Should the term ‘antipsychotic’ be changed to ‘multidimensional stabiliser’ in bipolar disorder? Towards a new denomination for ‘atypical antipsychotics’

Do the atypical antipsychotics need a new classification?

The treatment of bipolar disorder (BD) has evolved significantly with the introduction of the ‘atypical’ antipsychotics. Prior to this, for approximately 40 years, the treatment of BD was based on mood stabilisers and anticonvulsants, such as lithium or carbamazepine, for both acute episodes and prophylaxis. Depressive states were managed by combining antidepressants (AD) and mood stabilisers, but unfortunately AD use has been associated with switching to hypomania or mania, or with an increase of rapid cycling in the long term, particularly with tricyclic antidepressants (TCAs) (Mundo et al., 2006). ‘Classical’ antipsychotics were used for patients experiencing acute manic episodes, alone or in combination with mood stabilisers (Sachs et al., 2002). In the last 15 years, however, new compounds such as olanzapine, quetiapine, aripiprazole, risperidone and ziprasidone have been approved by the Food and Drug Administration (FDA) and, with few exceptions, by the European Medicines Agency (EMEA), for the treatment of BD.

The emergence of these compounds has drastically changed the landscape of BD treatment, since these novel molecules show good efficacy in both acute and maintenance phases, almost comparable to that of mood stabilisers (Altamura et al., 2011; Malhi et al., 2011). They have little in common with ‘classical’ antipsychotics and offer an alternative to established treatments, both as monotherapy and in combination, in both acute and long-term therapy. This broad action suggests that the term ‘antipsychotic’ may be outdated, ill-suited and misleading as a definition of the activity of ‘atypical’ compounds in BD. This finding parallels our experience in schizophrenia, where the ‘atypical’ antipsychotics have both led to new and innovative neurochemical hypotheses (beside the dopaminergic model) and proven to be effective in different psychopathological dimensions (Altamura, 1996, 2011). Their broad spectrum of activity on different dimensions of schizophrenia (psychotic, negative, affective, disorganised and impulsive) seems to be linked to their broader pharmacodynamic profile, in stark contrast to the dominant D₂ antagonism (and predominantly antipsychotic effect) of the drugs introduced in the 1950s, 60s and 70s. Accordingly, in BD they also act on different psychopathological dimensions and help in reaching an optimal clinical response, particularly when combined with other agents. We will briefly review these novel antipsychotics and their therapeutic activity, both in monotherapy and in combination with mood stabilisers, in the different phases of BD.

Mania

D₂ antagonist antipsychotics were used in monotherapy or in combination with mood stabilisers for many years to achieve rapid control of acute manic symptoms (Gelenberg and Hopkins, 1996), but their efficacy appeared limited, and they were often poorly tolerated (Sachs et al., 2002) due to sedation or extrapyramidal symptoms (EPS). For these reasons, ‘atypicals’ have become first-line treatments for manic episodes, alone or together with mood stabilisers. A recent comprehensive meta-analysis found that antipsychotic drugs were much more effective than mood stabilisers in controlling manic symptoms and that, within the antipsychotic class, olanzapine and risperidone were superior in efficacy and acceptability to older compounds other than haloperidol (Cipriani et al., 2011). In light of these findings, the same group suggested a revision of the clinical practice guidelines that currently support lithium, divalproex, olanzapine, risperidone and other second-generation antipsychotics (SGAs), both in monotherapy and in combination, as first-line treatments for mania (Canadian Network for Mood and Anxiety Treatments, CANMAT) (Yatham et al., 2009). The use of haloperidol, despite its good antimanic effect (Cipriani et al., 2011), remains controversial due to apparently poor efficacy in preventing depressive phases and the likelihood that it may even precipitate them.

Mixed state

Mixed states often respond poorly to monotherapy with mood stabilisers (Dunner, 2005), and patients suffering from mixed episodes tend to have a poorer outcome on lithium when compared to those with only manic or depressive phases. To date, there is a lack of controlled studies regarding mixed episodes and their treatment. However, owing to the complexity of mixed episodes, monotherapy is often insufficient and many patients require combination treatment. There is also some consensus about discontinuing antidepressants in mixed states, due to fears they may worsen symptomatology and increase suicide risk. ‘Atypical’ antipsychotics and divalproex are thus recommended as first-line treatment in mixed states (McIntyre, 2008). Recently, asenapine was found to be effective in bipolar I disorder patients experiencing acute manic or mixed episodes with clinically relevant depressive symptoms at baseline (Szegedi et al., 2011; Azorin et al., 2013).

Depression

Bipolar depression, the most common phase of BD, causes significant morbidity and mortality. Traditional drugs such as lithium, lamotrigine or AD each offer some clinical efficacy; however, this can be limited and side effects are sometimes problematic. Furthermore, it is important to note that AD treatment can cause acute mania and induce long-term rapid cycling, which can lead to a gradual worsening of the course of the illness. STEP-BD (Sachs et al., 2007), the first randomised discontinuation study with AD, not only showed that AD treatment produced no statistically significant symptomatic benefit in long-term management of BD, but that it also failed to prevent depressive episodes or improve remission rates (Ghaemi et al., 2010). There is, therefore, a major unmet need for effective, well-tolerated agents for the treatment of bipolar depression.

