Details of the quantitative analysis of mitochondria and dopaminergic terminals have been published previously (Roberts et al., 2009; Somerville, 2011a,b). For the present analysis, in each sample, 6 photomicrographs (at a magnification of 10,000x) were taken that formed a montage. The montages were printed (final viewing magnification was approximately 25,000x), and a counting box (approximate are of 100μm2) was drawn in each. The disector stereologic technique was utilized (Geinisman et al. 1996) and described in more detail elsewhere (Perez-Costas et al., 2007). All synapses appearing in the first montage in the series and all synapses that crossed the exclusion lines in any of the series were excluded. Any profiles that appeared for the first time in subsequent montages, that met criteria, were numbered and followed in this three-dimensional reconstruction method. All synapses were quantified and then subcategorized. Thus, we identified asymmetric axospinous (AS), asymmetric axodendritic (AD), symmetric axospinous (SS), and symmetric axodendritic (SD) synapses. Then, we combined these in various ways to tally all asymmetric synapses (AS + AD), all axospinous synapses (AS + AD), all symmetric synapses (SS + SD) and all axodendritic synapses (AD + SD). The analysis of synaptic organization was performed with the experimenter blinded to the diagnosis. Synaptic data throughout the text is the number of synapses per 10μm3 ± standard deviation. Over 100 synapses or mitochondria were counted for each region per case and data are reported as the mean ± standard deviation.

Group means and standard deviations for demographic data were obtained for each group or subgroup (Table 1). To determine whether the density of synapses was different between the controls, treatment responsive SZs and treatment nonresponsive SZs, an ANOVA followed by a posthoc t-test for multiple comparisons (least significant difference, LSD) was used. ANOVAs followed by the posthoc LSD t-test were used to determine if there were any group differences in age, PMI, race or gender between the three groups. Unpaired t-tests were used to compare parameters occurring between treatment responsive SZs and

was six serial sections for TH stained sections and fourteen for everything else.

exhibit any staining.

**2.2.3 Embedding**

**2.4 Statistics**

**2.3 Data collection and analysis**

Quantitative ultrastructural studies of postmortem human brain are rare outside of our laboratory, due in part to the difficulty in procuring the tissue so quickly after death. However, we have found the integrity of the tissue at the electron microscopic level to be quite acceptable for synapse identification and stereological analysis. Figure 5 shows examples of different kinds of synapses obtained from human postmortem striatum.

Fig. 5. Electron micrographs of postmortem human striatum.

Examples of different types of striatal synapses from control cases. Axon terminals (at) form asymmetric synapses (identified by white arrows with black borders), or symmetric synapses (black arrows). A) Several axospinous synapses are present in this field. B, C). Dendrites receive an asymmetric synapse (B) and a symmetric synapse (C). Scale bars = 0.5 μm. Figure reprinted from Figure 1 in Roberts et al., 2005b.

Ultrastructural Distinctions Between Treatment Responders

t-tests (\*, p<0.05; \*\*, p<0.008; \*\*\*, p<0.002).

**3.2 Striatal mitochondria**

Fig. 8. Mitochondria per synapse.

from Somerville et al., (2010b).

and Non-Responders in Schizophrenia: Postmortem Studies of the Striatum 271

Fig. 7. Asymmetric axospinous and axodendritic synapses in caudate and putamen.

Synaptic density is the number of synapses per 10 µm3. P values are shown for LSD posthoc

We have previously quantified mitochondria in cohorts of schizophrenia patients as a group and divided into various subsets (Somerville et al., 2011a,b). In a recent paper, we reported differences in mitochondrial density in SZ subjects divided by treatment response. Here we highlight the major changes we found in that study (Somerville et al., 2011b). The number of mitochondria per synapse was significantly different among groups for both the caudate

Graph comparing the number of mitochondria per synapse in the caudate nucleus and putamen. ANOVA showed significant group differences for both the caudate nucleus (p<0.025) and the putamen (p<0.002). In the caudate nucleus, treatment responsive SZ subjects had fewer mitochondria per synapse than that of the NCs. In the putamen, there were significantly fewer mitochondria per synapse in treatment responsive SZ subjects compared to both NCs and treatment resistant SZ subjects. Asterisks indicate results of LSD post-hoc t-tests:\* p< 0.05, \*\* p<0.01, \*\*\*, p<0.001. This graph is a modification of Figure 5

## **3.1 Striatal synaptic density**

Synaptic density was determined in all three groups (controls [NCs], TR and TNR) in various regions of the striatum: caudate, putamen, patch and matrix. No matter how we divided the striatum, changes in density were found only in the asymmetric types of synapses, which signify glutamatergic inputs. In the patches (Figure 6), the data show a dichotomy in synaptic organization between TR and TNR. TNR have increased synaptic density compared to TRs or NCs for all synapses combined, asymmetric axospinous and asymmetric synapses. The density of asymmetric axodendritic synapses was increased in the TR subjects compared to both the controls and the TNR subjects. In striatal matrix (Figure 6), controls had fewer asymmetric axodendritic synapses than TR and fewer asymmetric synapses than TNR. In the matrix, controls had fewer asymmetric axodendritic synapses than TR and fewer asymmetric synapses than TNR.

Fig. 6. Synaptic density in striatal patches and matrix.

Synaptic density (per 10µm3) is illustrated for various combinations of synapses in the patches and matrix (data combined for caudate and putamen). Total, all synapses combined, AS (asymmetric axospinous), AD (asymmetric axodendritic) and Asym (asymmetric synapses). P values are shown for LSD posthoc t-tests (\*, p<0.05).

Synaptic density was examined in the caudate nucleus and putamen (patches and matrix combined) and differences were found here as well (Figure 7). Asymmetric axospinous synapses were higher in density in treatment non-responders significantly in the putamen, with a similar nonsignificant pattern in the caudate. The density of this type of synapse was similar between treatment responders and controls. Asymmetric axodendritic synapses were selectively elevated in the treatment responders in comparison to both controls and treatment nonresponders (Figure 7).

Fig. 7. Asymmetric axospinous and axodendritic synapses in caudate and putamen. Synaptic density is the number of synapses per 10 µm3. P values are shown for LSD posthoc t-tests (\*, p<0.05; \*\*, p<0.008; \*\*\*, p<0.002).

## **3.2 Striatal mitochondria**

270 Mental Illnesses – Evaluation, Treatments and Implications

Synaptic density was determined in all three groups (controls [NCs], TR and TNR) in various regions of the striatum: caudate, putamen, patch and matrix. No matter how we divided the striatum, changes in density were found only in the asymmetric types of synapses, which signify glutamatergic inputs. In the patches (Figure 6), the data show a dichotomy in synaptic organization between TR and TNR. TNR have increased synaptic density compared to TRs or NCs for all synapses combined, asymmetric axospinous and asymmetric synapses. The density of asymmetric axodendritic synapses was increased in the TR subjects compared to both the controls and the TNR subjects. In striatal matrix (Figure 6), controls had fewer asymmetric axodendritic synapses than TR and fewer asymmetric synapses than TNR. In the matrix, controls had fewer asymmetric axodendritic

synapses than TR and fewer asymmetric synapses than TNR.

Fig. 6. Synaptic density in striatal patches and matrix.

treatment nonresponders (Figure 7).

synapses). P values are shown for LSD posthoc t-tests (\*, p<0.05).

Synaptic density (per 10µm3) is illustrated for various combinations of synapses in the patches and matrix (data combined for caudate and putamen). Total, all synapses combined,

AS (asymmetric axospinous), AD (asymmetric axodendritic) and Asym (asymmetric

Synaptic density was examined in the caudate nucleus and putamen (patches and matrix combined) and differences were found here as well (Figure 7). Asymmetric axospinous synapses were higher in density in treatment non-responders significantly in the putamen, with a similar nonsignificant pattern in the caudate. The density of this type of synapse was similar between treatment responders and controls. Asymmetric axodendritic synapses were selectively elevated in the treatment responders in comparison to both controls and

**3.1 Striatal synaptic density**

We have previously quantified mitochondria in cohorts of schizophrenia patients as a group and divided into various subsets (Somerville et al., 2011a,b). In a recent paper, we reported differences in mitochondrial density in SZ subjects divided by treatment response. Here we highlight the major changes we found in that study (Somerville et al., 2011b). The number of mitochondria per synapse was significantly different among groups for both the caudate

Fig. 8. Mitochondria per synapse.

Graph comparing the number of mitochondria per synapse in the caudate nucleus and putamen. ANOVA showed significant group differences for both the caudate nucleus (p<0.025) and the putamen (p<0.002). In the caudate nucleus, treatment responsive SZ subjects had fewer mitochondria per synapse than that of the NCs. In the putamen, there were significantly fewer mitochondria per synapse in treatment responsive SZ subjects compared to both NCs and treatment resistant SZ subjects. Asterisks indicate results of LSD post-hoc t-tests:\* p< 0.05, \*\* p<0.01, \*\*\*, p<0.001. This graph is a modification of Figure 5 from Somerville et al., (2010b).

Ultrastructural Distinctions Between Treatment Responders

synapses was similar among all groups.

\* \*

0 0.1 0.2 0.3 0.4 0.5 0.6

Synaptic density

of Figure 2, taken from Roberts et al., 2009.

**4. Discussion**

(den). A modification of Figure 1, taken from Roberts et al., 2009.

Fig. 10. Synaptic density of dopaminergic synapses in schizophrenia.

