The compounds ##STR1## in which R.sup.1 is 3-hydroxy, 4-hydroxy, 3-methoxy, 4-methoxy or 3,4-methylenedioxy; n is 1 or 2; and R.sup.2 is ##STR2## where R.sup.3 is hydrogen, alkoxy of 1 to 6 carbon atoms, halo or trifluoromethyl; or a pharmaceutically acceptable salt thereof possess anxiolytic and antidepressant activity and are useful in treating psychiatric disorders involving anxiety and/or depression.

BACKGROUND OF THE INVENTION 
Australian Patent Application No. 38726/85 discloses a group of 
antidepressant agents which includes the compound 
1-(1-hydroxy-1-cyclohexyl)-3-dimethylamino-1-phenyl-1-propene (Example 
65). 
DESCRIPTION OF THE INVENTION 
In accordance with this invention there is provided a group of 
1-[(.alpha.-substituted phenyl-.omega.-substituted 
piperazinyl)alkenyl]cyclohexanol derivatives which possess mixed 
anxiolytic-antidepressant activities and in a few instances, a moderate 
level of antipsychotic activity. The compounds of this invention are 
embraced by the following structural formula: 
##STR3## 
in which R.sup.1 is 3-hydroxy, 4-hydroxy, 3-methoxy, 4-methoxy or 
3,4-methylenedioxy; 
n is 1 or 2; and 
R.sup.2 is 
##STR4## 
where R.sup.3 is hydrogen, alkoxy of 1 to 6 carbon atoms, halo or 
trifluoromethyl; 
or a pharmaceutically acceptable salt thereof. 
In these compounds, the halo groups include chloro, bromo, iodo and fluoro 
substituents and the pharmaceutically acceptable salts of the basic 
compounds of this invention are formed conventionally by reaction of the 
free base with an equivalent amount of any acid which forms a non-toxic 
salt. Illustrative acids are either inorganic or organic, including 
hydrochloric, hydrobromic, fumaric, maleic, succinic, sulfuric, 
phosphoric, tartaric, acetic, citric, oxalic and similar acids. For 
parenteral administration, the use of water soluble salts is preferred, 
while either the free base or the pharmaceutically acceptable salts are 
applicable for oral administration. 
The compounds of this invention are prepared by conventional methods. In 
general, the compounds in which n is equal to one are efficiently obtained 
by the following procedure: 
##STR5## 
Alternatively, the intermediate piperazinobutyro or propio-phenones in 
which n is either 1 or 2 may be readily prepared by the following 
reaction: 
##STR6## 
The reaction product, obtained from either process, is converted to the 
trisisopropylbenzenesulfonylhydrazone using the Bond modification of the 
Shapiro reaction [A. R. Chamberlain, J. E. Stemke and F. T. Bond, J. Org. 
Chem. 43, 147 (1978)]. The hydrazone yields a vinyl anion which condenses 
with cyclohexanone to form the cyclohexanol. Debenzylation is achieved via 
a catalytic hydrogenation over Pd/C catalyst. The products are purified 
using column chromatography and the secondary amine re-benzylated using 
appropriately substituted benzyl halides. Demethylation of the 3-methoxy 
or 4-methoxyphenyl derivatives with boron tribromide (BBr.sub.3) as a 
final preparative step provides the hydroxyl substituted products. The 
N-benzyl intermediates are themselves final products in the invention. 
The following examples illustrate the preparative techniques employed in 
the production of the compounds of the invention.

EXAMPLE 1 
1-[1-(3-methoxyphenyl)-3-[4-(phenylmethyl)-1-piperazinyl]-1-propenyl]cycloh 
exanol 
A mixture of 3-methoxyacetophenone (53.8 g, 0.35 mole), paraformaldehyde 
(12.6 g), 1-benzylpiperazine dihydrochloride (106.2 g, 0.43 mole), ethanol 
(560 mL) and concentrated HCl (1.05 mL) was stirred and refluxed for 16 
hours. The reaction mixture was cooled in ice and 
1-(3-methoxyphenyl)-3-[4-(phenylmethyl)-1-piperazinyl]-1-propanone was 
separated. The dihydrochloride was filtered using ice-cold ethanol, washed 
with diethyl ether and dried in a desiccator under vacuum. Yield 50.8 g, 
m.p. 256.degree.-259.degree. C. 
