Pharmacotherapeutic interventions for bipolar disorder type II: addressing multiple symptoms and approaches with a particular emphasis on strategies in lower and middle-income countries

Figures & data

Figure 1. Utilization of psychotropic medicines in Bulgaria in recent years (source: (https://www.nhif.bg/page/218)).

NB: DID = DDDs/1000 inhabitants/day.

Table 1. Current treatment approaches to the management of patients with BD, especially BD-II among LMICs.

Country	Current management approaches
Lower middle-income countries
Ghana	Currently, there is no clear guidance in the STGs for patients with the different types of BD in Ghana, making it difficult for physicians to appropriately diagnose and treat the different types of BD [169].
	At the same time, the Mental Health Act in 2012 de-emphasizes institutional care in Ghana, encouraging greater decentralization of mental health care by enhancing the establishment of services and facilities at the PHC level [29].
	In addition, while some of the first-line medicines recommended for BD-II in international guidelines are listed in the current Essential Medicines List and the National Health Insurance Scheme medicine lists in Ghana, their lack of availability at most PHCs affects their accessibility. The few available alternatives at community pharmacies can be expensive with high co-payments [33].
	The newer generation psychotropic medicines are gradually being prescribed more for patients with schizophrenia and BD; however, there is still considerable prescribing of first-generation antipsychotics as they are inexpensive [33].
India	The Indian psychiatric society has regularly issued CPGs for the management of BD since 2005 in order to improve the care of these patients [90]
	The most recent update, published in 2017, clearly outlined the various treatment options and behavioral therapies for patients with BD [90], which included pharmacological and non-pharmacological interventions as well as ECT.
	Pharmacotherapy is the mainstay of treatment of patients with BD in India, with mood stabilizers used most frequently followed by antidepressants and antipsychotics. Available mood stabilizers include lithium, valproate, carbamazepine, lamotrigine, and topiramate [90]. Unmanageable patients who refuse medications or who have difficulties with adherence to treatment can be prescribed depot preparations of antipsychotics [90].
	A recent observational study found that lithium was the most frequently prescribed mood stabilizer, followed by sodium valproate and carbamazepine [170].
	The main goal of managing bipolar depression is to achieve a normal level of functioning and to avoid switching to hypomanic or manic episode. Typically, lithium and lamotrigine can be used as first-line treatment in patients with bipolar depression, with quetiapine monotherapy also seen as potentially beneficial. ECT may also be considered if the depression is severe [90].
	In their recent survey among psychiatrists in India, Reddy et al. ascertained that for acute depression, there was a preference for a combination of an antidepressant and a mood stabilizer, while ECT is the preferred option to manage severe depression [123]. However, there were concerns with the extent of antidepressants used to treat BP-II, which requires further investigation [123].
Nigeria	Both BP-I and BP-II are seen in Nigeria, with the age of onset in Nigeria similar to other published studies [171].
	There are concerns regarding access to care, although recommended treatments for BP-II are in line with international guidelines and encourage patients to seek help from a psychiatrist [172,173].
	The most common medicines prescribed by psychiatrists for patients with BD are typical antipsychotics either alone or in combination with mood stabilizers [174]. Tricyclic antidepressants were the most prescribed antidepressant in the majority of studies conducted in tertiary hospitals in patients with depressive symptoms, with lower costs if clinicians follow published STGs [175,176].
	There are organizations in Nigeria that encourage greater awareness and treatment of patients with mental health disorders such as the Mentally Aware Nigeria Initiative (MANI) [172], with awareness about BD and its consequences likely to grow following the high profile suicide of the iconic fashion designer Kate Spade [173].
	Issues of polypharmacy and adherence remain as additional critical concerns in the effective management of BD in Nigeria alongside co-payments [39,139,176,177].
Pakistan	The treatment of mental disorders is a continuing concern in Pakistan due to a lack of psychiatrists and trained physicians in addition to the stigma associated with mental disorders [178].
	These issues adversely affect access to appropriate care in Pakistan [54,179], exacerbated by increasing unemployment, disruptions in social norms and a high percentage of the population living below the poverty level [54,178,180].
	Despite concerns, CPGs are being followed in Pakistan for the management of BD including the prescribing of lithium, anticonvulsants, anti-depressants, and anti-psychotics [54].
	Culturally adapted psychoeducation (CaPE) has also been found to be useful for the management of BD in Pakistan [181].
Tunisia	There have been ongoing developments to improve the management of patients with mental health disorders in Tunisia in recent years following the publication of the Tunisian National Strategy for the Promotion of Mental Health in 2013 and the creation of the Committee for Mental Health Promotion in 2015 [11,182].
	More recently, there has been greater training of primary health-care physicians on mental health issues under the WHO mGAP project to address deficits in the provision of specialist services especially with 30–40% of consultations undertaken by primary health-care physicians relating to mental health care [11,26,183]. This should help with greater identification and management of patients with depression and symptoms related to psychosis.