Tyrosine hydroxylase (TH) was used to identify dopaminergic synapses. Graph of the density (per 10µm3) of TH-labeled (TH+) terminals forming synapses in controls (NC), treatment responsive (TR) and treatment resistant (TNR) subjects. ANOVA results: TH+ Total, p<0.057; TH+ SS, p<0.888; TH+ SD, p<0.017. Total refers to all TH-labeled synapses

TH+ Total TH+ SS TH+ SD

NC TR TNR

\*

\*

axodendritic (SD) synapses is greater in TR than NCs and TNR (\*=p<0.05). A modification

This chapter presents new data on the synaptic organization in the postmortem striatum of treatment responsive vs. non responsive schizophrenia subjects, as well as presenting methods and key results of two of our previous studies on dopaminergic synapses (Roberts

regardless of subtype. The density of total TH+ synapses and of TH+ symmetric

and Non-Responders in Schizophrenia: Postmortem Studies of the Striatum 273

symmetric synapses (curved white arrows outlined in black) in both micrographs. C) Boxed area in panel A is enlarged to show the symmetric synapse (curved white arrow outlined in black). D) TH-labeled axon makes a symmetric synapse (arrow) *en passant* with a dendrite

Briefly, the features of TH-labeled structures were qualitatively similar between NCs and SZ subjects. TH-labeled axons were often in close proximity to large unlabeled terminals that formed asymmetric synapses (Figure 9A,B). Synapses were formed by TH-labeled axon terminals (Figure 9A-C) and boutons *en passant* (Figure 9D). TH-labeled axon terminals

Next, we quantified TH-labeled axon terminals forming synapses in schizophrenia subjects divided by treatment response or resistance (Roberts et al., 2009). The total density of THlabeled synapses was larger in treatment responsive SZs than either the controls or the treatment resistant SZs (Figure 10). This represented a 43% and 51% larger density in the treatment responsive SZs versus the controls and the treatment non-responsive SZs, respectively. TH-labeled axodendritic synapses accounted for this difference with higher in density in treatment responsive SZs compared to treatment resistant SZ and the controls. This represented an 80% and 160% higher density in the treatment responsive SZ versus controls and treatment resistant SZs, respectively. The number of TH-labeled axospinous

formed short symmetric synapses with spines and dendritic shafts (Figure 9A-D).

and putamen (Figure 8). Compared to controls, TR schizophrenia subjects had a 37-43% decrease in the number of mitochondria per synapse in the caudate nucleus and putamen. In the putamen, treatment responsive subjects also had decreases in this measure compared to treatment resistant subjects (34%). Our results provide further support for a biological distinction between treatment response and treatment resistance in schizophrenia.

### **3.3 Dopaminergic terminals in the caudate nucleus**

The features of dopaminergic terminals and synapses have been described previously for normal human striatum (Kung et al., 1998) and quantified in schizophrenia (Roberts et al., 2009). Here we show the key features of those studies.

Fig. 9. Dopaminergic synapses in human caudate nucleus.

A,B) Serial sections showing several synaptic arrangements. TH-labeled axons (straight white arrows outlined in black) are adjacent to unlabeled axon terminals (at) that are forming asymmetric synapses (black arrows) with spines. TH-labeled terminals make

symmetric synapses (curved white arrows outlined in black) in both micrographs. C) Boxed area in panel A is enlarged to show the symmetric synapse (curved white arrow outlined in black). D) TH-labeled axon makes a symmetric synapse (arrow) *en passant* with a dendrite (den). A modification of Figure 1, taken from Roberts et al., 2009.

Briefly, the features of TH-labeled structures were qualitatively similar between NCs and SZ subjects. TH-labeled axons were often in close proximity to large unlabeled terminals that formed asymmetric synapses (Figure 9A,B). Synapses were formed by TH-labeled axon terminals (Figure 9A-C) and boutons *en passant* (Figure 9D). TH-labeled axon terminals formed short symmetric synapses with spines and dendritic shafts (Figure 9A-D).

Next, we quantified TH-labeled axon terminals forming synapses in schizophrenia subjects divided by treatment response or resistance (Roberts et al., 2009). The total density of THlabeled synapses was larger in treatment responsive SZs than either the controls or the treatment resistant SZs (Figure 10). This represented a 43% and 51% larger density in the treatment responsive SZs versus the controls and the treatment non-responsive SZs, respectively. TH-labeled axodendritic synapses accounted for this difference with higher in density in treatment responsive SZs compared to treatment resistant SZ and the controls. This represented an 80% and 160% higher density in the treatment responsive SZ versus controls and treatment resistant SZs, respectively. The number of TH-labeled axospinous synapses was similar among all groups.

Fig. 10. Synaptic density of dopaminergic synapses in schizophrenia.

Tyrosine hydroxylase (TH) was used to identify dopaminergic synapses. Graph of the density (per 10µm3) of TH-labeled (TH+) terminals forming synapses in controls (NC), treatment responsive (TR) and treatment resistant (TNR) subjects. ANOVA results: TH+ Total, p<0.057; TH+ SS, p<0.888; TH+ SD, p<0.017. Total refers to all TH-labeled synapses regardless of subtype. The density of total TH+ synapses and of TH+ symmetric axodendritic (SD) synapses is greater in TR than NCs and TNR (\*=p<0.05). A modification of Figure 2, taken from Roberts et al., 2009.

## **4. Discussion**

272 Mental Illnesses – Evaluation, Treatments and Implications

and putamen (Figure 8). Compared to controls, TR schizophrenia subjects had a 37-43% decrease in the number of mitochondria per synapse in the caudate nucleus and putamen. In the putamen, treatment responsive subjects also had decreases in this measure compared to treatment resistant subjects (34%). Our results provide further support for a biological

The features of dopaminergic terminals and synapses have been described previously for normal human striatum (Kung et al., 1998) and quantified in schizophrenia (Roberts et al.,

distinction between treatment response and treatment resistance in schizophrenia.

**3.3 Dopaminergic terminals in the caudate nucleus**

2009). Here we show the key features of those studies.

Fig. 9. Dopaminergic synapses in human caudate nucleus.

A,B) Serial sections showing several synaptic arrangements. TH-labeled axons (straight white arrows outlined in black) are adjacent to unlabeled axon terminals (at) that are forming asymmetric synapses (black arrows) with spines. TH-labeled terminals make

This chapter presents new data on the synaptic organization in the postmortem striatum of treatment responsive vs. non responsive schizophrenia subjects, as well as presenting methods and key results of two of our previous studies on dopaminergic synapses (Roberts

Ultrastructural Distinctions Between Treatment Responders

metabolism, and what goes awry in treatment resistance.

**4.4 Are ultrastructural changes related to state, trait or medication?**

We have previously discussed the relationship of medication on our findings (Roberts et al., 2009; Somerville et al., 2011b). Importantly for the present data sets is the potential problem that the APDs taken by subjects in the TR and TNR groups were statistically different.

**4.3 Dopaminergic synapses**

**4.2 Mitochondria**

and Non-Responders in Schizophrenia: Postmortem Studies of the Striatum 275

The main results of that study (Somerville et al., 2011b) show fewer numbers of mitochondria per synapse in treatment responsive SZs vs. NCs in both the caudate nucleus and the putamen. In addition, treatment responsive SZs had significantly fewer mitochondria per synapse than that of the treatment resistant subjects in the putamen. The observation that the treatment responders have fewer mitochondria per synapse compared to treatment resistant SZs suggests a possible compensatory mechanism that may be related to the ability to respond to treatment. Mitochondria change location in response to cellular energy demands and the stage of their own life cycle. It is unclear if the decrease in number of mitochondria per synapse is a reflection of death, fewer numbers, failure of the mitochondria to move from the cell bodies of origin or overall decreased function and return to the soma. In the same cases as those in the present paper we have shown an increase in the density of synapses in the caudate nucleus and putamen patches (Roberts et al 2005a,b). Synapses need energy to form and to function properly (Wong-Riley, 1989). The decrease in density of mitochondria in terminals forming synapses may be an adaptive response to normalize overactive neurotransmission. Future studies will address if the number of mitochondria is decreased in particular populations of synapses. Based on our data, mitochondrial density at the synapse is differentially affected in SZ according to treatment response. Understanding the role that mitochondria might play in SZ could lead to better comprehension of the mechanisms of APDs to alleviate psychotic symptoms and alter brain

The main results of that study (Roberts et al., 2009) showed that treatment responsive SZs have more dopaminergic synapses, as identified by TH-labeled terminals, than do treatment resistant SZs or controls. These changes were specific for the axodendritic subtype of THlabeled synapses. Several imaging studies have demonstrated enhanced dopamine release in response to an amphetamine challenge in drug free SZ subjects (Abi-Dargham et al., 1998; Breier et al., 1997; Laruelle et al., 1996, 1999; Lindstrom et al., 1999) or neuroleptic naïve SZ subjects (Laruelle et al., 1999) compared to controls. Importantly, drug free patients who eventually responded to antipsychotic drugs had elevated dopamine release compared to those subjects who never respond to treatment (Abi-Dargham et al., 2000). The higher density of dopaminergic synapses in TR SZs may explain the results of *in vivo* studies that have measured dopamine content in live patients. However, more dopaminergic synapses may not relate to higher tonic dopamine levels. There could be several other explanations for these data, including but not limited to: differential affinity for dopamine receptors, different postsynaptic mechanisms, and/or different amounts of dopamine. Differential blockade of D2 receptors does not appear to be responsible since treatment resistant SZs have 95% D2 receptor occupancy (Coppens et al., 1991). The results of our study suggest that one anatomical underpinning of TR may a higher density of terminals containing dopamine.

et al., 2009) and mitochondria (Somerville et al., 2011b) in these same subjects. We will discuss the results of each study and then a synthesis of all the results with respect to one another and what is known in the literature.

## **4.1 Differential organization of asymmetric synapses in TR vs. TNR**

Changes in density were found only in the asymmetric types of synapses, which signify glutamatergic inputs. In the striatal patches, which process limbic information, TNR have more cortical type synapses (AS) and more glutamatergic synapses than TR and normal controls (NC). Our findings of an increased density of synapses characteristic of corticostriatal inputs in the striatal compartment that processes limbic circuitry in TNR SZ is consistent with several reports in the literature. In vivo imaging studies have shown that regional cerebral blood flow in the anterior cingulate cortex, which is involved in limbic circuitry, is elevated in normal control people given the psychotomimetic ketamine (Lahti et al. 1995; Vollenweider et al. 1997). Similarly, a direct relationship between positive psychotic symptoms and regional cerebral blood flow has been found in the hippocampus, but only when the patients are off medication (Medoff et al. 2001). These findings suggest that psychosis is associated with more activity in the cingulate and hippocampus, an interpretation that is consistent with hyperinnervation farther downstream in the striatal patches. Moreover, psychotomimetics given to animals produce increased spine density and upregulation of markers of axon sprouting (Li et al. 2003; Ujike et al. 2002), suggesting a link between psychosis and increased numbers of axospinous synapses. Thus, we interpret that the increase in density of glutamatergic type synapses in striatal patches in SZ TNR may be related to psychosis and may be an integral part of the disease. If so, the failure to normalize this anomaly may contribute to treatment resistance and persistent psychosis.

Another change which distinguished TR from TNR was the density of asymmetric axodendritic synapses, which are typical of some cortical inputs, but mostly thalamic inputs (see Introduction for references). The TR group had more of this type of synapse than that of the controls or the TNR group. These changes were present in both patches and matrix, caudate and putamen. The increase in density may be compensatory and could play a role in treatment response.