Elemental Analysis for: C.sub.21 H.sub.26 N.sub.2 O.sub.2.2HCl Calculated: 
C, 61.31; H, 6.86; N, 6.81. Found: C, 61.25; H, 6.99; N, 6.89. 
To a suspension of 2,4,6-tris-isopropylbenzenesulfonylhydrazide (30 g, 0.01 
mole) in a mixture of methanol (80 mL), diethyl ether (70 mL) and 5N 
isopropanolic HCl (30 mL) was added 
1-(3-methoxyphenyl)-3-[4-(phenylmethyl)-1-propanone, dihydrochloride (42 
g, 0.1 mole) and water (45 mL). The mixture was stirred at room 
temperature for 16 hours. The solid precipitate was filtered, washed with 
ethyl acetate and air dried. The free base was obtained as follows: the 
solid was partitioned between ethyl acetate and 4N NaOH solution (800 mL; 
1:1 v/v). The phases were separated. The aqueous phase was extracted with 
ethyl acetate and the combined organic phase washed with brine, dried over 
magnesium sulfate and evaporated. The solid residue of 
2,4,6-tris-(1-methylethyl)benzenesulfonic acid 
[1-(3-methoxyphenyl)-3-[4-(phenylmethyl)-1-piperazinyl]propylidene]hydrazi 
de was washed and filtered with hexane and air dried, yield 42 g, m.p. 
256.degree.-259.degree. C. 
Elemental Analysis for: C.sub.36 H.sub.50 N.sub.4 O.sub.3 S.1/3H.sub.2 O 
Calculated: C, 69.20; H, 8.12; N, 8.97. Found: C, 69.30; H, 7.98; N, 8.85. 
2,4,6-Tris(1-methylethyl)benzenesulfonic acid 
[1-(3-methoxyphenyl)-3-[4-(phenylmethyl)-1-piperazinyl]propylidene]hydrazi 
de (42 g, 0.068 mole) was dissolved in dimethoxyethane (575 mL) under 
nitrogen with stirring. The solution was cooled to -78.degree. C. and 
N-butyllithium (78 mL, 2.5 moles) was added dropwise. The mixture was 
allowed to warm to 0.degree. C. and was stirred at this temperature for 15 
minutes, during which time the reaction mixture became dark brown in 
color. The mixture was cooled to -50.degree. C. and excess cyclohexanone 
(11.5 mL) added. The reaction mixture was stirred for 11/2 hours during 
which time the color dissipated as the reaction approached ambient 
temperature. The mixture was poured into a diethyl ether-N HCl mixture 
(400 mL; 1:1 v/v). The phases were separated. The aqueous phase was 
extracted with diethyl ether and the organic phase with N HCl. The 
combined aqueous (acidic) phase was basified with solid KOH and extracted 
twice with ethyl acetate. The extract was washed with brine, dried over 
magnesium sulfate and evaporated to an amorphous solid. Wt. 14 g. The 
product was dissolved in diethyl ether and the solution treated with 
excess 4N-isopropanolic HCl. The dihydrochloride of the title compound was 
obtained, m.p. 230.degree.-232.degree. C. 
Elemental Analysis for: C.sub.27 H.sub.36 N.sub.2 O.sub.2.2HCl.H.sub.2 O 
Calculated: C, 63.39; H, 7.88; N, 5.48. Found: C, 63.35; H, 7.78; N, 5.81. 
EXAMPLE 2 
1-[1-(4-methoxyphenyl)-3-[4-(phenylmethyl)-1-piperazinyl]-1-propenyl]cycloh 
exanol 
By replacing 2,4,6-tris(1-methylethyl)benzenesulfonic acid 
[1-(3-methoxyphenyl)-3-[4-(phenylmethyl)-1-piperazinyl]propylidene]hydrazi 
de in Example 1 with a molar equivalent amount of 
2,4,6-tris(1-methylethyl)benzenesulfonic acid 
[1-(4-methoxyphenyl)-3-[4-(phenylmethyl)-1-piperazinyl]propylidene]hydrazi 
de and following the procedure described therein, 
1-[1-(4-methoxyphenyl)-3-[4-(phenylmethyl)-1-piperazinyl]-1-propenyl]cyclo 
hexanol was obtained in 80% yield. The product was converted to the 
dihydrochloride using 4N-isopropanolic HCl, m.p. 214.degree.-216.degree. 