	In their recent study involving 1180 patients with BD across 6 LMICs including Tunisia, Samalin et al. (2016) found that mood stabilizers and antipsychotics were the most common medicines prescribed for patients with BD. BP-I patients received a higher number of antipsychotics and anxiolytics than those with BP-II (p < 0.001), and there was an increase in the prescribing of antidepressants in those BD patients with depressive symptoms (p < 0.001). Overall, the authors found there was an appreciable delay in diagnosis among the participating countries and, as mentioned, an overuse of antidepressants [96].
	There is also still a considerable social stigma associated with schizophrenia and BD in Tunisia, although significantly less for patients with BD [12]. This should be helped by ongoing initiatives under the WHO QualityRights initiative [56].
	Hopefully, the ongoing educational and other programs supported by the Ministry of Health in Tunisia will help improve the management of patients with BD in Tunisia in the future, providing exemplars to other countries.
Zambia	Little appears to have been achieved in Zambia in the management of mental disorders during the past decade due to financial constraints and few mental health practitioners in the country, especially psychiatrists, despite for instance efforts by the University of Zambia offering a Master of Medicine in Psychiatry (MMED), which has suffered from low enrollment.
	However, national STGs and EMLs were developed and approved in 2013 including patients with BD [184,185]. The guidelines discuss bipolar mood disorders including BP-I, however do not differentiate treatment approaches between BP-I, BP-II and those with mixed BD.
	Pharmacotherapy is the recommended mainstay of treatment. According to the STG, modalities for the treatment of mental disorders are based on the biopsychosocial model and associated symptomatology, with the clinical characteristics outlined to provide prescribing guidance [185]
	The STG recommends the use of lithium monotherapy for treatment of mild BP-I, carbamazepine for moderate BD, and sodium valproate in addition to an antipsychotic agent for severe BD associated with psychosis. However, typically in practice sodium valproate is prescribed as first line in view of the lack of facilities to monitor lithium levels.
	The recommended treatment for major depressive disorders in the STG consists of antidepressants, psychotherapy, and ECT or a combination of these [185]. Treatment selection should depend on illness severity, associated features such as rapid cycling or psychosis, and where possible, patient preference [185].
	These medicines are included on the Zambian EML and made available to patients in public health-care facilities [184].
	In practice though, each clinician generally prescribes medicines based on learned experiences either through their practice or from online resources. This is seen from the findings from a recent study assessing adherence to antipsychotic treatment guidelines among prescribers in managing the first episode of psychosis at the largest and only tertiary hospital for in- and out-patients in Zambia. Overall, only 3.2% of physicians prescribed antipsychotics in line with NICE 2014 guidelines [186], and most prescribers seemed unaware of any guidelines and, if available, how to use and interpret them.
	There are also concerns with differentiating between the various BD disorders as most clinicians will use DSM 5 or ICD-10 as a guide.
	As a result, typically BP-II is often misdiagnosed with antidepressants such as amitryptyline prescribed in the majority of cases and later discontinued when patients present with rapid cycling.
Upper-middle-income countries
Botswana	In Botswana, mood stabilizer anticonvulsants available for the management of BD include sodium valproate, carbamazepine, and lamotrigine, with sodium valproate the most widely prescribed mood stabilizer for BD.
	Second-generation antipsychotics available in the public system without co-payment include risperidone, olanzapine, and quetiapine. However, according to current guidance, these medications can only be initiated by a psychiatrist [187].
	Lithium is also available in Botswana to treat BD. However, most patients are rarely started on lithium due to difficulties in laboratory monitoring. Most hospital laboratories, even referral hospital laboratories, do not perform lithium assays.
	Consequently, most patients who present with BD in Botswana PHCs (typically the place for initial diagnosis and treatment) will be started on either sodium valproate (majority) or carbamazepine if initially seen by a psychiatric or general nurse. Lamotrigine is rarely started by nurses. Psychiatrists have a wider choice of medicines available to them.
	As there is also currently no STG in Botswana for the treatment of referred patients, any medicine initiated will currently depend on the psychiatrist’s assessment and preferences.
Brazil	There is a national STG for the treatment and management of BP-I; however, in view of current controversies, there is currently no national STG for BP-II in Brazil [188]. Consequently, in practice, management of patients with BP-II is similar to BP-I, with specific considerations for the type of disorder and characteristics of each patient.
	Pharmacotherapy is seen as fundamental for the treatment of BD although psychological approaches are also important [188]. Since the 1970s, Brazil has initiated ‘Psychiatric Reform’, which encourages the de-hospitalization of patients with mental disorders and increases their treatment in the community with an emphasis on outpatient care, without prejudice to general and psychiatric hospitalization when necessary [189,190].
	For pharmacotherapy of hypomania in patients with BD-II, it is possible for physicians to prescribe lithium, valproic acid, carbamazepine, and haloperidol, and for depression lithium, valproic acid and fluoxetine hydrochloride within the Brazilian public health system without any co-payment [191]