The glutamatergic system is heavily implicated in schizophrenia and examining possible aberrant circuitry or lack of plasticity may provide new insights into treatment options (Coyle 2006; Goff & Coyle 2001; Javitt 2004; Krystal 2008). Glutamate *hypofunction* has long been implicated in psychosis and schizophrenia based on the observation that psychotomimetic agents such as PCP and ketamine block NMDA receptors; however, therapeutic manipulations to restore glutamate tone have not been successful (Javitt & Zukin 1991; Javitt 2010; Kantrowitz & Javitt 2010a, b). A glutamate *hyperfunction* hypothesis has gained recent attention. There is recent MRS evidence of increased glutamate in the striatum in drug free and treated schizophrenia subjects (de la Fuente-Sandoval et al., 2009), which validates our finding of increased glutamatergic type synapses in the striatum of subjects with schizophrenia (Roberts et al., 2005a,b). Importantly for the present results, lamotrigine, which decreases glutamate release (Yuen, 1994), augments clozapine's effects in treatment resistant SZ and attenuates ketamine induced psychosis in normal controls (Dursun & Deakin 2001; Tiihonen et al. 2003). These clinical studies linking improvement in symptoms in TNR with an agent that blocks glutamate is supportive of our data showing increased glutamate type synapses only in treatment non-responders.

## **4.2 Mitochondria**

274 Mental Illnesses – Evaluation, Treatments and Implications

et al., 2009) and mitochondria (Somerville et al., 2011b) in these same subjects. We will discuss the results of each study and then a synthesis of all the results with respect to one

Changes in density were found only in the asymmetric types of synapses, which signify glutamatergic inputs. In the striatal patches, which process limbic information, TNR have more cortical type synapses (AS) and more glutamatergic synapses than TR and normal controls (NC). Our findings of an increased density of synapses characteristic of corticostriatal inputs in the striatal compartment that processes limbic circuitry in TNR SZ is consistent with several reports in the literature. In vivo imaging studies have shown that regional cerebral blood flow in the anterior cingulate cortex, which is involved in limbic circuitry, is elevated in normal control people given the psychotomimetic ketamine (Lahti et al. 1995; Vollenweider et al. 1997). Similarly, a direct relationship between positive psychotic symptoms and regional cerebral blood flow has been found in the hippocampus, but only when the patients are off medication (Medoff et al. 2001). These findings suggest that psychosis is associated with more activity in the cingulate and hippocampus, an interpretation that is consistent with hyperinnervation farther downstream in the striatal patches. Moreover, psychotomimetics given to animals produce increased spine density and upregulation of markers of axon sprouting (Li et al. 2003; Ujike et al. 2002), suggesting a link between psychosis and increased numbers of axospinous synapses. Thus, we interpret that the increase in density of glutamatergic type synapses in striatal patches in SZ TNR may be related to psychosis and may be an integral part of the disease. If so, the failure to normalize

**4.1 Differential organization of asymmetric synapses in TR vs. TNR**

this anomaly may contribute to treatment resistance and persistent psychosis.

increased glutamate type synapses only in treatment non-responders.

Another change which distinguished TR from TNR was the density of asymmetric axodendritic synapses, which are typical of some cortical inputs, but mostly thalamic inputs (see Introduction for references). The TR group had more of this type of synapse than that of the controls or the TNR group. These changes were present in both patches and matrix, caudate and putamen. The increase in density may be compensatory and could play a role

The glutamatergic system is heavily implicated in schizophrenia and examining possible aberrant circuitry or lack of plasticity may provide new insights into treatment options (Coyle 2006; Goff & Coyle 2001; Javitt 2004; Krystal 2008). Glutamate *hypofunction* has long been implicated in psychosis and schizophrenia based on the observation that psychotomimetic agents such as PCP and ketamine block NMDA receptors; however, therapeutic manipulations to restore glutamate tone have not been successful (Javitt & Zukin 1991; Javitt 2010; Kantrowitz & Javitt 2010a, b). A glutamate *hyperfunction* hypothesis has gained recent attention. There is recent MRS evidence of increased glutamate in the striatum in drug free and treated schizophrenia subjects (de la Fuente-Sandoval et al., 2009), which validates our finding of increased glutamatergic type synapses in the striatum of subjects with schizophrenia (Roberts et al., 2005a,b). Importantly for the present results, lamotrigine, which decreases glutamate release (Yuen, 1994), augments clozapine's effects in treatment resistant SZ and attenuates ketamine induced psychosis in normal controls (Dursun & Deakin 2001; Tiihonen et al. 2003). These clinical studies linking improvement in symptoms in TNR with an agent that blocks glutamate is supportive of our data showing

another and what is known in the literature.

in treatment response.

The main results of that study (Somerville et al., 2011b) show fewer numbers of mitochondria per synapse in treatment responsive SZs vs. NCs in both the caudate nucleus and the putamen. In addition, treatment responsive SZs had significantly fewer mitochondria per synapse than that of the treatment resistant subjects in the putamen. The observation that the treatment responders have fewer mitochondria per synapse compared to treatment resistant SZs suggests a possible compensatory mechanism that may be related to the ability to respond to treatment. Mitochondria change location in response to cellular energy demands and the stage of their own life cycle. It is unclear if the decrease in number of mitochondria per synapse is a reflection of death, fewer numbers, failure of the mitochondria to move from the cell bodies of origin or overall decreased function and return to the soma. In the same cases as those in the present paper we have shown an increase in the density of synapses in the caudate nucleus and putamen patches (Roberts et al 2005a,b). Synapses need energy to form and to function properly (Wong-Riley, 1989). The decrease in density of mitochondria in terminals forming synapses may be an adaptive response to normalize overactive neurotransmission. Future studies will address if the number of mitochondria is decreased in particular populations of synapses. Based on our data, mitochondrial density at the synapse is differentially affected in SZ according to treatment response. Understanding the role that mitochondria might play in SZ could lead to better comprehension of the mechanisms of APDs to alleviate psychotic symptoms and alter brain metabolism, and what goes awry in treatment resistance.

### **4.3 Dopaminergic synapses**

The main results of that study (Roberts et al., 2009) showed that treatment responsive SZs have more dopaminergic synapses, as identified by TH-labeled terminals, than do treatment resistant SZs or controls. These changes were specific for the axodendritic subtype of THlabeled synapses. Several imaging studies have demonstrated enhanced dopamine release in response to an amphetamine challenge in drug free SZ subjects (Abi-Dargham et al., 1998; Breier et al., 1997; Laruelle et al., 1996, 1999; Lindstrom et al., 1999) or neuroleptic naïve SZ subjects (Laruelle et al., 1999) compared to controls. Importantly, drug free patients who eventually responded to antipsychotic drugs had elevated dopamine release compared to those subjects who never respond to treatment (Abi-Dargham et al., 2000). The higher density of dopaminergic synapses in TR SZs may explain the results of *in vivo* studies that have measured dopamine content in live patients. However, more dopaminergic synapses may not relate to higher tonic dopamine levels. There could be several other explanations for these data, including but not limited to: differential affinity for dopamine receptors, different postsynaptic mechanisms, and/or different amounts of dopamine. Differential blockade of D2 receptors does not appear to be responsible since treatment resistant SZs have 95% D2 receptor occupancy (Coppens et al., 1991). The results of our study suggest that one anatomical underpinning of TR may a higher density of terminals containing dopamine.

#### **4.4 Are ultrastructural changes related to state, trait or medication?**

We have previously discussed the relationship of medication on our findings (Roberts et al., 2009; Somerville et al., 2011b). Importantly for the present data sets is the potential problem that the APDs taken by subjects in the TR and TNR groups were statistically different.

Ultrastructural Distinctions Between Treatment Responders

and resistance.

**7. References**

**6. Acknowledgments**

and Non-Responders in Schizophrenia: Postmortem Studies of the Striatum 277

either have normal amounts at the disease onset or may have abnormally dense synapses like the TNR, but are able to normalize this measure. TRs have more synapses characteristic of thalamic inputs and dopaminergic synapses than NCs and TNRs. In addition the number of mitochondria per synapse is less than that of NCs and TNR. Increased dopamine synapses may be trait dependent as first episode SZ subjects who eventually respond to treatment have more dopamine as shown in in vivo imaging studies. Increased thalamic input and decreased mitochondria per synapse may be trait dependent as well, or may be compensatory and contribute to treatment response. Our results provide further support for a biological distinction between treatment response and treatment resistance in schizophrenia. Our data show an anatomical distinction between TR and TNR. Moreover, these data have important implications suggesting a biological basis to treatment response

The authors wish to thank: 1) the members of the Maryland Brain Collection for the postmortem brain samples; 2) Drs. Adrienne Lahti and Roger Ridgeway for discussions and ideas about this line of research; and 3) Rosie Ricks for help with preparation of this manuscript. This research was supported in part by MH60744 (RCR) and MH073461 (SS).

Abi-Dargham, A., Gil, R., Krystal, J., Baldwin, R.M., Seibyl, J.P., et al. (1998). Increased

Abi-Dargham, A., Rodenhiser, J., Printz, D., Zea-Ponce, Y., Gil, R., et al. (2000). Increased

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Beerpoot, L.J., Lipska, B.K. & Weinberger, D.R. (1996). Neurobiology of treatment-resistant

Bennett, B.D. & Bolam, J.P. (1994). Synaptic input and output of parvalbumin-immunoreactive neurons in the neostriatum of the rat. *Neuroscience* 62 (3), pp. 707-719.

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schizophrenia: new insights and new models. *European Neuropsychopharmacology* 6

However, a regression analysis of APD type and the synaptic measures in which we found differences yielded no correlations. Moreover, APDs only help positive symptoms, and studies now show that with the exception of clozapine, typical and atypical APDs alleviate positive symptoms to the same extent (Kane et al., 2008; Lieberman et al., 2005; McEvoy, 2006; McEvoy et al., 2006). Therefore, even though the SZ subgroups were composed of different numbers of subjects on typical versus atypical APDs, the possibility that the difference in results between the groups is related to medication seems unlikely.

An important issue still unresolved in these sets of experiments is if the ultrastructural features that distinguish TR from TNR are present before or at disease onset, or reflect the ability or lack thereof to respond to treatment. Since psychotomimetics induce increased spine density and upregulation of markers of axon terminals (Li et al. 2003; Ujike et al. 2002), the increase in density of glutamatergic type synapses in SZ TNR may be related to psychosis. The interpretation we favor at this time is that the increased synaptic density in TNR reflects an integral part of the disease, which these subjects fail to normalize, and this lack of plasticity contributes to treatment resistance and persistent psychosis. With regard to our findings of increased dopaminergic synapses in TR cases, but normal numbers in TNR cases, our results are consistent with the dopaminergic hypothesis of schizophrenia and what has been shown with live people who are TR. SZ subjects who eventually respond to APDs have more striatal dopamine, while those SZ who remain TNR have normal levels. It is therefore not surprising that the TNR, who have normal levels of striatal dopamine, but who are psychotic, are not helped by drugs that block dopamine. The road to psychosis for TNR may be different from those subjects who are TR, and may include glutamate abnormalities in striatum. Of the three studies reported or reviewed herein, the mitochondria data is the hardest to understand. It remains to be determined whether the TRs, who have fewer mitochondria per synapse compared to TNR and NCs, have that feature at the onset of disease or if this is a compensatory mechanism that may be related to the ability to respond to treatment.