C., yield 42%. 
Elemental Analysis for: C.sub.27 H.sub.30 N.sub.2 O.sub.2.2HCl Calculated: 
C, 65.71; H, 7.76; N, 5.68. Found: c, 65.41; H, 7.39; N, 5.79. 
EXAMPLE 3 
1-[1-(3-methoxyphenyl)-3-[4-[(3-methoxyphenyl)methyl]-1-piperazinyl]-1-prop 
enyl]cyclohexanol 
A solution of 
1-[1-(3-methoxyphenyl)-3-(4-(phenylmethyl)-1-piperazinyl)-1-propenyl]cyclo 
hexanol dihydrochloride (8.5 g, 17 mmole) in ethanol (200 mL) was 
hydrogenated in a Parr apparatus over 10% Pd/C (0.8 g) for five days. The 
catalyst was filtered and the filtrate evaporated. The residue was 
dissolved in 4N-NaOH (200 mL) and the mixture extracted with ethyl acetate 
(2.times.100 mL). The combined extract was washed with brine, dried over 
MgSO.sub.4 and evaporated to an oil. Wt. 4.1 g. The product, 
1-[1-(3-methoxyphenyl)-3-(1-piprazinyl)-1-propenyl]cyclohexanol, was 
purified by column chromatography on silica gel with 10% methanol in 
chloroform yielding 1.4 g of pure product. 
3-Methoxybenzyl chloride (1.28 g, 7.5 mol) and Cs.sub.2 CO.sub.3 (5.9 g, 18 
mmole) were added to a solution of 
1-[1-(3-methoxyphenyl)-3-(1-piperazinyl)-1-propenyl]cyclohexanol (2.0 g, 6 
mmole) in DMF (50 mL) and the mixture stirred at room temperature for one 
hour. Triethylamine (0.25 mL) was then added and the reaction mixture 
stirred overnight. The solvent was evaporated and the residue dissolved in 
chloroform. The solution was washed with water and the water 
back-extracted with chloroform. The combined organic solution was washed 
with brine, dried over magnesium sulfate and evaporated. The product was 
purified using column chromatography with chloroform as eluent and the 
purified title compound was converted to the hydrochloride. Yield 530 mg, 
m.p. 169.degree.-171.degree. C. 
EXAMPLE 4 
1-[3-[4-[[(3-chlorophenyl)methyl]-1-piperazinyl]-1-(3-methoxyphenyl)-1-prop 
enyl]cyclohexanol 
By replacing 3-methoxybenzyl chloride with a molar equivalent of 
3-chlorobenzyl chloride in Example 3, and following the procedure 
described therein, the title compound was obtained as the dihydrochloride, 
monohydrate salt, m.p. 230.degree.-232.degree. C. Yield: 30%. 
Elemental Analysis for: C.sub.27 H.sub.35 N.sub.2 O.sub.2 Cl.2HCl.H.sub.2 O 
Calculated: C, 59.40; H, 4.20; N, 5.13. Found: C, 59.61; H, 7.08; N, 5.09. 
EXAMPLE 5 
1-[3-[4-[(4-chlorophenyl)methyl]-1-piperazinyl]-1-(3-methoxyphenyl)-1-prope 
nyl]cyclohexanol 
By replacing 3-methoxybenzyl chloride with a molar equivalent of 
4-chlorobenzyl chloride in Example 3, and following the procedure 
described therein, the title compound was obtained as the dihydrochloride, 
hemihydrate, m.p. 243.degree.-245.degree. C. Yield 28%. 
Elemental Analysis for: C.sub.27 H.sub.35 N.sub.2 O.sub.2 
Cl.2HCl.1/2H.sub.2 O Calculated: C, 60.39; H, 7.13; N, 5.22. Found: C, 
60.03; H, 7.14; N, 5.21. 
EXAMPLE 6 
1-[1-(3-methoxyphenyl)-3-[4-[[4-(trifluoromethyl)phenyl]methyl]-1-piperazin 
yl]-1-propenyl]cyclohexanol 
By replacing 3-methoxybenzyl chloride with a molar equivalent of 
4-trifluoromethylbenzyl chloride in Example 3, the title compound was 
obtained as the hydrochloride, hemihydrate, m.p. 188.degree.-190.degree. 