Data are now emerging to suggest that some ‘atypicals’ may also be effective in the treatment of the depressive phase of BD, although there are important efficacy and tolerability differences between agents. Quetiapine has been approved as first-line monotherapy for bipolar depression, and has demonstrated efficacy in treating depressive symptoms without increasing risk of treatment-emergent mania (Keating and Robinson, 2007). Furthermore, quetiapine is often used to treat unipolar depression and anxiety disorders, even if its use in these presentations is currently off label (Ravindran et al., 2010). The effect on depression and anxiety has been related to the activity of norquetiapine, the major metabolite of quetiapine, and with the plasma norquetiapine to quetiapine ratio (Altamura et al., 2012). Quetiapine’s broad use in bipolar and unipolar disorder, as well as in anxiety disorders, appears to be emblematic of the originality and eclecticism of ‘atypical’ antipsychotics in comparison to older agents, and likely reflects their broader pharmacodynamic profile (Altamura et al., 2008, 2011).

Long-term treatment

In the past, neuroleptics have been used for maintenance of bipolar patients, but their profile is more suited to the treatment of formal psychotic symptoms rather than mood-related symptoms. Moreover, they are associated with severe side effects and frequent depressive episodes (Ahlfors et al., 1981). Conversely, numerous reports have shown that atypicals may have specific prophylactic mood-stabilising capabilities, possibly based on their action on more neurotransmitter receptor types than older compounds – in fact, olanzapine, quetiapine, aripiprazole and asenapine seem to be effective in maintenance treatment, exhibiting both antimanic and antidepressant action. They also have a more favourable side-effect profile than older agents, and good efficacy on overall functioning. Although some data suggest these drugs are imperfect as monotherapy for maintenance of BD (Malhi et al., 2011), the majority of studies examining combination with ‘classical’ mood stabilisers has shown that this combination performs well when compared to monotherapy with lithium/valproate or antipsychotics (Citrome, 2010; Suppes et al., 2009). Finally, long-acting injectable risperidone has good efficacy in the long-term treatment of BD, both as an adjunctive treatment and in monotherapy, and this is present even in rapid cycling patients (Quiroz et al., 2010).

Towards a new denomination for atypicals

The term ‘antipsychotic’ therefore appears to be obsolete and misleading, in both BD and schizophrenia (Altamura, 2011). It does not explain the profile of these drugs in comparison with older compounds, with respect to both shared features and differences. Importantly, a psychotic dimension is not always present in BD and is not the main target of treatment. Whereas D₂ antagonists act mainly on delusional and hallucinatory symptoms, serotonergic, glutamatergic and GABAergic pathways are more likely to be involved in eliciting full-blown manic and depressive syndromes. As Malhi et al. (2011) recently stated, from a pharmacological perspective, ‘it is quite possible that atypicals are not just antipsychotics and that their actions are indeed much broader. … Further, some atypicals have managed to use bipolar disorder as a stepping stone to gain indications for the treatment of major depression and generalized anxiety (e.g. quetiapine).’

On the other hand, ‘atypical’ is a vague term which expresses little beyond a difference to ‘typicals’, but exactly ‘what’ this difference is remains unclear, and we can hardly define a next generation of drugs as atypical to atypicals. If this nomenclature fits with only one dimension of schizophrenia (namely psychosis), for BD it seems even more tenuous, as psychotic features are not a necessary component of bipolarity.

These compounds are effective in BD and approximate the efficacy of ‘classical’ mood stabilisers in maintenance and prophylaxis of manic and depressive states, in stark contrast to older compounds. New data have confirmed their efficacy, both as monotherapy and in synergistic combination with mood stabilisers (Yatham et al., 2009). This may in turn indicate a broad action on multiple dysfunctional neurochemical pathways compared to the ‘pure’ dopamine antagonists.

Moreover, the term ‘antipsychotic’ carries stigma, and, as prescribers, many of us commonly encounter BD patients who dislike being prescribed drugs for ‘psychosis’ or ‘schizophrenia’ and react against the implications of a terminologically loaded label for the drug. Changing the nomenclature of this class of drugs therefore has the potential to improve compliance, and thus long-term prognosis. As suggested for schizophrenia, a new name for this heterogeneous class of drugs should highlight their ability to act on different dimensions, both in schizophrenia and in BD. On the other hand, there is not yet enough evidence to classify them as mood stabilisers, for the reasons clearly outlined by Malhi et al. (2011), and thus they should be kept in a different class from classical mood stabilisers. ‘Multidimensional stabilisers’ thus seems to be a suitable name that would help to overcome the stigma associated with the label of ‘antipsychotic’.