	The choice of treatment will depend on the phase of BD, e.g. acute or maintenance treatment, as well as the history of previous responses combined with the clinical and personal characteristics of the patients.
	Other treatments such as lamotrigine and atypical antipsychotics can be used for patients with BP-II. These medicines can be prescribed through the private sector, i.e. via private insurance, otherwise 100% co-payment; alternatively supplied free-of-charge following a successful judicial review [192]. Currently, just under a quarter of the Brazilian population has private insurance.
Bulgaria	Current antipsychotic treatments for the management of schizophrenia in Bulgaria have improved outcomes for both patients and caregivers, with relatively low readmission rates at 1 year following discharge [193]. Such studies help to negate negative public attitudes that psychiatric treatment is not effective, with implications for improved management of patients with BD.
	Additional studies have shown that the burden of severe mental disorders can be considerable, which policymakers must consider when planning the care of such patients [194].
	There is a mixed utilization pattern with respect to the use of psychotropic medicines for the treatment of mental disorders in Bulgaria (Figure 1).
	The appreciable decrease in the utilization of risperidone in recent years (Figure 1) could be explained by supply concerns as well as increased prescribing of newer antipsychotics such as aripiprazole with less weight gain.
Namibia	Namibia made provision to improve the management of patients with BD-I and II in the Namibian STG [195]
	Bipolar Mood Disorder is defined as a history of depression with at least one episode of mania, with BP-I defined as mania and depression and BD-II as hypomania and depression.
	Pharmacotherapy is the mainstay of treatment in the STG, with suggested first-line treatments for patients with mood disorders being clozapine plus lithium or lithium plus valproate or topiramate.
	For depression, lithium with lamotrigine is recommended with a warning about Stevens-Johnson syndrome and DIC [195]
	Recommended second-line treatments are lithium (preferred) or citalopram, paroxetine or venlafaxine with a warning about rapid cycling potentially induced by antidepressants [195]
	However, specific diagnoses for this category of patients, especially among patients attending PHCs, appears to be lacking, in view of inadequate facilities and the necessary expertise to achieve optimal diagnosis and management in mental health [196].
	Consequently, BP-II is likely to be diagnosed as a depressive disorder rather than BD-II, and thus managed inappropriately.
South Africa	The South African government sought to improve the care of patients with mental health disorders through its strategic plan improving community residential, day care, and outpatient services. Under this system, trained nonspecialist workers could deliver evidence-based psychosocial interventions and clinical protocols would be available through Integrated Management Guidelines [197,198].
	The South African Depression and Anxiety group has produced a treatment and referral guide to improve the care of BD in South Africa, which includes definitions of BP-I and BP-II [199]. This can act as an exemplar to other countries.
	Based on current evidence, antipsychotics such as quetiapine and olanzapine as well as lamotrigine are recommended for the long-term management of depressive symptoms and to reduce relapses, with lithium potentially considered when symptoms have improved [115]. There is also concern that the prescribing of antidepressants may trigger mania [115]
	Alongside this, the 2018 treatment guidance (STG/EML) has just been launched for PHCs. In this, BD is described as a lifelong episodic illness with the presenting episodes including mania, hypomania, mixed or depressive symptoms [241]
	The 2018 STG/EML states that BD should be confirmed by a specialist, and may present with any mood state with for example treatment-resistant depression. BP-I includes a current or previous episode of mania with BP-II including hypomania, although this history is not always clear. This is an improvement from the 2012 STG/EML where there was no distinguishing between BP-I and II [200]
	Prior to this, the South African Society of Psychiatrists published comprehensive treatment guidelines for patients with psychiatric disorders in 2013 acknowledging that separation of BD patients into BP-I and BP-II can be a challenge. The recommended treatments for patients with bipolar depression included [201]:
	(a) First-line monotherapy includes: Quetiapine 300–600 mg/day, lamotrigine 200–500 mg/day, olanzapine 5–15 mg/day, lithium and valproate. Second-line options include the following as adjunctive or combination therapies: Adjunctive risperidone 2–4 mg/day; lithium and antidepressant combinations; olanzapine and fluoxetine combinations; valproate and lithium and lamotrigine as an add-on to lithium.
	(b) If a conventional antidepressant is prescribed, it should be concurrently administered with an antimanic maintenance agent to diminish switching and the dose gradually tapered after 2–3 months of sustained recovery. Antidepressants should not be prescribed in rapid-cycling BD patients. Venlafaxine (13 – 15%) and TCAs (7 – 11%) are associated with a relatively higher risk of inducing a manic switch than SSRIs (0 – 4%).
	(c) ECT should only be considered if the risk to self or others is high, if psychotic features are present, or if there has been a previous response to ECT.
	PHCs may become involved in the management of stable patients once diagnosed and initially treated by a specialist where there is a good insight into the condition and support [241]. In case of manic, agitated, or acutely disturbed patients, this includes stopping antidepressants if prescribed.