C. Yield 29%. 
Elemental Analysis for: C.sub.28 H.sub.35 N.sub.2 F.sub.3.2HCl.1/2H.sub.2 O 
Calculated: C, 58.95; H, 6.71; N, 4.91. Found: C, 59.02; H, 6.65; N, 4.69. 
EXAMPLE 7 
1-[1-(3-methoxyphenyl)-3-[4-(2-pyridinyl)-1-piperazinyl]-1-propenyl]cyclohe 
xanol 
By replacing 3-methoxybenzyl chloride in Example 3 with a molar equivalent 
amount of 2-chloropyrimidine, the title compound was obtained as the 
dihydrochloride, hemihydrate salt, m.p. 174.degree.-176.degree. C. Yield 
22%. 
Elemental Analysis for: C.sub.24 H.sub.32 N.sub.4 O.sub.2.2HCl.11/2H.sub.2 
O Calculated: C, 58.77; H, 7.19; N, 11.42. Found: C, 58.16; H, 6.99; N, 
11.84. 
Mass spectral analysis: Molecular weight 490 (M+1).sup.+ by C.I.M.S. 
EXAMPLE 8 
1-[3-[4-(6-chloro-2-pyrazinyl)-1-piperazinyl]-1-(3-methoxyphenyl)-1-(3-meth 
oxyphenyl)-1-propenyl]cyclohexanol 
By replacing 3-methoxybenzyl chloride in Example 3 with a molar equivalent 
amount of 2,6-dichloropyrazine and following the procedure described 
therein, the title compound was obtained. The product was converted to its 
fumarate salt via an acetone-diethyl ether solution, m.p. 
145.degree.-147.degree. C. Yield: 34%. 
Elemental Analysis for: C.sub.24 H.sub.31 N.sub.4 O.sub.2 Cl.C.sub.4 
H.sub.4 O.sub.4 Calculated: C, 60.16; H, 6.31; N, 10.02. Found: C, 60.43; 
H, 6.20; N, 9.53. 
EXAMPLE 9 
1-[1-(4-methoxyphenyl)-3-[4-[[4-(trifluoromethyl)phenyl]methyl]-1-piperazin 
yl]-1-propenyl]cyclohexanol 
Debenzylation of the product of Example 2 provides the intermediate which, 
like the corresponding 3-methoxyphenyl substituted compounds may be 
re-benzylated to tailor that group as desired. Debenzylation of the 
4-methoxyphenyl derivative was performed as follows: 
1-[1-(4-methoxyphenyl)-3-(4-phenylmethyl)-piperazinyl)-1-propenyl]cyclohexa 
nol, dihydrochloride (5 g, 10.1 mmole) was dissolved in ethanol (225 mL) 
and was hydrogenated in a Parr apparatus over 5% Pd/C (0.5 g) for 72 
hours. The catalyst was filtered and the filtrate evaporated. The residue 
was partitioned between ethyl acetate and 4N NaOH. The layers were 
separated. The aqueous layer was extracted with ethyl acetate and the 
combined organic solution was washed with brine, dried over MgSO.sub.4 and 
evaporated. The oil obtained was chromatographed on silica gel using 
varying concentrations of methanol in chloroform. Yield of 
1-[1-(4-methoxyphenyl)-3-(1-piperazinyl)-1-propenyl]cyclohexanol was 1.8 
g. 
By replacing 
1-[1-(3-methoxyphenyl)-3-(1-piperazinyl)-1-propenyl]cyclohexanol with a 
molar equivalent of 
1-[1-(4-methoxyphenyl)-3-(1-piperazinyl)-1-propenyl]cyclohexanol in 
Example 6, the title compound was obtained. It was converted to the 
fumarate (1:2) salt, m.p. 222.degree.-225.degree. C. Yield: 23% 
Elemental Analysis for: C.sub.28 H.sub.35 N.sub.2 O.sub.3 F.sub.3.2C.sub.4 
H.sub.4 O Calculated: C, 59.9; H, 6.01; N, 3.89. Found: C, 60.77; H, 6.13; 
