the system of phosphatidylinositol (PI) regulating synaptic transduction and many cellular processes. Neurobiological research demonstrated an excessive PKC activity in the brain of bipolar patients (Wang and Friedman 2001), whereas one of the recent genome-wide association studies (GWAS) revealed a relationship between predisposition to bipolar disorder with the gene of diacylglycerol kinase eta (DGKH), an enzyme related with the activity of the PI system and PKC (Baum et al., 2008). Lithium inhibits PKC activity by reducing phosphorylation of MARCKS (Myristoylated alanine-rich C-kinase substrate); a similar effect is also displayed by another first generation mood stabilizing drug - valproate (Quiroz et al., 2010).
Attempts to use tamoxifen in patients with bipolar disorder are linked with the fact that it is the only specific PKC inhibitor that passes through the blood-brain barrier. Note that in experimental conditions, the concentration of tamoxifen required for inhibiting the PKC activity is very high (10-20μM), which is not achieved in the clinical setting. The first research into the effectiveness of tamoxifen used in 40-80mg/day in the treatment of manic patients was carried out by Bebchuk et al. in 2000. The results indicated an improvement (reduction of symptom intensity by 50% or more in the Young Mania Rating Scale) after, on average, 8 days of treatment in 5 out of 7 treated patients. Another research, published in 2006, demonstrated beneficial effects of tamoxifen in the treatment of women in mania, in the dose of 40mg, used in addition to lithium and valproate (Kulkarni et al., 2006). Zarate et al. (2007) carried out a double-blind study, using tamoxifen in the dose 20-140mg/day in 16 patients in the manic state, and demonstrated a significant therapeutic effect after only 5 days of treatment which was maintained for three weeks. Turkish researchers, on the other hand, conducted a controlled placebo research of 66 patient in the state of mania, and showed a significant difference between tamoxifen and the placebo after three weeks of treatment. Severity of symptoms in the first group was reduced on average by 5.8 points/week (according to the Young scale), whereas it increased on average by 1.5 point a week in the placebo group (Yildiz et al., 2013). Iranian authors demonstrated that adding tamoxifen to the lithium treatment in the dose of 80mg/day significantly increased the effectiveness of lithium in the treatment of acute mania (Amrollahi et al., 2011). In the recent CANMAT (Canadian Network for Mood and Anxiety Treatments) recommendations, tamoxifen has been mentioned as a possible addition to mood stabilisers for treating mania (Yatham et al., 2013).
New atypical antipsychotics
Atypical antipsychotics, such as clozapine, olanzapine, quetiapine, aripiprazole and risperidone were initially introduced in the treatment of schizophrenia, yet further clinical studies demonstrated their essential properties as mood stabilizers, so they have been also recognized as second generation mood stabilizers (Rybakowski 2007, 2008; Quiroz et al., 2010).
We can assume that the mood stabilizing effect of these drugs is related, apart from their impact the dopaminergic system, with their varied effect on the serotonergic and other neurotransmitter systems. In the recent years, researchers demonstrated opportunities offered by mood stabilizing drugs in relation to other atypical antipsychotics available in Poland, such as ziprasidone, asenapine and paliperidone, and lurasidone marketed in the USA. It has been demonstrated that all these drugs have antimanic properties, whereas clinical experience has shown that some of them can be of possible prophylactic and antidepressant use in bipolar depression.
Ziprasidone acts as an antagonist on dopamine receptors D2, serotonin receptors 5-HT1D, 5-HT2A, 5-HT2C and agonist on 5-HT1A receptors. It also blocks the reuptake of serotonin and noradrenaline (Rzewuska 2012). The antimanic effect of ziprasidone monotherapy was demonstrated in a placebo-controlled study 10 years ago (Keck et al., 2003), and confirmed in subsequent research (Potnik et al., 2005). Manic states may be also lifted by ziprasidone injections with short-term effect. However, recently Sachs et al. (2012) failed to confirm any beneficial effect of adding ziprasidone to lithium or valproate treatment of acute manic states, even though CANMAT still recommends ziprasidone monotherapy as the first line treatment of acute mania (Yatham et al., 2013).
The results of a six-month research into adjunctive ziprasidone therapy, where ziprasidone was used alongside lithium and valproate in the maintenance of bipolar disorder were published last year. This procedure was assessed as notably effective in reaching remission of the illness and maintaining it (Pae et al., 2012). In the recent guidelines CANMAT recommends adding ziprasidone to mood stabilisers as a significant option in the pharmacological prophylactics of BD (Yatham et al., 2013).
However, our hopes as to the beneficial effects of ziprasidone in the treatment of bipolar depression turned out to be unfounded, in spite of the fact that they were well rooted in its pharmacological profile. Recent evaluation of two controlled studies gave no grounds for thinking of ziprasidone as useful in the treatment of bipolar depression (Lombardo et al., 2012).