#### **5. Conclusion**

Our previous studies has shown that compared to controls, the striatum of SZ subjects has increased synaptic density, decreased spine size, and changes in mitochondrial distribution. In the studies summarized herein, we show differential changes in ultrastructural organization that distinguish treatment responsive from nonresponsive SZ subjects. Our postmortem results are consistent with in vivo studies suggesting a biological basis to treatment response and resistance. We hypothesized that SZ subjects that were psychotic (off drug or nonresponders) would have different alterations than treatment responsive SZ subjects. Striatal synaptic organization has been worked out in animals and by identifying morphological features of the synapse, it is possible to infer connectivity and function. In the striatal patches, which process limbic information, TNR seem to have more cortical type synapses and more glutamatergic type synapses than TR and normal controls (NC). The abnormal density of corticostriatal inputs in areas that process limbic information in TNR may be an integral part of the disease, as psychosis is linked to abnormally large amounts of synapses. If so, the failure to normalize this may contribute to treatment resistance and persistent psychosis. TR subjects have normal amounts of corticostriatal type synapses and either have normal amounts at the disease onset or may have abnormally dense synapses like the TNR, but are able to normalize this measure. TRs have more synapses characteristic of thalamic inputs and dopaminergic synapses than NCs and TNRs. In addition the number of mitochondria per synapse is less than that of NCs and TNR. Increased dopamine synapses may be trait dependent as first episode SZ subjects who eventually respond to treatment have more dopamine as shown in in vivo imaging studies. Increased thalamic input and decreased mitochondria per synapse may be trait dependent as well, or may be compensatory and contribute to treatment response. Our results provide further support for a biological distinction between treatment response and treatment resistance in schizophrenia. Our data show an anatomical distinction between TR and TNR. Moreover, these data have important implications suggesting a biological basis to treatment response and resistance.

## **6. Acknowledgments**

The authors wish to thank: 1) the members of the Maryland Brain Collection for the postmortem brain samples; 2) Drs. Adrienne Lahti and Roger Ridgeway for discussions and ideas about this line of research; and 3) Rosie Ricks for help with preparation of this manuscript. This research was supported in part by MH60744 (RCR) and MH073461 (SS).

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An important issue still unresolved in these sets of experiments is if the ultrastructural features that distinguish TR from TNR are present before or at disease onset, or reflect the ability or lack thereof to respond to treatment. Since psychotomimetics induce increased spine density and upregulation of markers of axon terminals (Li et al. 2003; Ujike et al. 2002), the increase in density of glutamatergic type synapses in SZ TNR may be related to psychosis. The interpretation we favor at this time is that the increased synaptic density in TNR reflects an integral part of the disease, which these subjects fail to normalize, and this lack of plasticity contributes to treatment resistance and persistent psychosis. With regard to our findings of increased dopaminergic synapses in TR cases, but normal numbers in TNR cases, our results are consistent with the dopaminergic hypothesis of schizophrenia and what has been shown with live people who are TR. SZ subjects who eventually respond to APDs have more striatal dopamine, while those SZ who remain TNR have normal levels. It is therefore not surprising that the TNR, who have normal levels of striatal dopamine, but who are psychotic, are not helped by drugs that block dopamine. The road to psychosis for TNR may be different from those subjects who are TR, and may include glutamate abnormalities in striatum. Of the three studies reported or reviewed herein, the mitochondria data is the hardest to understand. It remains to be determined whether the TRs, who have fewer mitochondria per synapse compared to TNR and NCs, have that feature at the onset of disease or if this is a compensatory mechanism that may be related to

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**Part 4**

**Pharmacotherapy**

## **Part 4**

**Pharmacotherapy**

286 Mental Illnesses – Evaluation, Treatments and Implications

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**16**

**Advances in the Pharmacotherapy**

**of Bipolar Affective Disorder**

Ashok Kumar Jainer, Rajkumar Kamatchi,

*Caludon Centre, Coventry,*

 *United Kingdom*

Marek Marzanski and Bettahalasoor Somashekar

Bipolar affective disorder is a chronic, relapsing and remitting mental illness with lifetime risk between 0.5 and 1.6% worldwide (Weissman et al. 1996). This prevalence increases to 5.5% for bipolar spectrum disorders comprising bipolar I, bipolar II and other subtypes (Reegeer et al. 2004). Bipolar disorder is a significant source of distress, disability, and loss of life through suicide (Woods 2000). It causes significant psychological and socioeconomic burden both to the patients and their carers. It remains as the sixth leading cause of disability among neuropsychiatric disorders in the world (WHO 1996). Almost 80% of the costs of bipolar disorder are indirect and only 5% is spent on drugs and another 15% on hospital charges (Dardennes et al 2006). If bipolar disorder is not treated adequately, relapses will occur more frequently with longer duration of episodes, decreased intervals

In this chapter we review the recent advances in the pharmacotherapy of bipolar affective disorder, the management of which is constantly evolving due to better understanding of its

The evolution of pharmacotherapy of bipolar disorder could be described in three stages: introduction of Lithium, discovery of mood stabilizing properties of anticonvulsants and development of atypical antipsychotics and other agents. Lithium carbonate has been used in the treatment of acute mania and in prophylaxis of bipolar affective disorders since 1949. First generation antipsychotics such as Haloperidol and Chlorpromazine were also helpful in the management of acute mania. However the response rate for Lithium was around 60% only, which made further search for other medications necessary. Anticonvulsants like Valproate and Carbamazepine have been introduced to the treatment of both acute phase and as maintenance therapy since the 1970's. Second generation antipsychotics began to emerge in the 1990's and numerous trials have systematically examined and proved their effectiveness. Olanzapine, Risperidone, Quetiapine, Ziprasidone and Aripiprazole have good efficacy in acute mania and some of them are also useful maintenance agents. Combinations of second generation antipsychotics with mood stabilisers have shown some advantages in comparison to monotherapy with Lithium and Valproate. Recently Lamotrigine has been investigated for

between episodes and increased number of hospitalisation.

pathophysiology and introduction of new drug treatments.

**2. Evolution of pharmacotherapy of bipolar disorder**

**1. Introduction**

## **Advances in the Pharmacotherapy of Bipolar Affective Disorder**

 Ashok Kumar Jainer, Rajkumar Kamatchi, Marek Marzanski and Bettahalasoor Somashekar *Caludon Centre, Coventry, United Kingdom*

## **1. Introduction**

Bipolar affective disorder is a chronic, relapsing and remitting mental illness with lifetime risk between 0.5 and 1.6% worldwide (Weissman et al. 1996). This prevalence increases to 5.5% for bipolar spectrum disorders comprising bipolar I, bipolar II and other subtypes (Reegeer et al. 2004). Bipolar disorder is a significant source of distress, disability, and loss of life through suicide (Woods 2000). It causes significant psychological and socioeconomic burden both to the patients and their carers. It remains as the sixth leading cause of disability among neuropsychiatric disorders in the world (WHO 1996). Almost 80% of the costs of bipolar disorder are indirect and only 5% is spent on drugs and another 15% on hospital charges (Dardennes et al 2006). If bipolar disorder is not treated adequately, relapses will occur more frequently with longer duration of episodes, decreased intervals between episodes and increased number of hospitalisation.

In this chapter we review the recent advances in the pharmacotherapy of bipolar affective disorder, the management of which is constantly evolving due to better understanding of its pathophysiology and introduction of new drug treatments.

## **2. Evolution of pharmacotherapy of bipolar disorder**

The evolution of pharmacotherapy of bipolar disorder could be described in three stages: introduction of Lithium, discovery of mood stabilizing properties of anticonvulsants and development of atypical antipsychotics and other agents. Lithium carbonate has been used in the treatment of acute mania and in prophylaxis of bipolar affective disorders since 1949. First generation antipsychotics such as Haloperidol and Chlorpromazine were also helpful in the management of acute mania. However the response rate for Lithium was around 60% only, which made further search for other medications necessary. Anticonvulsants like Valproate and Carbamazepine have been introduced to the treatment of both acute phase and as maintenance therapy since the 1970's. Second generation antipsychotics began to emerge in the 1990's and numerous trials have systematically examined and proved their effectiveness. Olanzapine, Risperidone, Quetiapine, Ziprasidone and Aripiprazole have good efficacy in acute mania and some of them are also useful maintenance agents. Combinations of second generation antipsychotics with mood stabilisers have shown some advantages in comparison to monotherapy with Lithium and Valproate. Recently Lamotrigine has been investigated for

Advances in the Pharmacotherapy of Bipolar Affective Disorder 291

Valproate is an umbrella term used to describe the different preparations of Valproic Acid, the active component of the drugs. Various formulations like Sodium Valproate, Valproic Acid, Semisodium Valproate and Valpromide are available on the market and the most commonly used formulation is Semisodium Valproate (Depakote). The exact mechanism of action is not clear and it seems to be related to the enhancement of inhibitory neurotransmitter GABA. The anti-manic efficacy of Valproate was first seen as early as in 1966 (Lambert et al. 1966). Subsequently its usefulness in acute mania has been investigated both as monotherapy and in combination with antipsychotics. A Cochrane review of randomised controlled trials found that Valproate is an effective treatment for acute mania and this evidence was consistent in most studies (Macritchie et al. 2003). Valproate has similar anti-manic efficacy to Lithium (Bowden et al. 1994, 2008), Haloperidol (McElroy et al. 1996) and Olanzapine

Valproate is superior in overall outcome (both clinical and functional) compared to

Of all the anticonvulsants used in the treatment of mania, Valproate has greater efficacy in reducing manic symptoms with a response rate of 50% compared to placebo effect of 20- 30%. It also has a better antimanic effect than Lithium in rapid cycling and mixed episodes. The loading dose of 20-30mg/kg body weight is more effective than slow titration regimes (Rosa et al. 2011). Gastrointestinal problems, sedation and tremor are the most commonly

Carbamazepine is a dibenzazepine derivative which has been used for prophylactic

Carbamazepine was found to be effective in acute mania soon after its introduction (Okuma et al. 1973). It is significantly superior to placebo and equally effective compared with antipsychotics, Valproate and Lithium as evidenced in randomised controlled studies (Weisler et al. 2004 & 2005). The onset of action is slower compared to antipsychotics and Valproate but faster than Lithium. The use of Carbamazepine in the treatment of acute mania has declined recently with the advent of other drugs. However, it may still be useful in certain subtypes of bipolar disorder which include dysphoric mania, mania co-morbid with substance misuse, mania with mood incongruent delusions and with negative family

**Oxcarbazepine** is chemically related to Carbamazepine. However, its antimanic properties are not convincing (Hirschfeld and Kasper 2004). **Phenytoin** showed antimanic properties as add-on to Haloperidol in a small placebo-controlled trail (Mishory et al. 2000) but its sideeffect profile and availability of better drugs makes it an unlikely choice for mania. Other agents like Topiramate, Gabapentin, Lamotrigine, Levitiracetam and Zonisamide have been

**Haloperidol** has been used in the acute treatment of mania for several decades, but only recently significant evidence was established. A meta-analysis of various studies using

treatment of bipolar disorder in patients not responding to Lithium.