N. 3.95. 
EXAMPLE 10 
1-[1-(4-methoxyphenyl)-4-[4-(phenylmethyl)-1-piperazinyl]-1-butenyl]cyclohe 
xanol 
A mixture of .gamma.-chloro-p-methoxybutyrophenone (45 g, 210 mole), 
1-benzylpiperazine (35 mL, 200 mole) and anhydrous potassium carbonate 
(250 g) in methylisobutylketone (800 mL) was refluxed under nitrogen for 
40 hours. The reaction mixture was cooled, poured into a beaker containing 
ice, then ethyl acetate was added. The layers were separated. The organic 
phase was washed with water, brine, dried over K.sub.2 CO.sub.3 and 
evaporated to an oil. This residue was dissolved in diethyl ether (200 mL) 
and treated with excess 4N-isopropanolic HCl. The hydrochloride of 
1-(4-methoxyphenyl)-4-[4-phenylmethyl)-1-piperazinyl]-1-butanone was 
obtained. Wt. 53 g. The product was converted to the free base with NaOH 
and purified by column chromatography. It was then converted to the 
dihydrochloride, m.p. 173.degree.-175.degree. C. 
Elemental Analysis for: C.sub.23 H.sub.28 N.sub.2 O.sub.2.2HCl.11/2H.sub.2 
O Calculated: C, 58.4; H, 6.69; N, 6.19. Found: C, 58.48; H, 7.09; N, 
6.05. 
By replacing 2,4,6-tris-(1-methylethyl)benzenesulfonic acid 
[1-(3-methoxyphenyl)-3-[4-(phenylmethyl)-1-piperazinyl]propylidene]hydrazi 
de in Example 1 with 2,4,6-tris-(1-methylethyl)benzenesulfonic acid 
[1-(4-methoxyphenyl)-4-[4-(phenylmethyl)-1-piperazinyl]butylidene]hydrazid 
e and following the procedure described therein, the title compound was 
obtained. The product was dissolved in diethyl ether and treated with an 
isopropanolic solution of succinic acid (2 equivalents). The d-succinate 
was obtained in crystalline form, m.p. 146.degree.-148.degree. C. yield. 
Elemental Analysis for: C.sub.28 H.sub.38 N.sub.2 O.sub.2.2C.sub.4 H.sub.6 
O.sub.4 Calculated: C, 64.46; H, 7.53; N, 4.17. Found: C, 64.11; H, 7.29; 
N, 4.30. 
The antidepressant activity of the compounds of this invention was 
established by demonstrating their ability to inhibit synaptosomal uptake 
of norepinephrine (.sup.3 H-NE) and/or serotonin (.sup.14 C-5-HT) 
following the test procedure of Wood et al., J. Neurochem., 37 795 (1981). 
The additional excellent anxiolytic property possessed by the compounds of 
this invention was established by demonstrating their strong affinity at 
5-HT.sub.1A receptor binding sites through inhibition of [.sup.3 H] 
8-hydroxy-2-(di-n-propylamino)tetraline binding at 5-HT binding sites in 
rat hippocamphal tissue, following the procedure of Hall et al., J. 
Neurochem., 44 1685 (1985). 
Furthermore, as may be seen from the pharmacological data presented infra, 
some of the compounds embraced by the compound genus of this invention 
demonstrate marginal affinity for dopamine D.sub.2 receptors, which is 
indicative of some element of limited antipsychotic activity [Seeman, 
Pharmacol. Rev. 32, 230 (1981)]. Examples of these compounds are those of 
Examples 1 and 4-6 demonstrating about 80% inhibition of .sup.3 
H-haloperidol binding at D.sub.2 receptors found in homogenized limbic 
brain tissue at 1 .mu.M concentration of the test compound as determined 
in a modification of the test procedure of Fields et al., Brain Res., 136, 
578 (1977) and Yamamura et al., eds., Neurotransmitter Receptor Binding, 
Raven Press, N.Y. (1978) as discussed in U.S. Pat. No. 4,636,563. The 
actual percentage reduction of .sup.3 H-haloperidol binding is reported 
infra and the larger the number, the greater the potential for dopamine 
D.sub.2 receptor binding and antipsychotic activity. 