Asenapine acts as an antagonist on dopamine (D1, D2, D3, D4), serotonin 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6 and 5-HT7, histamine H1H2 and adrenergic α1 α2 receptors and agonist of 5-HT1A receptors (Shahid et al., 2009). It is used in the form of 5 and 10 mg sublingual tablets. Therapeutic effect of asenapine in a dose of 10-20 mg/day in the manic and mixed manic states has been very well documented in controlled studies. Asenapine turned out to be significantly more effective than the placebo and similarly effective to olanzapine, as demonstrated by both the 3-week and 12-week studies (McIntyre et al. 2009a, 2009b). In the CANMAT recommendations asenapine is listed as the first-line treatment for mania, both in monotherapy and in addition to mood stabilizers (Yatham et al. 2013). It has been also registered for the treatment of manic states in Poland.
Asenapine has been also proven effective in a long-term (52 weeks) treatment in the prophylactics of BD relapses (McIntyre et al., 2010). Its use in monotherapy or in adjunctive therapy, has been recommended in the recent CANMAT guidelines as the third-line therapy (Yatham et al., 2013).
Encouraging results have been also reached regarding the antidepressant activity of asenapine in bipolar disorder. The retrospective analysis into the effectiveness of asenapine in the treatment of bipolar mania Szegedi et al. (2011) demonstrated its significant antidepressant effect in patients who initially displayed the symptoms of depression.
Paliperidone, similarly to risperidone, is an antagonist of dopamine receptors D2 and serotonin receptors 5-HT2A. It also blocks serotonin receptors 5-HT7 and adrenergic α1 (Rzewuska 2012). Its main use is in the long-acting formulation (paliperidone palmitate) which has an advantage over injections of long-acting risperidone, as it is indicated for once-monthly dose without the need to take the medication orally in the initial phase. Long-acting paliperidone has been proven to be effective in the treatment of mania at a dose of 9-12mg/day in monotherapy (Bearwaerts et al., 2012; Vieta et al., 2010), and also as added to lithium or valproate (Bearwaerts et al., 2011). In this context paliperidone has been recommended as primary treatment in the recent CANMAT guidelines (Yatham et al., 2013) However, new publications are expected in the near future analysing the long-term use of paliperidone in bipolar depression, as monotherapy or in adjunctive treatment with mood stabilisers.
Lurasidone acts as antagonist of dopamine receptors D2, serotonin receptors 5-HT2A, 5-HT2C and 5-HT7 and adrenergic receptor α2. It was first introduced on the US market in 2010 for the treatment of schizophrenia. Lurasidone is commonly used in the doses of 40-160mg/day. When it comes to its possible use in bipolar disorder, it has a confirmed antidepressant effect on bipolar depression (20-120mg/day) both in monotherapy (Ketter et al., 2013), and also when used with lithium and valproate (Calabrese et al. 2013). In this context lurasidone has been recommended as second-line therapy in the recent CANMAT guidelines (Yatham et al., 2013).
It is without a doubt that the most important antidepressant of novel mechanism, introduced to psychiatry in the first decade of the 21st century, has proven to be agomelatine, developed in the laboratories of the pharmaceutical company Servier. Agomelatine acts through melatonergic mechanism with an effect on melatonergic receptors M1 and M2 with an inhibiting effect on serotonin receptors 5-HT2C. It proved to be effective both in a short- and long-term therapy of depression, without major side effects, such as increased body weight, discontinuation effect and disturbed sexual function. Recent study of the efficacy of combining agomelatine, in a dose of 25mg/night, with lithium or valproate, in 28 patients with bipolar depression has demonstrated a beneficial therapeutic effect after six weeks. If continued for eight months, the treatment significantly improved sleep disturbance and contributed to the loss of body weight (Fornaro et al., 2013).
Apart from the medication mentioned at the beginning of this paper i.e. ketamine and memantine, it is probably useful to mention the results of experiments with other antidepressants which are modulators of the glutamatergic system. Riluzole, a drug used in the treatment of amyotrophic lateral sclerosis, acting on the glutamatergic system by stimulating the glumatergic receptor AMPA (alfa-amino-3 hydroxy-5-methylisoxazole-4-propionic acid). The antidepressant effect of riluzole in bipolar depression is associated with an increase in N-acetyl aspartate in the anterior cingulate (Brennan et al., 2010). Among other substances whose activity on the glutamatergic receptor AMPA can be linked with antidepressant effect are D-cycloserine, which is a partial agonist of the NMDA receptor, associated with its glycine place. Heresco-Levy et al. (2013) have recently demonstrated the potentiation by this drug of the efficacy of antidepressants in patients with drug-resistant depression.
We should also mention the important role of zinc and magnesium ions in the pathogenesis of affective illnesses, particularly of depression. Serum concentration of these ions is lower in the depression phase but it responds to antidepressant treatment. Zinc and magnesium ions modulate glutamatergic system through their binding sites on the NMDA receptor. Research into zinc supplementation showed a reduction of depressive symptoms in patients treated with clomipramine, amitriptyline, citalopram and fluoxetine and in the imipramine treatment of drug-resistant depression (Nowak et al., 2003; Siwek et al., 2009). Apart from blocking the NMDA receptors, zinc and magnesium cause modulation of the AMPA receptors, stimulation of serotonin neurotransmission, inhibition of glycogen synthase kinase (GSK-3) and activation of the BDNF system, which may also play a role in their antidepressant effect (Szewczyk et al., 2008). Further studies will show whether these findings can also apply to depression in bipolar disorder.
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