NB: BD: Bipolar disorders; BP-I: Bipolar I; BP-II: Bipolar II; CPGs: Clinical practice guidelines; ECT: electroconvulsive therapy; EML: Essential Medicines List; PHCs = Primary Healthcare Centers; STGs – Standard Treatment Guidelines

Table 2. Key challenges facing LMICs in the management of patients with BD-II especially lower middle-income countries.

Country	Key challenges
Lower-middle-income countries
Ghana	Identified challenges include:
	a lack of accurate diagnosis and treatment due to the high number of untrained personnel providing mental health care in PHC facilities. poor access to psychotropic medicines due to a weak supply system. limited capacity for local production of good quality medicines. high costs of newer medicines and a lack of dedicated budgets to support procurement of pertinent medicines.
India	The treatment of mental disorders remains a much-neglected area in India despite many national, state and district level programs [202]. However, progress is being made with the development of CPGs for patients with BD [90]. Another major challenge is the lack of insurance to cover patients with mental illnesses, especially important because of currently high co-payments for medicines [203]. This means that patients with severe mental disorders spend a median of 12% of their per capita income on direct treatment costs [204]. This may start to change with the government seeking to increase funding for healthcare [205]. Another major challenge to the appropriate care of patients with BD is insufficient number of trained physicians, especially psychiatrists [206], worsened by well-trained medical practitioners and other health professionals migrating to developed countries [207]. Inappropriate referral systems also adversely affect patient outcomes [208]. The lack of awareness about mental illnesses among family members and the community at large limits the effectiveness of prescribed therapies. Typically, family members play a major role in deciding treatment options in addition to meeting the financial and social needs of patients [48]. Educating and motivating patients and their caregivers would greatly improve the quality of decision-making in patients with BD.
Nigeria	Challenges regarding the effective treatment of patients with BD in Nigeria include mis-information regarding its causes, inadequate number of mental health specialists, long distances to travel to regional health-care facilities and a poor referral system. For instance, there is only one neuro-psychiatric hospital for over four million people in the Niger Delta region of Nigeria [209]. There are also issues with affordability of the medications for patients with mental health disorders [139,209,210]. These issues need to be addressed along with generally strengthening health system governance around mental health issues because these disorders have been a neglected area. The revised mental health policy in Nigeria is promising hope for the future [211].
Pakistan	A major challenge for treatment of mental disorders in Pakistan is the scarcity of health-care professionals. There is generally only one psychiatrist for every 10,000 people and one psychiatrist for 4 million children in Pakistan suffering from psychiatric conditions [179], with documented ratios up to one psychiatrist to half a million people [212]. A second challenge is paucity of information to GPs. Naqvi et al. found that the majority of GPs in Pakistan were unaware of the ICD-10 diagnostic criteria for various mental disorders [42]. Benzodiazepines were the most commonly used medication for all mental disorders with few GPs familiar with SSRIs or tricyclic antidepressants. In addition, most GPs had not received any recent medical education about mental disorders, with serious gaps in GPs’ knowledge about the management of mental disorders having serious implications for the rational use of psychotropic medications [42]. Other challenges for the appropriate management of patients with BD include a lack of time with physicians and patients’ financial constraints [54,213].
Tunisia	Key challenges include: Lack of health-care professionals to manage patients with BD, although being eased by greater training of primary health-care physicians on mental health issues [11,26]. Time before a full diagnosis of BD as well as an overuse of antidepressants [96]. Adequately addressing issues of the stigma associated with BD to improve future management aided by the QualityRights initiative [12,56].