The pharmacological test data obtained for a representative number of 
compounds of this invention in accordance with the standard experimental 
test procedures disclosed above appear in the following table: 
______________________________________ 
Receptor Binding Neuronal Uptake 
Ki (nM) IC.sub.50 (.mu.M) 
or % Inhibition or % Inhibition 
at 1 .mu.M at 10 .mu.M 
Compound 
5HT.sub.1A D.sub.2 NE 5HT 
______________________________________ 
Example 1 
3 nM 80% 0.64 .mu.M 
1.69 .mu.M 
Example 2 
4 nM 66% 1.26 .mu.M 
3.18 .mu.M 
Example 4 
0.7 nM 17 nM 100% 100% 
Example 5 
99% 76% 
Example 6 
99% 76% 
Example 7 
49 nM 61% 4.82 .mu.M 
2.09 .mu.M 
Example 8 
138 nM 
Example 10 
74% 53% 0.19 .mu.M 
0.92 .mu.M 
Buspirone 
10 nM 97%) 84% (78 nM) 
______________________________________ 
In qualitatively evaluating the above data, high activity values in NE and 
5-HT uptake correlate with antidepressant activity; high affinity values 
for 5-HT.sub.1A receptors (about 90% to 100%) correlate (by analogy with 
buspirone) with anxiolytic activity; high affinity values for D.sub.2 
receptor binding (greater than 80%) begin to show some antipsychotic 
activity. 
From these data, the activity profile of the compounds of this invention 
are seen to be useful in the treatment of psychiatric disorders, in some 
instances, combining very desirable antidepressant-anxiolytic properties. 
Hence, the compounds of this invention are antidepressant, anxiolytic 
agents useful in the treatment of depression and in alleviating anxiety. 
As such, they may be administered neat or with a pharmaceutical carrier to 
a patient in need thereof. The pharmaceutical carrier may be solid or 
liquid. 
A solid carrier can include one or more substances which may also act as 
flavoring agents, lubricants, solubilisers, suspending agents, fillers, 
glidants, compression aids, binders or tablet-disintegrating agents; it 
can also be an encapsulating material. In powders the carrier is a finely 
divided solid which is in admixture with the finely divided active 
ingredient. In tablets the active ingredient is mixed with a carrier 
having the necessary compression properties in suitable proportions and 
compacted in the shape and size desired. The powders and tablets 
preferably contain up to 99% of the active ingredient. Suitable solid 
carriers include, for example, calcium phosphate, magnesium stearate, 
talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl 
cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low 
melting waxes and ion exchange resins. 
Liquid carriers are used in preparing solutions, suspensions, emulsions, 
syrups, elixirs and pressurized compositions. The active ingredient can be 
dissolved or suspended in a pharmaceutically acceptable liquid carrier 
such as water, an organic solvent, a mixture of both of pharmaceutically 
acceptable oils or fats. The liquid carrier can contain other suitable 
pharmaceutical additives such as solubilisers, emulsifiers, buffers, 
preservatives, sweeteners, flavoring agents, suspending agents, thickening 
agents, colors, viscosity regulators, stabilisers or osmo-regulators. 
Suitable examples of liquid carriers for oral and parenteral 
administration include water (particularly containing additives as above, 
e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose 
solution), alcohols (including monohydric alcohols and polyhydric 
alcohols, e.g., glycols) and their derivatives, and oils (e.g. 
fractionated coconut oil and arachis oil). For parenteral administration 
the carrier can also be an oil ester such as ethyl oleate and isopropyl 
myristate. Sterile liquid carriers are used in sterile liquid form 
compositions for parenteral administration. The liquid carrier for 
pressurised compositions can be halogenated hydrocarbon or other 
pharmaceutically acceptable propellent. 
Liquid pharmaceutical compositions which are sterile solutions or 
suspensions can be utilized by, for example, intramuscular intraperitoneal 
or subcutaneous injection. Sterile solutions can also be administered 
intravenously. When the compound is orally active it can be administered 
orally either in liquid or solid composition form. 
Preferably the pharmaceutical composition is in unit dosage form, e.g. as 
tablets or capsules. In such form, the composition is sub-divided in unit 
dose containing appropriate quantities of the active ingredient; the unit 
dosage forms can be packaged compositions, for example packeted powders, 
vials, ampoules, prefilled syringes or sachets containing liquids. The 
unit dosage form can be, for example, a capsule or table itself, or it can 
be the appropriate number of any such compositions in package form. 
The dosage to be used in the treatment of anxiety or depression must be 
subjectively determined by the attending physician. The variables involved 
include the specific state of depression or anxiety and the size, age and 
response pattern of the patient.