**Valproate**

(Zajecka et al. 2002).

reported side-effects. **Carbamazepine**

**Other anticonvulsants**

**3.1.3 Antipsychotics Typical antipsychotics**

Carbamazepine (Vasudev et al. 2000).

history of bipolar disorder (Post et al. 2007).

tried but had no efficacy in acute mania.

both acute and prophylactic treatment of bipolar II disorder. Other agents like Topiramate and Tamoxifen have also been studied but with no convincing results.

## **3. Advances in the treatment of bipolar disorder**

The evidence for each of these various medications and therapeutic strategies is reviewed in the treatment of acute mania and mixed episodes, bipolar depression and in maintenance therapy.

#### **3.1 Acute mania and mixed episodes**

Mania is characterised by elated, expansive mood, increased activity, pressure of speech and flight of ideas, grandiose delusions and impaired insight. In mixed episodes, both manic and depressive symptoms co-exist i.e.: a patient may be agitated and over-talkative but has severe depressive cognitions at the same time. The majority of the manic and mixed episodes require treatment in the hospital setting. Medications play an important role in their initial management.

### **3.1.1 Lithium**

Lithium salts occur naturally in rocks, spa waters, plants and animal fluids and in the human body. It is a metal ion which is distributed widely and can penetrate cell membranes. The mechanism of action of lithium is still unclear but probably it works via second messenger systems and enhancement of 5-HT responses.

Lithium was first used by John Cade in 1949 to treat acute mania and it still has an important role in the therapy of bipolar disorder. Traditionally Lithium and anticonvulsants have been called "mood- stabilisers" to differentiate them from the first generation antipsychotics which were thought to have only anti-manic effects. The distinction has been blurred since the introduction of second generation (atypical) antipsychotics which have shown efficacy in both acute and long term treatment.

Lithium is more effective than placebo in acute mania (Bowden et al. 1994; Kushner et al. 2006; Keck et al. 2007) and nearly 50% of the symptoms improved markedly. More than 50% of patients suffer a relapse within 10 weeks of stopping lithium treatment (Suppes et al. 1991). Lithium is also effective in reducing both psychotic and depressive symptoms similar to Quetiapine (Bowden et al. 2005).

A Lithium plasma level in the range of 0.6 to 1.3mmol/L is required to obtain a therapeutic anti-manic effect (Bowden et al. 1994). The common side-effects include tremor, weight gain, polydipsia, polyuria, and worsening of skin problems. In long term, it causes renal impairment, thyroid and parathyroid problems. Lithium has a relatively slow onset of action and weak sedative property. Therefore, it is frequently necessary to add an adjunct antipsychotic or benzodiazepine in treating acute mania. The need to regularly monitor its plasma levels to prevent toxicity, as well as its side-effects makes Lithium less useful when equally effective alternatives are available.

#### **3.1.2 Anticonvulsants**

Anticonvulsants have been used in the treatment and prophylaxis of bipolar disorder since the 1970's when Sodium Valproate was first used in mania. Although various anticonvulsants have been investigated, only Valproate and Carbamazepine were found to be effective in the acute mania. Other agents have shown little or no efficacy.

## **Valproate**

290 Mental Illnesses – Evaluation, Treatments and Implications

both acute and prophylactic treatment of bipolar II disorder. Other agents like Topiramate and

The evidence for each of these various medications and therapeutic strategies is reviewed in the treatment of acute mania and mixed episodes, bipolar depression and in maintenance

Mania is characterised by elated, expansive mood, increased activity, pressure of speech and flight of ideas, grandiose delusions and impaired insight. In mixed episodes, both manic and depressive symptoms co-exist i.e.: a patient may be agitated and over-talkative but has severe depressive cognitions at the same time. The majority of the manic and mixed episodes require treatment in the hospital setting. Medications play an important role in

Lithium salts occur naturally in rocks, spa waters, plants and animal fluids and in the human body. It is a metal ion which is distributed widely and can penetrate cell membranes. The mechanism of action of lithium is still unclear but probably it works via second

Lithium was first used by John Cade in 1949 to treat acute mania and it still has an important role in the therapy of bipolar disorder. Traditionally Lithium and anticonvulsants have been called "mood- stabilisers" to differentiate them from the first generation antipsychotics which were thought to have only anti-manic effects. The distinction has been blurred since the introduction of second generation (atypical) antipsychotics which have

Lithium is more effective than placebo in acute mania (Bowden et al. 1994; Kushner et al. 2006; Keck et al. 2007) and nearly 50% of the symptoms improved markedly. More than 50% of patients suffer a relapse within 10 weeks of stopping lithium treatment (Suppes et al. 1991). Lithium is also effective in reducing both psychotic and depressive symptoms similar

A Lithium plasma level in the range of 0.6 to 1.3mmol/L is required to obtain a therapeutic anti-manic effect (Bowden et al. 1994). The common side-effects include tremor, weight gain, polydipsia, polyuria, and worsening of skin problems. In long term, it causes renal impairment, thyroid and parathyroid problems. Lithium has a relatively slow onset of action and weak sedative property. Therefore, it is frequently necessary to add an adjunct antipsychotic or benzodiazepine in treating acute mania. The need to regularly monitor its plasma levels to prevent toxicity, as well as its side-effects makes Lithium less useful when

Anticonvulsants have been used in the treatment and prophylaxis of bipolar disorder since the 1970's when Sodium Valproate was first used in mania. Although various anticonvulsants have been investigated, only Valproate and Carbamazepine were found to be

effective in the acute mania. Other agents have shown little or no efficacy.

Tamoxifen have also been studied but with no convincing results.

**3. Advances in the treatment of bipolar disorder**

messenger systems and enhancement of 5-HT responses.

shown efficacy in both acute and long term treatment.

to Quetiapine (Bowden et al. 2005).

equally effective alternatives are available.

**3.1.2 Anticonvulsants**

**3.1 Acute mania and mixed episodes**

their initial management.

**3.1.1 Lithium**

therapy.

Valproate is an umbrella term used to describe the different preparations of Valproic Acid, the active component of the drugs. Various formulations like Sodium Valproate, Valproic Acid, Semisodium Valproate and Valpromide are available on the market and the most commonly used formulation is Semisodium Valproate (Depakote). The exact mechanism of action is not clear and it seems to be related to the enhancement of inhibitory neurotransmitter GABA.

The anti-manic efficacy of Valproate was first seen as early as in 1966 (Lambert et al. 1966). Subsequently its usefulness in acute mania has been investigated both as monotherapy and in combination with antipsychotics. A Cochrane review of randomised controlled trials found that Valproate is an effective treatment for acute mania and this evidence was consistent in most studies (Macritchie et al. 2003). Valproate has similar anti-manic efficacy to Lithium (Bowden et al. 1994, 2008), Haloperidol (McElroy et al. 1996) and Olanzapine (Zajecka et al. 2002).

Valproate is superior in overall outcome (both clinical and functional) compared to Carbamazepine (Vasudev et al. 2000).

Of all the anticonvulsants used in the treatment of mania, Valproate has greater efficacy in reducing manic symptoms with a response rate of 50% compared to placebo effect of 20- 30%. It also has a better antimanic effect than Lithium in rapid cycling and mixed episodes. The loading dose of 20-30mg/kg body weight is more effective than slow titration regimes (Rosa et al. 2011). Gastrointestinal problems, sedation and tremor are the most commonly reported side-effects.

### **Carbamazepine**

Carbamazepine is a dibenzazepine derivative which has been used for prophylactic treatment of bipolar disorder in patients not responding to Lithium.

Carbamazepine was found to be effective in acute mania soon after its introduction (Okuma et al. 1973). It is significantly superior to placebo and equally effective compared with antipsychotics, Valproate and Lithium as evidenced in randomised controlled studies (Weisler et al. 2004 & 2005). The onset of action is slower compared to antipsychotics and Valproate but faster than Lithium. The use of Carbamazepine in the treatment of acute mania has declined recently with the advent of other drugs. However, it may still be useful in certain subtypes of bipolar disorder which include dysphoric mania, mania co-morbid with substance misuse, mania with mood incongruent delusions and with negative family history of bipolar disorder (Post et al. 2007).

### **Other anticonvulsants**

**Oxcarbazepine** is chemically related to Carbamazepine. However, its antimanic properties are not convincing (Hirschfeld and Kasper 2004). **Phenytoin** showed antimanic properties as add-on to Haloperidol in a small placebo-controlled trail (Mishory et al. 2000) but its sideeffect profile and availability of better drugs makes it an unlikely choice for mania. Other agents like Topiramate, Gabapentin, Lamotrigine, Levitiracetam and Zonisamide have been tried but had no efficacy in acute mania.