Zambia	Mental illness, despite constituting an appreciable proportion of the burden of disease in Zambia, taking into account predisposing factors including HIV/AIDS, poverty and unemployment [214], currently receives inadequate attention with only 0.38% of the national health-care budget directed toward mental illness in 2008 [215]. Overall, the challenges for patients with BP-II include a lack of STGs on diagnosis and treatment, a lack of techniques to monitor therapeutic drug levels where pertinent, erratic supply/unavailability of medicines in mental health hospitals and a limited number of mental health practitioners to make correct diagnoses and suggest treatment. Currently in Zambia, there are only 15 psychiatrists and one psychiatry pharmacy specialist. There are ongoing initiatives and strategies to strengthen the healthcare system including potentially deploying more psychiatry specialists into PHC facilities alongside instigating laboratory monitoring facilities to guide the use of lithium. The government has also made appreciable strides recently to increase the number of mental health workers through the new specialist training program (STP) for physicians, an undergraduate degree in mental health, and the recently enacted mental health act which passed into Law in April 2019. Improved patient and physician education can hopefully address current concerns with widespread social stigma and discrimination against people with mental disorders in Zambia [46].
Upper-middle-income countries
Botswana	Current challenges include difficulties with obtaining reliable estimates of the prevalence of BD in Botswana, including BP-II, in order to guide future strategies. Currently, national statistics records only show a broad diagnosis of BD, and even recent studies do not make a distinction between BP-I and BP-II [216,217]. In addition, since initial diagnosis and treatment of most patients with mental disorders in Botswana, including those with BP-II, is carried out by psychiatric or general nurses, and there are currently no national STGs for the management of BP-II, there is a high probability of missing an accurate diagnosis. Consequently, patients presenting in the depressive phase are likely to be initiated on antidepressant monotherapy. Unpredictable medication availability is another challenge. Whilst BD patients who are referred to the national referral hospital or hospitals with a psychiatrist may be started on lamotrigine or a second-generation antipsychotic, these medications are typically not available at all times especially in more remote areas. Consequently, treatment choices are dictated by which medicines are available which can cause concern.
Brazil	There are challenges in successfully diagnosing BP-II in Brazil in view of the difficulties in differentiation from unipolar depression with a higher prevalence of depressive than hypomanic symptoms in BP-II [218]. There are currently no STGs for the treatment and management of BD-II in Brazil, which can adversely impact on care delivery and available medicines in the public health-care system. It is essential to expand expertise and availability of mental health services in ambulatory care in Brazil for the effective care of patients with BP-II and other mental disorders in the future. Such integration will improve diagnosis, enhance adherence to treatments, reduce emergency consultations, and extend follow-up care to patients with severe mental disorders such as BP-II [219].
Namibia	Considerable challenges still remain with accurate diagnosis of patients with BD-II among PHCs and more widely in Namibia. This needs to be addressed through educational and other activities to improve the care of these patients.
South Africa	There are concerns with the lack of health-care professionals managing patients with mental disorders in the public sector in South Africa, which represents the largest proportion of patients in South Africa (approximately 84%) [220,221,252]. Currently, the majority of psychiatrists in South Africa work in the private sector (approximately 60%) causing problems in the public sector [222]. The situation is even more challenging among public primary health-care centers in rural settings where currently there are only 0.03 psychiatrists per 100 000 population [223]. As a result, the vision of the South African Government has not been met (Table 1) – not helped by the lack of investment in community-based psychiatric and psychosocial rehabilitative services in recent years to support de-institutionalization of services. However, this may change with greater integration of mental health services in primary care and greater task-sharing [36,220,224,225]. The lack of investment was highlighted by the number of deaths of mentally ill patients in Gauteng Province following the instigation of the National Mental Health Policy Framework [226]. There continue to be concerns with lack of transport to accessing care as well as issues such as stigmatization and traditional cultural beliefs that need to be addressed alongside issues of available trained staff and facilities to improve care for BD patients [221]. There are also continued concerns with the availability of essential medicines for patients with BD in the public system including olanzapine, lithium, and citalopram. Improved supply chain management will help here [252].