### **3.1.3 Antipsychotics**

### **Typical antipsychotics**

**Haloperidol** has been used in the acute treatment of mania for several decades, but only recently significant evidence was established. A meta-analysis of various studies using

Advances in the Pharmacotherapy of Bipolar Affective Disorder 293

Risperidone is well tolerated at low doses but at 6mgs/day, nearly 50% patients may

Quetiapine is a benzothiazepine, which is moderately sedative and has low risk of acute extrapyramidal side-effects. Quetiapine has been studied in the treatment of acute mania,

Quetiapine is more effective than placebo in acute mania as monotherapy and has equal efficacy to Lithium, Haloperidol and Paliperidone (Bowden et al. 2005, McIntyre et al. 2005, and Vieta et al. 2010a). It is effective across a broad range of symptoms in mania according to a systematic review (McIntyre et al. 2007).Quetiapine has also had a beneficial effect in rapid cycling bipolar disorder and there was no treatment emergent depression (DelBello et al. 2006). Quetiapine combination with Lithium or Valproate has better results than Lithium

Quetiapine XL- extended release formulation also has good antimanic properties (Cutler et al. 2008). The efficacy can be noted as early as day 4 and the usual dose range is 400 – 800mgs/day. The common side-effects include somnolence, tachycardia, hypotension,

Aripiprazole is different from other atypical antipsychotics. It is a dopamine- serotonin system stabiliser and acts as a dopamine D2 receptor partial agonist. Aripiprazole was initially used in acute mania but now there is emerging evidence for its good effects in

Aripiprazole is an effective antimanic agent both as monotherapy (Sachs et al. 2006; Keck et al.2007b & Young et al.2009) and in combination with Lithium or Valproate. The combination is superior to Lithium or Valproate alone (Vieta et al. 2009a). Further, its

Aripiprazole is effective, safe and well tolerated both in bipolar mania and mixed episodes. It has rapid onset of action with improvement as early as day 4. This was proved by significant reduction in YMRS scores within few days of treatment. The dose range varies from 15 to 30mgs /day. The common side-effects include headache, somnolence and dizziness. The lack or minimal effects on weight gain, prolactin or QT interval are the main

Ziprasidone is a benzothiazolylpiperazine derivative and has been used in both schizophrenia and bipolar disorder. It is well tolerated and has a low risk of extrapyramidal side-effects. It is effective against mania with psychotic symptoms and mixed affective states and it has been proved in double-blinded controlled trials (Vieta et al. 2009b; Greenberg and Citorme 2007). The dose range is 80- 160mgs/day and the common side-effects are somnolence, dizziness, akathisia and headache. However, the use of Ziprasidone is restricted in some countries due to its cardio-vascular side-effects such as QT prolongation

**Clozapine** is regarded as a last resort therapy for treatment resistant mania, refractory to both mood stabilisers and other antipsychotics. It is very effective and well tolerated which

intramuscular formulation has similar antimanic efficacy (Sanford and Scott 2008).

develop extra pyramidal side-effects (Khanna et al. 2005).

or Valproate alone (Sachs et al. 2004 & Yatham et al. 2004).

bipolar depression and in maintenance therapy.

maintenance treatment (Keck et al. 2006; 2007).

advantages compared to other atypical antipsychotics.

**Quetiapine**

dizziness and weight gain.

**Aripiprazole**

**Ziprasidone**

and elevation of blood pressure.

**Other antipsychotics**

Haloperidol as comparator drug showed it was significantly better than placebo (Cipriani et al. 2006). Haloperidol has been equally effective as Olanzapine (Tohen et al. 2003), Aripiprazole (Vieta et al. 2005a), Valproate (McElroy et al. 1996), Carbamazepine (Brown et al. 1989) and Lithium (Segal et al. 1998). It is also helpful in combination therapies. Unfortunately bipolar patients are more prone to extrapyramidal side-effects of Haloperidol compared to schizophrenic patients according to naturalistic studies (Keck et al. 2000).

**Chlorpromazine** has equal efficacy to Lithium and Carbamazepine in acute mania (Prien et al. 1972; Okuma et al. 1979). It has been also superior to Lithium in agitated manic patients (Prien et al. 1972). Chlorpromazine can cause sedation, photo-sensitivity of the skin and liver abnormalities.

The use of typical antipsychotics such as Haloperidol and Chlorpromazine has declined over the years due to its propensity to cause extra-pyramidal side- effects in short term and tardive dyskinesia in long term treatment.

#### **Atypical antipsychotics**

The introduction of atypical antipsychotics has considerably changed the treatment of bipolar disorder. Efficacy of atypical antipsychotics has been systematically tested in numerous trials both as monotherapy and in combination with mood-stabilisers. Evidence for effectiveness of each of these drugs in acute mania is discussed below.

#### **Olanzapine**

Olanzapine is a thienobenzodiazepine derivative and one of the most extensively investigated atypical antipsychotics. It has significantly higher efficacy than placebo in monotherapy (Tohen et al. 2000, 2007, 2009). It has better outcomes than Lithium (Berk et al. 1999) and Valproate (Tohen et al. 2003b). The patients responded within a week and it was maintained. Intra muscular injection of Olanzapine is significantly superior to placebo and Lorazepam in patients with agitated mania (Meehan et al. 2001).

Olanzapine in combination with Lithium or Valproate has better results than either Lithium or Valproate alone (Tohen et al. 2002). However, in combination with Carbamazepine, it did not show any difference to placebo, probably due to Carbamazepine induced Olanzapine metabolism (Tohen et al. 2008). A more recent large study (EMBLEM - pan- European naturalistic mania study) showed good efficacy of Olanzapine as monotherapy and in combination with other medications (Vieta et al. 2008). Recommended dose for acute mania is 15mgs/day as monotherapy and 10mgs/day in combination treatment. The common side-effects include drowsiness, dizziness and weight gain. The adverse metabolic effects ranging from hyperglycaemia to diabetes and hyperlipidemia may limit its clinical use.

#### **Risperidone**

Risperidone belongs to the benzisoxazole group and has been used in the treatment of acute mania both as monotherapy and in combinations. Risperidone is significantly better than placebo (Hirschfeld et al. 2004 & Khanna et al. 2005) and has equal efficacy to Lithium, Haloperidol (Segal et al. 1998) and Olanzapine (Perlis et al. 2006). There is significant reduction in symptoms of mania as assessed by Young Mania Rating scale (YMRS).

In combination with Lithium or Valproate (Sachs et al. 2002 & Yatham et al. 2003), Risperidone has better results than Lithium or Valproate alone but failed to have the same effects with Carbamazepine. The improvements are noted as early as day 3 and most patients respond within a week. The effective dose range is from 1 to 6mgs/day. Risperidone is well tolerated at low doses but at 6mgs/day, nearly 50% patients may develop extra pyramidal side-effects (Khanna et al. 2005).

## **Quetiapine**

292 Mental Illnesses – Evaluation, Treatments and Implications

Haloperidol as comparator drug showed it was significantly better than placebo (Cipriani et al. 2006). Haloperidol has been equally effective as Olanzapine (Tohen et al. 2003), Aripiprazole (Vieta et al. 2005a), Valproate (McElroy et al. 1996), Carbamazepine (Brown et al. 1989) and Lithium (Segal et al. 1998). It is also helpful in combination therapies. Unfortunately bipolar patients are more prone to extrapyramidal side-effects of Haloperidol compared to schizophrenic patients according to naturalistic studies (Keck et al. 2000). **Chlorpromazine** has equal efficacy to Lithium and Carbamazepine in acute mania (Prien et al. 1972; Okuma et al. 1979). It has been also superior to Lithium in agitated manic patients (Prien et al. 1972). Chlorpromazine can cause sedation, photo-sensitivity of the skin and

The use of typical antipsychotics such as Haloperidol and Chlorpromazine has declined over the years due to its propensity to cause extra-pyramidal side- effects in short term and

The introduction of atypical antipsychotics has considerably changed the treatment of bipolar disorder. Efficacy of atypical antipsychotics has been systematically tested in numerous trials both as monotherapy and in combination with mood-stabilisers. Evidence

Olanzapine is a thienobenzodiazepine derivative and one of the most extensively investigated atypical antipsychotics. It has significantly higher efficacy than placebo in monotherapy (Tohen et al. 2000, 2007, 2009). It has better outcomes than Lithium (Berk et al. 1999) and Valproate (Tohen et al. 2003b). The patients responded within a week and it was maintained. Intra muscular injection of Olanzapine is significantly superior to placebo and

Olanzapine in combination with Lithium or Valproate has better results than either Lithium or Valproate alone (Tohen et al. 2002). However, in combination with Carbamazepine, it did not show any difference to placebo, probably due to Carbamazepine induced Olanzapine metabolism (Tohen et al. 2008). A more recent large study (EMBLEM - pan- European naturalistic mania study) showed good efficacy of Olanzapine as monotherapy and in combination with other medications (Vieta et al. 2008). Recommended dose for acute mania is 15mgs/day as monotherapy and 10mgs/day in combination treatment. The common side-effects include drowsiness, dizziness and weight gain. The adverse metabolic effects ranging from hyperglycaemia to diabetes and hyperlipidemia may limit its clinical use.

Risperidone belongs to the benzisoxazole group and has been used in the treatment of acute mania both as monotherapy and in combinations. Risperidone is significantly better than placebo (Hirschfeld et al. 2004 & Khanna et al. 2005) and has equal efficacy to Lithium, Haloperidol (Segal et al. 1998) and Olanzapine (Perlis et al. 2006). There is significant

In combination with Lithium or Valproate (Sachs et al. 2002 & Yatham et al. 2003), Risperidone has better results than Lithium or Valproate alone but failed to have the same effects with Carbamazepine. The improvements are noted as early as day 3 and most patients respond within a week. The effective dose range is from 1 to 6mgs/day.

reduction in symptoms of mania as assessed by Young Mania Rating scale (YMRS).

for effectiveness of each of these drugs in acute mania is discussed below.

Lorazepam in patients with agitated mania (Meehan et al. 2001).

liver abnormalities.

**Atypical antipsychotics**

**Olanzapine**

**Risperidone**

tardive dyskinesia in long term treatment.

Quetiapine is a benzothiazepine, which is moderately sedative and has low risk of acute extrapyramidal side-effects. Quetiapine has been studied in the treatment of acute mania, bipolar depression and in maintenance therapy.

Quetiapine is more effective than placebo in acute mania as monotherapy and has equal efficacy to Lithium, Haloperidol and Paliperidone (Bowden et al. 2005, McIntyre et al. 2005, and Vieta et al. 2010a). It is effective across a broad range of symptoms in mania according to a systematic review (McIntyre et al. 2007).Quetiapine has also had a beneficial effect in rapid cycling bipolar disorder and there was no treatment emergent depression (DelBello et al. 2006). Quetiapine combination with Lithium or Valproate has better results than Lithium or Valproate alone (Sachs et al. 2004 & Yatham et al. 2004).

Quetiapine XL- extended release formulation also has good antimanic properties (Cutler et al. 2008). The efficacy can be noted as early as day 4 and the usual dose range is 400 – 800mgs/day. The common side-effects include somnolence, tachycardia, hypotension, dizziness and weight gain.

## **Aripiprazole**

Aripiprazole is different from other atypical antipsychotics. It is a dopamine- serotonin system stabiliser and acts as a dopamine D2 receptor partial agonist. Aripiprazole was initially used in acute mania but now there is emerging evidence for its good effects in maintenance treatment (Keck et al. 2006; 2007).

Aripiprazole is an effective antimanic agent both as monotherapy (Sachs et al. 2006; Keck et al.2007b & Young et al.2009) and in combination with Lithium or Valproate. The combination is superior to Lithium or Valproate alone (Vieta et al. 2009a). Further, its intramuscular formulation has similar antimanic efficacy (Sanford and Scott 2008).

Aripiprazole is effective, safe and well tolerated both in bipolar mania and mixed episodes. It has rapid onset of action with improvement as early as day 4. This was proved by significant reduction in YMRS scores within few days of treatment. The dose range varies from 15 to 30mgs /day. The common side-effects include headache, somnolence and dizziness. The lack or minimal effects on weight gain, prolactin or QT interval are the main advantages compared to other atypical antipsychotics.

### **Ziprasidone**

Ziprasidone is a benzothiazolylpiperazine derivative and has been used in both schizophrenia and bipolar disorder. It is well tolerated and has a low risk of extrapyramidal side-effects. It is effective against mania with psychotic symptoms and mixed affective states and it has been proved in double-blinded controlled trials (Vieta et al. 2009b; Greenberg and Citorme 2007). The dose range is 80- 160mgs/day and the common side-effects are somnolence, dizziness, akathisia and headache. However, the use of Ziprasidone is restricted in some countries due to its cardio-vascular side-effects such as QT prolongation and elevation of blood pressure.

#### **Other antipsychotics**

**Clozapine** is regarded as a last resort therapy for treatment resistant mania, refractory to both mood stabilisers and other antipsychotics. It is very effective and well tolerated which

Advances in the Pharmacotherapy of Bipolar Affective Disorder 295

1. Add an atypical antipsychotic if the maintenance agent has been a mood stabiliser

1. Start an atypical antipsychotic (Olanzapine, Risperidone, Quetiapine, Aripiprazole)

3. Benzodiazepines such as Lorazepam and Clonazepam can be used in agitated

People suffering from bipolar I and II disorders have more depressive episodes (67% and 94% respectively) than manic episodes (Judd et al. 2002 & 2003). However bipolar depression is a relatively new clinical concept. Bipolar depression is characterised by prolonged unstable mood, increased suicide risk, increased risk of substance misuse, higher risk of rapid cycling and increased mortality (not only by suicide but also due to cardiovascular and all causes). Most of these episodes are associated with poor outcome and

The treatment of bipolar depression is complex and challenging for clinicians. The evidence

The evidence for the use of antidepressants in bipolar depression is limited and diverse. The use of antidepressants was favoured earlier because of the widespread belief that they had high efficacy and the risk of switch to mania seemed to be similar to placebo (Gijsman et al. 2004). However the recent evidence suggests that their efficacy in bipolar depression is modest and their routine use is not encouraged (Sidor and McQueen 2011). Therefore antidepressants are restricted to treatment resistant depression (Vieta 2009) as an adjunct

3. If still no response, different combination therapy can be tried

2. Some evidence for Olanzapine and Aripiprazole efficacy

1. Clozapine or combination of Lithium and Valproate can be tried

Patients on long term maintenance treatment

2. Increase the dose of maintenance agent

2. If no response, add Lithium or Valproate - Use Lithium in less agitated patients

3. Valproate seems to be better than Lithium

Box. 1. Treatment of acute mania or mixed episode

higher degree of disability if not managed properly.

for various treatment options are considered below.

with a mood stabiliser or an antipsychotic.

4. Antidepressants to be avoided

patients and sleep problems

Treatment resistant mania

2. ECT to be considered Mixed affective states 1. Treat as acute mania

**3.2 Bipolar depression**

**3.2.1 Antidepressants**

Patients with no long-term maintenance treatment

has been shown in case reports and open-labelled trials (Degner et al. 2000; Green et al. 2000; Suppes et al. 2003). Combination of Clozapine and Lamotrigine is also very helpful both in acute and maintenance treatment for refractory and rapid cycling bipolar disorders (Calabrese & Gajwani 2000; Bastiampillai et al. 2010).

**Amisulpride** was used in the treatment of mania before other atypical antipsychotics became available. Its efficacy is modest in acute mania (Vieta et al. 2005) and there is no additional benefit in combination with Valproate (Thomas et al. 2008). It causes hyperprolactinemia in higher doses which is usually required to treat mania.

**Asenapine** is another atypical antipsychotic with superior efficacy compared to placebo in the treatment of acute mania both as monotherapy (McIntyre et al. 2008) and in combination with mood-stabilisers (Calabrese et al. 2008). It causes moderate weight gain but the metabolic side-effects are unclear (McIntyre et al 2009).

**Paliperidone,** a derivative of Risperidone, has recently been introduced in the treatment of mania. It is superior to placebo and equally effective as Quetiapine (Vieta et al. 2010a). It is generally well tolerated. However, at higher doses, it is similar to Risperidone regarding the risk of extrapyramidal side-effects. The other side-effects include headache, somnolence, dizziness and dyspepsia. It can also cause hyperprolactinemia.

## **3.1.4 Other medications used in mania**

**Benzodiazepines** are frequently used as an adjunct in acute mania, mainly due to their anxiolytic and sedative properties. Although there is some evidence suggesting their more specific antimanic action, it does not seem to be significant.

**Tamoxifen,** an anti-oestrogen and protein kinase C inhibitor, has some antimanic efficacy (Hah and Hallmayer 2007; Yildiz et al. 2008). However its safety in routine use is not clear.

**Calcium channel blockers** such as **Verapamil** and **Nimodipine** have been examined for their antimanic efficacy but have not proven to be convincingly effective. Their use in routine practice can be limited by the hypotensive effects.

#### **3.1.5 Combination therapy in mania**

Combination treatment has become common in medical practice, mainly due to the frequent partial response to monotherapy. It may be also indicated when a patient relapses on longterm treatment.

 In acute mania, combination of an atypical antipsychotic with Lithium or Valproate is frequently used in clinical practice. Other combinations such as Lithium and Valproate, Lithium and Carbamazepine have also been helpful. Sometimes a triple combination (Lithium, an anticonvulsant and an atypical antipsychotic) may be needed in treatment resistant mania.

Combinations of Olanzapine, Quetiapine, Risperidone and Aripiprazole with a mood stabiliser are more effective than therapy with a single mood stabiliser (Yatham 2005; Smith et al. 2007; Ketter 2008). Combinations are also useful in long term maintenance treatment.

After an acute manic episode, psychosocial interventions may play further role to improve recovery of the patient. This could include psychoeducation focusing on importance of maintaining regular routine, prophylactic medications, monitoring mood, recognise early warnings of relapse and improve coping strategies.

Recommendations of treatment for acute mania based on currently available evidence is summarised in the Box 1.

Patients on long term maintenance treatment

Patients with no long-term maintenance treatment

	- Use Lithium in less agitated patients
	- Avoid Valproate in women of child bearing age

Treatment resistant mania

Mixed affective states

294 Mental Illnesses – Evaluation, Treatments and Implications

has been shown in case reports and open-labelled trials (Degner et al. 2000; Green et al. 2000; Suppes et al. 2003). Combination of Clozapine and Lamotrigine is also very helpful both in acute and maintenance treatment for refractory and rapid cycling bipolar disorders

**Amisulpride** was used in the treatment of mania before other atypical antipsychotics became available. Its efficacy is modest in acute mania (Vieta et al. 2005) and there is no additional benefit in combination with Valproate (Thomas et al. 2008). It causes

**Asenapine** is another atypical antipsychotic with superior efficacy compared to placebo in the treatment of acute mania both as monotherapy (McIntyre et al. 2008) and in combination with mood-stabilisers (Calabrese et al. 2008). It causes moderate weight gain but the

**Paliperidone,** a derivative of Risperidone, has recently been introduced in the treatment of mania. It is superior to placebo and equally effective as Quetiapine (Vieta et al. 2010a). It is generally well tolerated. However, at higher doses, it is similar to Risperidone regarding the risk of extrapyramidal side-effects. The other side-effects include headache, somnolence,

**Benzodiazepines** are frequently used as an adjunct in acute mania, mainly due to their anxiolytic and sedative properties. Although there is some evidence suggesting their more

**Tamoxifen,** an anti-oestrogen and protein kinase C inhibitor, has some antimanic efficacy (Hah and Hallmayer 2007; Yildiz et al. 2008). However its safety in routine use is not clear. **Calcium channel blockers** such as **Verapamil** and **Nimodipine** have been examined for their antimanic efficacy but have not proven to be convincingly effective. Their use in

Combination treatment has become common in medical practice, mainly due to the frequent partial response to monotherapy. It may be also indicated when a patient relapses on long-

 In acute mania, combination of an atypical antipsychotic with Lithium or Valproate is frequently used in clinical practice. Other combinations such as Lithium and Valproate, Lithium and Carbamazepine have also been helpful. Sometimes a triple combination (Lithium, an anticonvulsant and an atypical antipsychotic) may be needed in treatment

Combinations of Olanzapine, Quetiapine, Risperidone and Aripiprazole with a mood stabiliser are more effective than therapy with a single mood stabiliser (Yatham 2005; Smith et al. 2007; Ketter 2008). Combinations are also useful in long term maintenance treatment. After an acute manic episode, psychosocial interventions may play further role to improve recovery of the patient. This could include psychoeducation focusing on importance of maintaining regular routine, prophylactic medications, monitoring mood, recognise early

Recommendations of treatment for acute mania based on currently available evidence is

hyperprolactinemia in higher doses which is usually required to treat mania.

(Calabrese & Gajwani 2000; Bastiampillai et al. 2010).

metabolic side-effects are unclear (McIntyre et al 2009).

**3.1.4 Other medications used in mania**

**3.1.5 Combination therapy in mania**

term treatment.

resistant mania.

summarised in the Box 1.

dizziness and dyspepsia. It can also cause hyperprolactinemia.

specific antimanic action, it does not seem to be significant.

routine practice can be limited by the hypotensive effects.

warnings of relapse and improve coping strategies.

Box. 1. Treatment of acute mania or mixed episode

## **3.2 Bipolar depression**

People suffering from bipolar I and II disorders have more depressive episodes (67% and 94% respectively) than manic episodes (Judd et al. 2002 & 2003). However bipolar depression is a relatively new clinical concept. Bipolar depression is characterised by prolonged unstable mood, increased suicide risk, increased risk of substance misuse, higher risk of rapid cycling and increased mortality (not only by suicide but also due to cardiovascular and all causes). Most of these episodes are associated with poor outcome and higher degree of disability if not managed properly.

The treatment of bipolar depression is complex and challenging for clinicians. The evidence for various treatment options are considered below.

### **3.2.1 Antidepressants**

The evidence for the use of antidepressants in bipolar depression is limited and diverse. The use of antidepressants was favoured earlier because of the widespread belief that they had high efficacy and the risk of switch to mania seemed to be similar to placebo (Gijsman et al. 2004). However the recent evidence suggests that their efficacy in bipolar depression is modest and their routine use is not encouraged (Sidor and McQueen 2011). Therefore antidepressants are restricted to treatment resistant depression (Vieta 2009) as an adjunct with a mood stabiliser or an antipsychotic.