NB: BD = bipolar disorders; GPs = General Practitioners; PHCs = Primary Health Care; STGs: Standard Treatment Guidelines.

Box 1. Common challenges in the management of BD-II among LMICs

(a) Infrastructure and funding issues

A lack of priority in countries for managing patients with mental disorders versus infectious diseases and other non-communicable diseases (NCDs). This is reflected by concerns with current infrastructures as well as resources devoted to mental health disorders versus other NCDs – demonstrated by the lack of professionals including psychiatrists and psychiatric nurses. Lack of training of health-care professionals, e.g. physicians, pharmacists, and nurses, especially in ambulatory care in the management of BD. This is reflected by concerns with differential diagnosis of BD in practice as well as potentially rapid cycling if BD patients are prescribed anti-depressants in isolation. In addition, concerns with the high use of benzodiazepines for BD patients in some countries.

(b) Management issues

Difficulties diagnosing patients with BD and subsequently differentiating between BP-I, BP-II, and mixed disorders. Lack of local STGs in LMICs especially for patients with BP-II given current controversies and evidence, as well as a lack of monitoring of prescribing against current guidelines where these are available. Unpredictable availability of medicines to treat patients with BP-II coupled with poor access to psychotropic medicines in addition to high patient co-payments in a number of LMICs. Concerns with insufficient time with patients to fully discuss the condition with them and available treatment options. This is particularly important in patients with co-morbidities including those with cardiovascular disease and HIV. Insufficient resources and time given to increasing adherence to prescribed medicines – which can be a particular issue in BD patients, especially those with existing co-morbidities. Lack of facilities to monitor the use of lithium – including for those patients with BD-II. Lack of awareness of mental disorder issues among family members, as well as mis-information regarding the causes of BD and possible treatment approaches including BD-II.

NB: BD = Bipolar disorders; LMICs = Lower and Middle-income countries; HIV = Human Immunodeficiency Virus; STG = Standard Treatment Guidelines.

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