Advances in the Pharmacotherapy of Bipolar Affective Disorder 297

Lithium or Valproate and antidepressant or antipsychotic combinations have been effective. Recently a triple combination (Lithium, Lamotrigine and Paroxetine) has been used for patients who were not responding to Lithium-Lamotrigine combination. The triple combination can be useful in both acute depressive phase (van der Loss et al. 2010) and

Psychological interventions like Cognitive- Behavioural therapy (CBT), Interpersonal therapy can be used along with medications in bipolar depression. The combination of medications plus CBT may speed up the recovery process, improves the social functioning and reduces the relapses (Lam et al. 2003). Further CBT is found to be effective for patients with less than 12 previous episodes (Scott et al. 2006), indicating that psychological

Recommendations of treatment for acute bipolar depression based on currently available

4. If still no response, non-pharmacological treatments like Electroconvulsive therapy

Maintenance treatment is crucially important in bipolar disorder due to its chronic and recurrent course. According to the naturalistic studies more than 50% of the patients have a relapse in a 2 - 4 year period (Tohen et al. 2003d). Prophylactic treatment prevents further relapses and reduces both morbidity and mortality. The current trend is to consider long term maintenance treatment earlier on, even after a single manic episode. The treatment should be continued for at least 2 years and in many cases indefinitely, unless risk to benefit ratio changes. Various medications used in acute phase are beneficial in maintenance treatment. The evidence for various medications used in maintenance treatment is discussed

Lithium still remains as a cornerstone in the long-term treatment of bipolar disorder (Nivoli

Lithium is more effective than placebo in preventing all relapses and especially manic relapses. Its efficacy in preventing depressive episodes is equivocal as shown in a systematic

3. Other combinations like Lamotrigine-Lithium, or mood stabiliser and an

maintenance treatment (van der Loss et al. 2011).

treatment is effective early in the course of illness.

2. Add an anti-depressant if no response

antipsychotic can be considered

Box. 2. Treatment of acute bipolar depression

**3.3 Maintenance treatment of bipolar disorder**

or Transcranial magnetic stimulation can be tried 5. Avoid using antidepressants as the first line treatment

evidence is summarised in the Box 2.

1. Start with a mood- stabiliser

and Lamotrigine

profile

below.

**3.3.1 Lithium**

et al. 2010).

## **3.2.2 Lithium**

Lithium has modest efficacy in acute depression (Young et al. 2000; Nemeroff et al. 2001). It is used in augmentation therapy with antidepressants in both unipolar and bipolar depression.

It is as effective as a tricyclic antidepressant at serum levels above 0.8mmol/L but tolerability can be a problem at such high doses (Nemeroff et al.2001). It is also effective in combination with Valproate (Young et al. 2000). Although the evidence base for lithium monotherapy in acute bipolar depression is rather weak, its effectiveness as an antidepressant cannot be dismissed.

## **3.2.3 Anticonvulsants**

**Lamotrigine** has become a recognised treatment in bipolar depression, despite its modest efficacy as proved by systematic reviews of all controlled trials (Calabrese et al. 2008; Geddes et al. 2009). It requires a slow titration, especially in combinations with Valproate and this may restrict its use in acute episodes where quick symptom relief is needed. Lamotrigine - Lithium combination is also effective in bipolar depression and there is nearly 50% reduction in symptoms (Lamlit study; van der Loss et al. 2009). Lamotrigine can cause rash in 10% of the patients and it may lead to Steven Johnson syndrome, which warrants its careful monitoring and slow titration. As a result it remains a controversial treatment option for bipolar depression.

**Valproate** also has modest efficacy in bipolar depression (Davis et al. 2005; Ghaemi et al. 2007; Smith et al. 2010). Smith et al reported 50% reduction in symptoms but the sample size was too small to suggest any concrete evidence.

**Carbamazepine** has a weak evidence base and is not a first- line agent in the treatment of bipolar depression. However it may have a role in refractory depression as proved by a crossover trail (Post et al. 1986) and is more effective in combination with Lithium than monotherapy (Kramlinger & Post 1989; Small 1990).

## **3.2.4 Antipsychotics**

It is well recognised that both typical and atypical antipsychotics are effective in the treatment of acute mania and depression either as monotherapy or in combination with other drugs. The use of antipsychotics in bipolar depression has increased with the introduction of atypical antipsychotics and Quetiapine has been proved to be especially effective.

Quetiapine is effective as monotherapy in treating acute bipolar depression (BOLDER studies; Calabrese et al. 2005; Thase et al. 2006). It is well tolerated and the incidence of treatment emergent mania or hypomania is similar to placebo. The dose range varies between 300- 600mgs/day. It is superior to Lithium and equally effective as Paroxetine in treating acute depressive episodes (EMBOLDEN studies; Young et al. 2010; McElroy et al. 2010).

**Olanzapine and Fluoxetine combination** was more effective than Olanzapine alone in bipolar depression (Tohen et al. 2003c). **Perphenazine,** a typical antipsychotic**,** added to a mood stabiliser prevented depressive episodes when used as maintenance treatment (Zarate and Tohen 2004).

## **3.2.5 Combination therapy in bipolar depression**

Similar to acute mania, combination therapies work better than monotherapy in bipolar depression. Olanzapine- Fluoxetine combination, Lamotrigine - Lithium combination,

Lithium has modest efficacy in acute depression (Young et al. 2000; Nemeroff et al. 2001). It is used in augmentation therapy with antidepressants in both unipolar and bipolar

It is as effective as a tricyclic antidepressant at serum levels above 0.8mmol/L but tolerability can be a problem at such high doses (Nemeroff et al.2001). It is also effective in combination with Valproate (Young et al. 2000). Although the evidence base for lithium monotherapy in acute bipolar depression is rather weak, its effectiveness as an

**Lamotrigine** has become a recognised treatment in bipolar depression, despite its modest efficacy as proved by systematic reviews of all controlled trials (Calabrese et al. 2008; Geddes et al. 2009). It requires a slow titration, especially in combinations with Valproate and this may restrict its use in acute episodes where quick symptom relief is needed. Lamotrigine - Lithium combination is also effective in bipolar depression and there is nearly 50% reduction in symptoms (Lamlit study; van der Loss et al. 2009). Lamotrigine can cause rash in 10% of the patients and it may lead to Steven Johnson syndrome, which warrants its careful monitoring and slow titration. As a result it remains a controversial treatment option

**Valproate** also has modest efficacy in bipolar depression (Davis et al. 2005; Ghaemi et al. 2007; Smith et al. 2010). Smith et al reported 50% reduction in symptoms but the sample size

**Carbamazepine** has a weak evidence base and is not a first- line agent in the treatment of bipolar depression. However it may have a role in refractory depression as proved by a crossover trail (Post et al. 1986) and is more effective in combination with Lithium than

It is well recognised that both typical and atypical antipsychotics are effective in the treatment of acute mania and depression either as monotherapy or in combination with other drugs. The use of antipsychotics in bipolar depression has increased with the introduction of atypical

Quetiapine is effective as monotherapy in treating acute bipolar depression (BOLDER studies; Calabrese et al. 2005; Thase et al. 2006). It is well tolerated and the incidence of treatment emergent mania or hypomania is similar to placebo. The dose range varies between 300- 600mgs/day. It is superior to Lithium and equally effective as Paroxetine in treating acute

**Olanzapine and Fluoxetine combination** was more effective than Olanzapine alone in bipolar depression (Tohen et al. 2003c). **Perphenazine,** a typical antipsychotic**,** added to a mood stabiliser prevented depressive episodes when used as maintenance treatment (Zarate

Similar to acute mania, combination therapies work better than monotherapy in bipolar depression. Olanzapine- Fluoxetine combination, Lamotrigine - Lithium combination,

antipsychotics and Quetiapine has been proved to be especially effective.

depressive episodes (EMBOLDEN studies; Young et al. 2010; McElroy et al. 2010).

**3.2.2 Lithium**

depression.

antidepressant cannot be dismissed.

was too small to suggest any concrete evidence.

monotherapy (Kramlinger & Post 1989; Small 1990).

**3.2.5 Combination therapy in bipolar depression**

**3.2.3 Anticonvulsants**

for bipolar depression.

**3.2.4 Antipsychotics**

and Tohen 2004).

Lithium or Valproate and antidepressant or antipsychotic combinations have been effective. Recently a triple combination (Lithium, Lamotrigine and Paroxetine) has been used for patients who were not responding to Lithium-Lamotrigine combination. The triple combination can be useful in both acute depressive phase (van der Loss et al. 2010) and maintenance treatment (van der Loss et al. 2011).

Psychological interventions like Cognitive- Behavioural therapy (CBT), Interpersonal therapy can be used along with medications in bipolar depression. The combination of medications plus CBT may speed up the recovery process, improves the social functioning and reduces the relapses (Lam et al. 2003). Further CBT is found to be effective for patients with less than 12 previous episodes (Scott et al. 2006), indicating that psychological treatment is effective early in the course of illness.

Recommendations of treatment for acute bipolar depression based on currently available evidence is summarised in the Box 2.

Box. 2. Treatment of acute bipolar depression

## **3.3 Maintenance treatment of bipolar disorder**

Maintenance treatment is crucially important in bipolar disorder due to its chronic and recurrent course. According to the naturalistic studies more than 50% of the patients have a relapse in a 2 - 4 year period (Tohen et al. 2003d). Prophylactic treatment prevents further relapses and reduces both morbidity and mortality. The current trend is to consider long term maintenance treatment earlier on, even after a single manic episode. The treatment should be continued for at least 2 years and in many cases indefinitely, unless risk to benefit ratio changes. Various medications used in acute phase are beneficial in maintenance treatment. The evidence for various medications used in maintenance treatment is discussed below.

## **3.3.1 Lithium**

Lithium still remains as a cornerstone in the long-term treatment of bipolar disorder (Nivoli et al. 2010).

Lithium is more effective than placebo in preventing all relapses and especially manic relapses. Its efficacy in preventing depressive episodes is equivocal as shown in a systematic

Advances in the Pharmacotherapy of Bipolar Affective Disorder 299

Valproate, it is more efficient in preventing relapses than Lithium or Valproate combination

**Olanzapine** is used both as monotherapy and in combinations with Lithium or Valproate in the long-term treatment of bipolar disorder. It is superior to placebo (Tohen et al. 2006) and reduces the incidence of both manic and depressives episodes. In comparison with Lithium, Olanzapine was better in preventing manic relapses and similar in preventing depressive episodes (Tohen et al. 2005). Olanzapine is especially effective in patients who have responded to it during an acute manic or mixed episode and in those who did not respond